Thèses : « Interactive toxicity »

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Lyle, Zoe Jean. « The interactive toxicity of benzo(a)pyrene and ultraviolet radiation : an in vitro investigation ». Thesis, University of Plymouth, 2008. http://hdl.handle.net/10026.1/2203.

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The work presented here adopted an in vitro approach with cell types from different species (fish: Epithelioma Papillosum Cyprini (EPCA1), Rainbow Trout Gonad (RTG-2); mammals: Chinese Hamster Ovary (CHO-K01), primary human fibroblast cells (84BR)) to elucidate the potential genotoxic effects of the interaction of the polycyclic aromatic hydrocarbon (PAH), benzo(a)pyrene (B(a)P) (0.0, 0.1, 1.0 and 3.2 µg mlˉ¹) with ultraviolet radiation (UVA/UVB) (typically 25, 50, 100, 200, 500, 1000, 2000, 4000, 6000, 8000 J mˉ²). Initially the experimental techniques and conditions were optimised and validated in the CHO-K1, EPCA1 and RTG-2 cell lines. It was shown that mammalian (CHO-Kl) and fish cells (EPCA1 and RTG-2) exhibited similar sensitivities to chemicals with different modes of action i.e. clastogenic ethyl methansulphonate (EMS) (0.0, 0.8, 1.6 and 3.2 mM) and aneugenic colchicine (COL) (0.0, 0.1, 1.0 and 1.8 µg mlˉ¹) following cytotoxicity experiments with neutral red retention (NRR). Similarly, using the micronucleus assay (Mn) all the cell lines tested showed a similar response to EMS and COL and the use of the anti-kinetochore stain provided a useful approach with which to distinguish between clastogenic and aneugenic effects in the cell. Following comet assay experiments the importance of optimising and validating variables was demonstrated. The optimal variables chosen for the comet assay were 20 minutes unwinding for fish cells (EPCA1 and RTG-2) and 40 minutes unwinding time for mammalian cells (CHO-K1 and 84BR) with 20 minutes electrophoresis for all cell types. Following these validation studies, the cytotoxic and genotoxic effects produced in cells of aquatic (EPCA1, RTG-2) and mammalian (CHO-K1, 84BR) origin following treatment with B(a)P and UVR was investigated. The incubation of all cells (EPCA1, RTG-2, CHO-K1) with B(a)P alone caused limited cytotoxicity (NRR), increased DNA damage (comet assay) and altered cellular functions that were from aneugenic and clastogenic mechanisms (Mn assay). EPCA1, RTG-2 and CHO-K1 cells irradiated with UVB displayed a significant increase in cytotoxicity (NRR) and DNA damage (comet assay). Cells irradiated with UVA (RTG-2, CHO-K1, 84BR) showed no significant increases in cytotoxicity and only CHO-K1 showed increased DNA damage (comet assay). There were significant increases in cellular alterations (Mn assay) following UVA irradiation. All cells (RTG-2, CHO-K1, 84BR) incubated with B(a)P followed by irradiation with UVA showed a synergistically increased cytotoxicity (NRR) and DNA damage (comet assay) from a 1.2-fold increase up to a 4-fold increase in DNA damage. There were also altered cellular mechanisms that may be due to both aneugenic and clastogenic mechanisms (Mn assay). Oxidative stress as a product of the formation of the hydroxyl radical was shown to be a key element in these processes (Electron Spin Resonance (ESR)). It is therefore concluded that the genotoxic effects of the PAH B(a)P and UVA irradiation are synergistically increased when both insults are experienced in combination. This worrying result was observed within both fish and mammalian cell types and appeared to be mediated via an oxidative stress mechanism which included the formation of the hydroxyl radical.

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Betancourt-Lozano, Miguel. « Interactive toxicity of a triazole-derivative fungicide and an organophosphate pesticide in the marine shrimp Litopenaeus vannamei (Boone, 1931) ». Thesis, University of Stirling, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365004.

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Vevers, William F. « Deoxynivalenol : toxicological profile and potential for reducing cereal grain contamination using bacterial additives in fermented animal feed ». Thesis, University of Plymouth, 2015. http://hdl.handle.net/10026.1/4305.

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Deoxynivalenol (DON) contamination of grain destined for animal feeds is a major toxicological risk to monogastrics and is suspected of restricting productivity in ruminants. Whereas bacterial additives have been developed that can detoxify DON in the rumen and lower intestine, there are currently no commercial inoculants able to perform this task in crimped grain (CG) silage, a regionally important method of moist grain preservation based on homo- and heterofermentative lactic acid bacteria or chemical additives. Determining whether this ensiling process alongside the action of detoxifying bacteria has the potential to remove DON in CG prior to ingestion, was explored in mini-silo ensiling experiments. CG was heat treated (100 °C, 60 min) or ensiled fresh in triplicate 50 g silos, spiked with 5 mg/kg DON and inoculated with lactic acid bacteria derived from wild birds, natural epiphytic inoculants and commercially sourced silage additives (21 d). DON recovery was only significantly reduced (31.2 ± 14.4% recovery, p < 0.001, n= 30) by heat treatment, as determined by IAC-RP-HPLC-UV. Bacterial assemblage analysis by 16S rRNA PCR-DGGE-SEQ identified Weissella cibaria, Pantoea agglomerans, Bacillus subtilis, B. licheniformis and Hafnia alvei as candidate detoxification agents, of which W. cibaria and H. alvei decreased DON recovery in vitro (11.3 and 6.2% recovery respectively, p < 0.05, n = 18), which translated to inoculated W. cibaria yielding a decrease in DON recovery (67.2± 14.4%, 28 d) in naturally contaminated crimped wheat (13.5 ± 1.0 mg/kg, 35-40% moisture, p < 0.05, n =15). As W. cibaria is a lactic acid bacteria already associated with fermented CG by default it has promise as a novel DON detoxification agent in CG silage. DON is however just one of many hepatotoxic co-contaminants. Retrorsine, a DNA-crosslinking pyrrolizidine alkaloid derived from Ragwort (Senecio sp.) was investigated for interactive toxicity with DON in an in vitro co-exposure experiment. HepG2 cells were exposed to Log10 multifactorial binary exposures for 48 h followed by a suite of assays to elucidate mechanisms of interactive cytotoxicity, genotoxicity and modulation of the proteome. Retrorsine was tentatively confirmed to form DNA/protein crosslinks in the comet, micronucleus and crosslinking assays, whilst DON was found to potently induce cytotoxicity and apoptosis. Co-exposure yielded a complex toxicity response, with low doses yielding antagonistic effects and high doses trending towards additive effects, although DON dose was generally the principle component. The difficulties associated with undertaking an interactive toxicity study where both toxins have multiple metabolic and cellular targets are highlighted.

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Howarth, Julie Anne. « Aspects of the interaction between cadmium and the acute inflammatory response ». Thesis, University of Surrey, 1988. http://epubs.surrey.ac.uk/847535/.

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The main aims of this thesis were to establish whether an acute inflammatory response is provoked in rats by the subcutaneous administration of cadmium, and to evaluate the possible role that such a response might play in the alterations in metal homeostasis and the development of anaemia which accompanies the use of this model of cadmium intoxication. An intense local reaction to the subcutaneous administration of cadmium was found. Many of the systemic changes, most notably in haematological parameters and in levels of iron, copper and plasma proteins, mimicked those seen in the acute inflammatory response. Possible causes of the resultant anaemia are discussed and inflammation is implicated as a predominant factor in its development. The results suggest that many of the effects which in previously published work have been attributed to a direct interaction of cadmium with the system under investigation, may in fact be secondary consequences of cadmium-induced inflammation. Comparison of the effects of subcutaneous administration of cadmium and other selected metal salts with changes occurring in two recognised models of acute inflammation revealed marked differences in the local tissue reaction to different substances as well as in the magnitude of various components of the systemic response. The oedematous, necrotic and extensively destructive nature of the cadmium-induced lesion has been highlighted and shown to be partially alleviated by pre- and simultaneous treatment with zinc. Explanations for this protective phenomenon are offered, based on possible target sites of cadmium, particularly in terms of interaction with zinc-dependent processes. With a view to understanding the mechanisms involved in acute cadmium toxicity, luminol-amplified chemiluminescence, which is indicative of free radical formation and the production of reactive oxygen species, was measured directly from intact tissue samples. Inflamed tissue sampled from subcutaneous sites of cadmium administration emitted substantially more chemiluminescence than noninflamed tissue or tissue from sites to which other metals or turpentine was administered. It was demonstrated that intact tissue samples can also be used to assess free radical generation, as detected by chemiluminescence, during in vitro treatment. A pronounced dose-related response was seen with cadmium which could be inhibited by various pretreatment procedures, such as incubation with zinc or certain metal chelators. The significance of these results in relation to the mechanism of toxic action of cadmium as well as to the potential use of this chemiluminescence technique is discussed.

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Perdrizet, Isabelle. « Toxicité du cisplatine ». Paris 5, 1988. http://www.theses.fr/1988PA05P113.

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Santos, Bárbara Rosa da Fonseca. « Toxicity interaction of cooper and salinity on Perez frog life stages ». Master's thesis, Universidade de Aveiro, 2011. http://hdl.handle.net/10773/7519.

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Mestrado em Ecologia, Biodiversidade e Gestão de Ecossistemas
Populations of amphibians are declining worldwide. Among the major causes for such decline are chemical contamination and climate changes (e.g. increase in temperature, salinization of coastal freshwater ecosystems). Actually, the group of amphibians may be very sensitive to these stressors as they possess a thin and permeable skin with no physical protection that allows cutaneous respiration but also the diffusion of chemical agents present in the environment. Furthermore, their biphasic life cycle exposes amphibains both to aquatic, terrestrial and atmospheric contamination, potentiating the period of exposure. Consequently, it is necessary to understand the effects that chemical contamination may pose to this group of organisms and how other factors may influence their sensitivity to chemical stress. Accordingly, the present work intended at evaluating how life stage and the combination with other stressors may influence the toxicity of copper to the Perez´s frog Pelophylax perezi (Seoane). To attain this main goal, two specific objectives were delineated: (i) to compare the sensitivity of different life stages, embryos versus tadpoles, to copper (Experimental design 1), and (ii) to evaluate the influence of increased salinity (an indirect effect of climate changes in coastal freshwater lagoons) on the toxicity of copper to embryos and tadpoles of P. perezi (Experimental design 2). For this, eggs at Gosner stage 10-11 and tadpoles at Gosner stage 25 were used to carry out 96h exposure assays. For the first experiment, the two life stages were exposed to a gradient of copper plus a control (FETAX). In the second experiment, embryos and tadpoles were exposed to combinations of copper and NaCl (to simulate an increased salinity) in a complete bifactorial experimental design. In the two experiments the following endpoints were monitored: (i) for embryos, mortality was registered every 24h and at the end of the assay the final body length and malformations rate of surviving larvae were assessed; (ii) for tadpoles mortality and swimming behavior were monitored every 24h. Additionally, at the end of the experimental desing 2 the enzymatic activity, of surviving larvae/tadpoles, was quantified for catalase (CAT), cholinesterase (ChE), glutathione S-transferase (GST) and lactate dehydrogenase (LDH). The obtained results showed that embryos were less sensitive to copper than tadpoles (aproximately 50% of mortality at 1.6 mg/L Cu and LC50=0.93 mg/L Cu, respectively). Furthermore, it was observed that NaCl did not influence the lethal toxicity of copper to tadpoles, but, it significantly reduced the copper toxicity to embryos. Regarding enzymatic responses, a clear and consistent response was not observed for the tested treatments. However, for some copper concentration, the presence of NaCl induced an increase of the activity of CAT, relatively to that observed when orgaisms were exposed solely to copper, both for embryos and tadpoles. Also, in some copper concentrations, the presence of NaCl caused an increase or decrease in the activity of LDH in embryos and tadpoles, respectively. In addition, and contrarirly to what was reported for copper, it was observed that embryos were more sensitive to increased salinity (NaCl) than tadpoles. The results obtained in the present study, highlighted the need, within the context of ecological risk evaluation, to characterize the sensitivity of different life stages of amphibians to different chemicals and to the combination of diverse stressors.
As populacões de anfíbios estão em declínio a nível mundial. Duas das principais causas para este declínio são a contaminação química e alterações climáticas (e.g. aumento das temperaturas, salinização de zonas costeiras). De facto, os anfíbios podem ser muito sensíveis a estes agentes perturbadores, visto possuírem uma pele fina e permeável, sem protecção física, que permite a respiração cutânea mas também a difusão de agentes químicos presentes no ambiente. Além disso, o seu ciclo de vida bifásico expõe-os a contaminação aquática, terrestre, e atmosférica, potenciando o seu período de exposição. Consequentemente, é necessário compreender os efeitos que a contaminação química pode ter neste grupo de organismos, e de que modo outros factores podem influenciar a sua sensibilidade à perturbação química. Deste modo, o presente estudo pretendeu avaliar a influência do estádio de vida e da presença de outros agentes perturbadores na toxicidade de cobre em rã verde, Pelophylax perezi (Seoane). Para atingir este objectivo principal, foram delineados dois objectivos específicos: (i) comparar a sensibilidade de diferentes estádios de vida (embriões verusus girinos) ao cobre (Experiência 1), e (ii) avaliar a influência do aumento de salinidade (efeito indirecto das alterações climáticas em lagoas de água doce costeiras) na toxicidade de cobre para embriões e girinos de P.perezi (Experiência 2). Para tal, foram usados ovos no estádio de Gosner 10-11 e girinos no estádio de Gosner 25 para realizar ensaios de toxicicidade com 96h de exposição. Na primeira experiência, os dois estádios de vida foram expostos a um gradiente de cobre mais um controlo (FETAX). Na segunda experiência, os embriões e girinos foram expostos a combinações de cobre e NaCl (para simular um aumento de salinidade) num desenho experimental bifactorial completo. Nas duas experiências foram monitorizadas as seguintes respostas aos agentes perturbadores: (i) para os embriões, a mortalidade foi registada a cada 24h e no final do ensaio o tamanho corporal final e a taxa de malformações nas larvas sobreviventes; (ii) no caso dos girinos, a mortalidade e o comportamento natatório foram monitorizados a cada 24h. Adicionalmente, no final da segunda experiência (em que foi avaliada a influência de NaCl na toxicidade de cobre), foi quantificada a actividade enzimática da catalase (CAT), colinesterase (ChE), glutationa S-transferase (GST) e lactato desidrogenase (LDH) nas larvas (que eclodiram no final do ensaio-96h) e nos girinos. Os resultados obtidos demonstraram que os embriões foram menos sensíveis ao cobre do que os girinos (cerca de 50% de mortalidade na concentração de 1.6 mg/L Cu e LC50=0.93 mg/L Cu respectivamente). Mais ainda, foi observado que o NaCl não influenciou a toxicidade letal do cobre nos girinos, mas reduziu significativamente a toxicidade do cobre nos embriões. Relativamente às respostas enzimáticas, não foi observado um padrão consistente de repostas aos vários tratamentos. No entanto, em algumas concentrações de cobre, combinadas com NaCl, observou-se que a presença de NaCl induziu a actividade da enzima CAT relativamente ao efeito observado apenas pela presença de cobre. Verificou-se ainda que, em algumas concentrações de cobre, a presença de NaCl induziu uma redução e um aumento da actividade da LDH em girinos e embriões, respectivamente, em comparação com a actividade da enzima em exposições só a cobre. Mais ainda, e contrário ao que foi registado para o cobre, foi observado que os embriões apresentaram uma maior sensibilidade ao aumento da salinidade (NaCl) do que os girinos. Os resultados obtidos no presente estudo destacam a necessidade de, num contexto das avaliações de risco ecológico, caracterizar a sensibilidade dos diferentes estádios de vida dos anfibios a diferentes químicos e a combinações de de agentes perturbadores.

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Waterman, Kellie Lynne. « Interaction of Gold Nanoparticles with a Supported Lipid Bilayer Using Quartz Crystal Microblance with Dissipation ». Digital WPI, 2013. https://digitalcommons.wpi.edu/etd-theses/291.

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Nanoparticle toxicity has become a major topic of interest due to the inevitable exposure of these nanomaterials to both humans and the environment. Nanotechnology is a rapidly growing industry with diverse material resources and an extensive market for commercialization and introduction of nanomaterials into consumer products. The problem with this flourishing technology is that it has far outgrown research based on the safety and toxicity of the nanomaterials, which in bulk are generally nontoxic. The need for research in determining the toxic effects on cells and the implications it may have on the environment have grown but the different techniques, cell systems and nanoparticles employed are generally to diverse and conflicting in overall results that determination toxicity is nearly impossible. The need for a universal technique to study the interaction of nanoparticles with cells and decouple the molecular effects (chemical properties) from the“nanospecific" effects (including size, concentration, surface charge, functionality and polarity) is apparent. It is additionally necessary to determine the mechanisms associated with nanoparticle-induced cytotoxicity in order to better understand the problems posed to both human and environmental health and then develop new safer nanoparticles. Therefore, the focus of this study is to determine the nano-specific (physical) properties, including size and functionalization that cause toxicity, specifically through interaction with a cell membrane. A supported lipid bilayer (SLB) composed of L-ÃŽÂ±-phosphatidylcholine (egg PC) was used as a model cell membrane to test the effects of 2, 5, 10 and 40 nm gold nanoparticles (AuNPs). Given the imminent exposure of nanoparticles to the environment it is important to determine how nanoparticles would behave in the presence of natural organic matter or polymers which are naturally present in environmental systems. Poly(methacrylic acid) (PMA) can be used to represent the polymers normally found in the environment. AuNPs were diluted in PMA in order to simulate fundamental environmental conditions. Analysis was done using a quartz crystal microbalance with dissipation (QCM-D), which measures the frequency (f) and dissipation (D) changes directly associated with mass and conformation changes of the SLB. Different overtones for f and D allow for theoretical interpretation of changes correlated to different layers of the membrane. The 2 and 5 nm particles were found to interact strongly with the lipid bilayer by adsorbing to and/or partially/completely penetrating into the lipid bilayer presumably due to a hydrophobic coating caused by PMA adsorption to the NP surface. The penetration caused a much more rigid membrane due to higher lipid packing caused by nanoparticle addition. The 10 and 40 nm particles interaction with the bilayer were not affected by the presence of PMA. Both AuNP sizes removed mass from the membrane with losses similar in de-ionized water and PMA solution. Removal of membrane mass (lipids/hydration) caused a more flexible membrane. It was determine that sized is the limiting factor for nanoparticle solubilization into the membrane. It can be concluded from the results that size coupled with natural organic matter affects the cytotoxicity of the nanoparticles to the membrane. A study was done with 12 nm functionalized AuNPs in the presence of humic acid, a well-known and more complex and realistic model for natural organic matter. A PC lipid bilayer was used to simulate a model cell membrane and QCM-D techniques were utilized in the determination of toxicity and mechanistic interaction of nanoparticles with a lipid bilayer. Functionalized AuNPs were shown to decrease the rigidity of the lipid bilayer by increasing the dissipation and decreasing the mass associated with the adsorbed film (SLB). The presence of humic acid stabilized the nanoparticles and provided increased electrostatic repulsion which resulted in decreased mass losses from the membrane and much smaller decreases in membrane rigidity. It was concluded that presence of humic acid reduces the effects of functionalized nanoparticle interaction with a lipid bilayer. These results may mean that natural organic matter has the ability to reduce the cytotoxic effects of nanoparticles released into the environment. Overall, the QCM-D was found to provide valuable information regarding the possible toxic properties and mechanisms in which different gold nanoparticle interact with a supported lipid bilayer under environmental conditions. The information provided by the studies performed has shed much light on the interaction of gold nanoparticles with a supported lipid bilayer in the presence of model natural organic matter. The experiments done in this study are the first steps towards developing an assay with the ability to determine the toxic physical properties and mechanisms by which nanoparticles interact with lipid bilayers will greatly aid in development of non-toxic nano-materials. The technology and techniques used in this study will greatly improve the field by solidifying one technique to use in the quantitative approach studying nanoparticle/cell interactions. The use of AFM techniques in conjunction with the QCM-D would be highly beneficial by facilitating better understanding of the exact mechanisms by which nanoparticles induce cytotoxicity.

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Tashjian, Diran Hovsep. « Selenium toxicokinetics, chronic toxicity, and interaction with salinity stress in white sturgeon / ». For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2005. http://uclibs.org/PID/11984.

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Hsieh, Gin-Chang. « The Immunological and Neurochemical Toxicity of Benzene and its Interaction with Toluene in Mice ». DigitalCommons@USU, 1988. https://digitalcommons.usu.edu/etd/4645.

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Benzene and toluene are known groundwater contaminants . Male CD-I mice were continuously exposed to 0, 31, 166, and 790 mg/ L benzene and 0, 17, 80, and 405 mg/L toluene, respectively, in drinking water for four weeks. Benzene caused a reduction of leukocytes, lymphocytes and erythrocytes, and resulted in a macrocytic anemia. Lymphocyte response to both B- and T-cell mitogens, mixed lymphocyte response to alloantigens, and the ability of cytotoxic lymphocytes to lyse tumor cells were enhanced at the lowest dose of benzene and depressed in the higher dosage animals. Benzene at doses of 166 and 790 mg/L decreased the number of sheep red blood cell (SRBC) -specific plaque-forming cells, the level of serum anti-SRBC antibody, and the activity of interleukin-2 (IL -2). Benzene treatment increased endogenous concentrations of the brain biogenic amines norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and concomitantly, elevated the levels of their respective major metabolites vanillymandelic acid (VMA), 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in several brain regions . In most cases, the changes were dose related; in several instances, maximum effects occurred at the 166 mg/L benzene dose. Toluene did not adversely affect the hematological parameters. Depression of immune function was evident at the highest dose (405 mg/L), except for mitogeneses. Increased neurochemical concentrations caused by toluene displayed a dose-dependent biphasic manner which began at a dose of 17 mg/L, peaked at 80 mg/L, and decreased at 405 mg/L. Toluene treatment had more selective effects on NE, 5-HT ,VMA and 5-HIAA, than DA, DOPAC and HVA. Both compounds, by increasing concentrations of the hypothalamic NE and its major metabolite VMA, stimulated the hypothalamic-pituitary-adrenocortical axis activity, resulting in an elevated plasma adrenocorticotropic hormone and serum corticosterone which had an additive adverse effect on IL-2 synthesis. Toluene, 325 mg/ L, completely inhibited benzene-induced cytopenia and immunosuppression when it was coadministered with benzene (166 mg/L). The low dose of toluene (80 mg/L ) did not antagonize benzene immunotoxicity. Mice given the combined exposures exhibited raised levels of regional neurochemicals when compared to the untreated controls. Increased levels of monoamine metabolites in several brain regions were greater in the combined treatments of benzene and toluene than when either chemical was used alone. The results of the interaction studies support the known metabolic interaction mechanisms of benzene and toluene.

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Md, Amin Roswati. « Copepods in Skeletonema-dominated food webs : Toxicity and nutritional quality as factors controlling copepod-diatom interactions ». Doctoral thesis, Umeå universitet, Institutionen för ekologi, miljö och geovetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-49411.

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My thesis focuses on copepod-diatom interactions, specifically on the effects of food quality and toxicity on copepod feeding, reproductive success and behavior but as a frame, also includes a quantitative evaluation of copepod carbon requirements compared to other trophic plankton groups. My aim was to evaluate the function of copepods in diatom-dominated spring blooms. I thereby used a series of mesocosm and laboratory experiments. For a realistic extrapolation of the results to natural environments I used different strains of a diatom species, Skeletonema marinoi, which is a common spring blooming species in the Baltic Sea. This species is known to produce polyunsaturated aldehydes (PUA; mainly heptadienal, octadienal and decadienal), which have previously been identified as the potential reasons for the detrimental effects of diatoms on copepod reproduction. All strains varied in size, mineral and biochemical content, and PUA production. I tested the effects on different dominant copepod species from northern temperate waters; Acartia sp. (A. clausi and A. tonsa), Calanus finmarchicus, Pseudocalanus elongatus, and Temora longicornis, as well as the dominant species in the northern Baltic Sea, Eurytemora affinis. The specific contributions of respiratory carbon requiment of mesozooplankton and lower size fractions to carbon cycling during PUA-producing diatom blooms are poorly documented. My results show that nanoplankton and microzooplankton dominated the carbon cycling (> 50% of primary production) whereas the contribution of bacterioplankton varied. Mesozooplankton was always of minor importance with contribution of <6% of primary production. This illustrates the importance of lower size fractions during a phytoplankton spring bloom. Irrespective of their small contribution to the total community carbon cycling, copepods displayed non-selective and typically high feeding rate on different PUA-producing S. marinoi strains, indicating that there was no feeding deterrence. The effect of feeding on copepod reproductive success, however, varied between different strains, and depending on copepod species. In experiments with monospecific diatom diets reduced egg production rate and hatching success were mainly related to food quality measured as fatty acids and sterols, or algae growth rate, low assimilation efficiency or PUA production / ingestion. On the other hand, copepod reproduction and population development in the diverse diet, including a high concentration of S. marinoi and PUA (both particulate and dissolved), increased with increasing food concentration and was unaffected by the presence of toxic diatoms. I conclude that although a negative correlation between different reproductive variables and PUA production / ingestion may sometimes be observed in laboratory incubations, this is highly dependent on the strain / species used, and the effect of the algal strain can be stronger than the effect of the e.g., growth-stage dependent PUA production. Although copepod grazing might not be very important during a diatom spring bloom, even a highly PUA-producing S. marinoi can be considered an appropriate food source for copepods when occurring among the natural food assemblage, inducing a high reproductive output.

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Johansson, Niclas. « Neonatal Exposure to Highly Brominated Diphenyl Ethers and Perfluorinated Compounds : Developmental Dependent Toxicity and Interaction ». Doctoral thesis, Uppsala universitet, Ekotoxikologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-99255.

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This thesis investigated the developmental neurotoxic effects of neonatal exposure to highly brominated diphenyl ethers (PBDEs) and perfluorinated compounds (PFCs), alone or in combinations, during a critical period of the brains’ rapid growth and development, in mice. The compounds investigated were the decaBDE (PBDE 209), nonaBDE (PBDE 206), octaBDE (PBDE 203), heptaBDE (PBDE 183), and three PFCs, PFOS, PFOA, and PFDA. PBDEs and PFCs have been identified as emerging classes of persistent environmental compounds, present in wildlife as well as humans, and present at higher levels in infants/children, compared to older persons. Individuals can be exposed to these compounds throughout her/his lifetime and newborn/children can be exposed to toxicants both via the mothers’ milk and directly via ingestion and inhalation. The brain growth spurt (BGS) is defined by rapid growth and developmental of the brain. For rodents (mice and rats), the BGS is postnatal spanning the first 3-4 weeks after birth. In humans this period begins during the third trimester of pregnancy and continues throughout the first two years of life. It has been shown that several environmental toxicants can induce permanent disorders in brain function when administered to the neonatal mouse, during the BGS. This thesis shows that highly brominated PBDEs, including PBDE 209, PBDE 206, and PBDE 203 can cause developmental neurotoxic effects, when given directly to the neonatal mouse. Of the investigated PFCs, PFOS and PFOA were shown to cause similar effects as the PBDEs. Furthermore, PBDE 209 and PFOA can at low doses interact and enhance the neurotoxic effects in mice. Effects in the adult animal included; deranged spontaneous behavior, reduced or lack of habituation, decreased learning and memory abilities, and increased susceptibility of the cholinergic system. Both classes of compounds were shown to affect proteins (CaMKII, GAP-43, synaptophysin, and tau) important for neuronal growth and synaptogenesis in the neonatal mouse brain.

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Schilling, Judith [Verfasser]. « The Mutant HTT mRNA-Protein Interactome : Implications in RNA Toxicity in Huntington’s Disease / Judith Schilling ». Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/1171900392/34.

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Swann, Jonathan Richard. « Influence of gene-environment interaction on the gut microflora-mammalian contribution to metabolism and toxicity ». Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/8595.

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Gut microbial composition and activity exert a strong influence on the metabolic phenotype of the host, and variation in the metabolic phenotype is a major factor underlying inter-individual variation in drug responses. In this thesis, the role of gut microflora on the mammalian metabolic system was explored with specific focus on the influence on xenobiotic metabolism and toxicity. Systems biology approaches were utilised to examine microfloral-mammalian interactions and mechanisms of drug toxicity. Multi-omic techniques, namely transcriptomics and metabonomics, were employed to characterise animal models used for investigating microfloral-mammalian interactions. These included germ-free, antibiotic-treated, and 'conve-ntional' rats. The utility of applying systems biology approaches to elucidate mechanisms of toxicity was demonstrated in conventional animals administered methapyrilene using metabonomic and protein-analysis techniques. Finally, the influence of the gut microbiota on the metabolism and toxicity of hydrazine was explored using an integrated transcriptomic and metabonomic approach. Microfloral absence modulated host metabolism directly and indirectly at the transcriptome and metabonome level, specifically drug, lipid and energy metabolism. Temporary suppression of the microbiota through antibiotic treatment did not disrupt the biological system greatly but minor disruption was observed upon re-colonisation. Methapyrilene dosing modified the structure and activity of a urea cycle enzyme and by integrating metabonomics and focused assays the potential for these protein modifications to be a mechanism of toxicity were investigated. In germ-free anitn~ls the effect of hrdrazine was variable, \A{ith toxicity enhanced in two of the three members compared to conventional animals. This highlights the potential for microbiota to influence host susceptibility towards drug toxicity and shows that toxic responses can be diverse in the absence of a functional microbiome. These studies demonstrate the use of applying systems biology approaches to investigate complex biological systems and indicate that gut microorganisms can modulate host metabolism and potentially be a factor in idiosyncratic drug responses.

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Legrand, Philippe. « Amphotéricine B et amphotéricine B vectorisée : autoassociation, toxicité et interaction avec les macrophages ». Paris 11, 1994. http://www.theses.fr/1994PA114820.

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Harley, Rachel. « Ion transport physiology and its interaction with trace element accumulation and toxicity in inanga (Galaxias maculatus) ». Thesis, University of Canterbury. School of Biological Sciences, 2015. http://hdl.handle.net/10092/10738.

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Inanga (Galaxias maculatus) are a culturally and economically important fish species in New Zealand and abroad. However, very little is known about their ability to deal with trace element contamination. As a scaleless fish with the ability to survive in relatively extreme environments, they may not fit toxicity models (such as the biotic ligand model; BLM) based on other fish species. The aim of this study was to determine how this fish responds to elevated trace elements in both the laboratory and field in order to determine the applicability of these toxicity models. In order to determine the impacts of stress on ion transport and subsequent metal toxicity, inanga were exposed to handling stress and measures of ion uptake were collected. Handling stress was shown to result in increased ventilation rates, resulting in stimulated sodium (Na+) efflux. A compensatory increase in Na+ influx was also measured as a result of this stress. Inanga largely recovered from this ionoregulatory stress within 2 hours, with full recovery after 24 hours. This was indicative of a rapid homeostatic response for maintaining ion balance. Enhanced Na+ uptake in response to this stress resulted in increased copper (Cu) uptake in Cu-contaminated water, suggesting stressed fish will accumulate more Cu (and likely other Na+ mimics) than an unstressed fish. These results suggest a heightened vulnerability of inanga to this type of contaminant as a result of exercise stress during migrations. A combination of field and laboratory studies was used in order to measure trace element accumulation in inanga. In situ field studies showed changes to aluminum (Al) and iron (Fe) body burdens when inanga were placed in streams of varying trace element concentrations along the West Coast of the South Island. However, other trace elements measured did not alter over the period of exposure (9-10 days). Biochemical biomarker analysis showed no changes in the activity of Na+/K+-ATPase (NKA), but a marker of lipid peroxidation (thiobarbituric acid reactive substances; TBARS) was elevated in one stream. Analysis suggested that stream pH was the major driver of this effect, whether directly or via changes to metal bioavailability. Subsequent laboratory exposures (96 h) of inanga to 1.2, 2.7, 10.8, and 44 µg L-1 dissolved Fe and 5.6, 23.3, 60.7, and 128.7 µg L-1 dissolved zinc (Zn) showed no difference in whole body trace element accumulation, ammonia excretion, ion influx (Ca2+ and Na+), and TBARS. There were significant differences in oxygen consumption (MO2) after Fe exposures, with increases in the 2.7 and 44 µg L-1 dissolved Fe exposures. Laboratory exposure results suggest inanga are relatively insensitive to short-term Fe and Zn exposures. Both in vivo (whole body partitioning) and in vitro (Ussing chamber) techniques were used to determine the influence of cutaneous ion transport on preventing trace element accumulation. Results suggest inanga use their skin as an additional site of calcium (Ca2+) and Na+ uptake. This is the first study to confirm these ion transport capabilities in inanga, and revealed that up to 48% of Na+ uptake may occur across the skin. Pharmacological inhibition of Ca2+ uptake was achieved by known Ca2+ channel blockers (verapamil and lanthanum). Furthermore Fe and Zn impaired cutaneous Ca2+ transport, indicating that ion transport pathways in the skin modulate in response to these metals.

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Crevecoeur, Sophie. « Toxicologie de l'érythromycine ». Paris 5, 1991. http://www.theses.fr/1991PA05P025.

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Frisk, Peter. « Expressions of mercury-selenium interaction in vitro ». Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-4913-1/.

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TenBrook, Patti Lyn. « Clomazone : toxicity, biotransformation, resistance and interaction with P450 inhibitors in rice (Oryza sativa) and watergrasses (Echinochloa spp.) / ». For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2005. http://uclibs.org/PID/11984.

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Anjum, Farida. « Relative toxicity of insecticides to crucifer pests and their natural enemies : interaction of insecticide and insect behaviours ». Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24773.

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Pesticides remain a necessary component of many agricultural systems and used judiciously they can play an important role in Integrated Pest Management (IPM) programmes. The aim of the present study was to investigate factors influencing the differential toxicity of insecticides against a cosmopolitan insect pest of crucifer crops, the diamondback moth, Plutella xylostella, and its respective hymenopteran parasitoid, Cotesia vestalis. Such knowledge can help in the effective use of insecticides with biological control agents in IPM. Three insecticides regarded as being compatible with some natural enemies (abamectin, spinosad, indoxacarb) and a compound generally regarded as harmful to natural enemies (lambda-cyhalothrin) were examined. Similar tests were also carried out with the peach potato aphid Myzus persicae and its parasitoid Aphidius colemani due to the loss of the Cotesia vestalis culture. A comparative measure of the intrinsic toxicity of fresh deposits (Day 0) of insecticides on Chinese cabbage was determined for both pest and parasitoid species. Lambda-cyhalothrin and abamectin were the most toxic compounds against both pests and their parasitoids, while indoxacarb and spinosad were less toxic. Residual bioassays were conducted using sprayed plants maintained under glasshouse conditions for 0-28 days after insecticide application. Results indicated lambda-cyhalothrin was the most persistent compound and abamectin and spinosad the least persistent. A leaf wax stripping technique was used with bioassays to compare the distribution of insecticide residues between the epicuticular wax layer and underlying leaf tissues. Wax removal significantly reduced the toxicity of all insecticides. No-choice and choice behavioural assays were conducted for both parasitoid species with leaf discs treated with LC5 and LC50 levels of insecticides. Both parasitoids tended to avoid insecticide-treated leaves, giving preference to untreated leaves or the arena. Emergence of adult parasitoids from cocoons/mummies on insecticide-treated leaves was not significantly different from untreated controls. The results are discussed in terms of the bioavailability of insecticides to phytophagous and non-phytophagous insect species.

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Hessler, Christopher Mark. « The Influence of Capsular Extracellular Polymeric Substances on the Toxicological Interaction Between Titanium Dioxide Nanoparticles and Planktonic Bacteria ». University of Toledo / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1321645743.

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Ta, Ha Phuong. « Etude de la relation structure - toxicité des protéines amyloïdes en interaction avec des membranes modèles ». Thesis, Bordeaux 1, 2011. http://www.theses.fr/2011BOR14361/document.

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Ce mémoire rapporte les études de protéines amyloïdes en interaction avec des membranes modèle afin d’établir une relation structure toxicité. Nous avons choisi différents modèles membranaires (monocouches, bicouches) de composition lipidique et charges différentes et utilisé différentes méthodes physico-chimiques afin de caractériser les interactions des protéines amyloïdes avec les membranes.Nous avons montré l’importance de la contribution électrostatique dans les interactions de la protéine amyloïde HET-s (218-289) et ses mutants avec les membranes modèles.L’ellipsométrie a démontré que les mutants toxiques de HET-s (218-289) (M8, WT.Y1Y2V2) perturbentfortement les monocouches lipidiques à l’interface air-eau. La structure riche en feuillets β antiparallèles des protéines àl’interface air-eau et dans l’interaction avec les monocouches de lipides a été démontrée par la spectroscopie PMIRRAS (Polarization Modulation – Infrared Reflection Absorption Spectroscopy). Nous avons établie que l’interface air-eau peut modifier l’agrégation des protéines amyloïdes. A l’aide de la spectroscopie de fluorescence, la spectroscopie PWR (Plasmon-Waveguided Resonance) et la spectroscopie ATR-FTIR (Attenuated Total Reflection – Fourier Transform Infrared), nous avons mis en évidence que la protéine toxique M8 adopte une structure riche en feuillets β antiparallèles en altérant fortement l’intégrité des bicouches lipidiques. Au contraire, la protéine non toxique WT se structure en feuillets β parallèles dans ces interactions et elle ne perturbe pas l’homogénéité des membranes. La toxicité de la protéine M8 semble liée à son organisation différente et à sa capacité à réorganiser les membranes.Nos résultats confortent également l’hypothèse de la toxicité des oligomères amyloïdes.Une étude sur la fabrication d’une cellule microfluidique pour la séparation de différents types d’autoassemblage afin de les détecter et de les étudier en interaction avec des liposomes par spectroscopie infrarouge est présentée. Une cellule microfluidique de CaF2 de 8 μm d’épaisseur de canaux est obtenue et est utilisée pour la détection d’une protéine de test
This manuscript reports the studies of amyloid proteins in interaction with membrane models in order to establish their structure-toxicity relationship.Membrane models (monolayer, bilayer) of different charge and lipid composition were used. We used various physico chemical methods to characterize the interaction of these amyloid proteins with membranes.We showed the importance of the electrostatic contribution in the interactions of the amyloid protein HET-s(218-289) and its mutants with model membranes.Ellipsometry showed that the toxic mutants of HET-s (218-289) (M8, WT.Y1Y2V2) strongly disturbed thelipid monolayers at the air-water interface. The structure rich in antiparallel β sheets of auto-assembled proteins at theair-water interface and in interaction with lipid monolayers at the air-water interface has been demonstrated by the PMIRRAS spectroscopy (Polarization Modulation - Infrared Reflection Absorption Spectroscopy). We established that theair-water interface can change the aggregation properties of amyloid proteins.By using fluorescence spectroscopy, PWR spectroscopy (Plasmon Resonance-Waveguided spectroscopy) and ATR-FTIR spectroscopy (Attenuated Total Reflection - Fourier Transform Infrared spectroscopy), we found that thetoxic protein (M8) adopted a structure rich in antiparallel β sheets greatly altered the integrity of lipid bilayers. Incontrast, the protein non-toxic (WT) organized in a structure rich in parallel β sheets in these interactions and it did notdisturb the homogeneity of the membranes. The toxicity of the protein M8 appears to be related to its differentorganization and its ability to rearrange membranes.Our results also support the hypothesis of the toxicity of amyloid oligomers.A study on the fabrication of a microfluidic cell for the separation of different aggregation states of amyloidproteins in order to detect these assemblies and to study their interaction with liposomes by infrared spectroscopy is presented. A CaF2 microfluidic cell with channels of 8 μm of thickness was obtained and was used for the detection of atested protein

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Le, Thanh Huong. « Toxicity of the cocktail of contaminants deoxynivalenol & ; cadmium to mammals with in vitro models ». Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30034.

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Le Cd est un métal lourd toxique très répandu. L'homme peut être exposé à ce contaminant environnemental par la fumée, la nourriture et l'eau. Le déoxynivalénol (DON) est l'une des mycotoxines les plus répandues dans les céréales. Si de nombreuses études ont étudié la toxicité du DON et du Cd individuellement, leur toxicité combinée est très peu connue. Cependant, les consommateurs peuvent être exposés à un mélange DON et Cd. Dans la présente étude, nous nous sommes concentrés sur les effets du DON et du Cd, seuls ou en combinaison, en utilisant une approche in vitro. Différentes lignées cellulaires humaines provenant du rein (HEK-293), de l'intestin (Caco-2), du sang (HL-60) et du foie (HepG2) ont été exposées à une gamme de doses de DON et Cd seuls et en combinaison. La toxicité induite a été évaluée avec le test CellTiter-Glo(r) Luminescent Assay, basé sur la mesure de la teneur en ATP, proportionnelle au nombre de cellules viables. Les interactions entre DON et Cd ont été analysées à l'aide de la méthode de l'indice de combinaison /isobologramme basée sur de l'équation à effet médian de la loi d'action de masse de Chou et Talalay (2006). Les cellules HEK-293 ont été exposées à des doses croissantes de DON, Cd et leur combinaison à différents ratios (DON / Cd de 2/1, 1/1, 1/2 et 1/8). Indépendamment du ratio, le type d'interaction observé dans les cellules HEK-293 allait de l'antagonisme modéré à presque additif. Dans les cellules Caco-2, les interactions variait de la légère synergie à l'antagonisme, quel que soit le ratio. Au ratio 1/1, dans les cellules HL-60 et HepG2, les interactions variaient de la synergie à l'antagonisme en fonction du niveau de cytotoxicité. Dans le milieu additionné de 1% de sérum de veau fœtal (FCS), la nature des interactions entre le DON et Cd sur les cellules HEK-293 et Caco-2 n'a pas montré de différence significative par rapport au milieu avec 10% de FCS. Les effets du DON et du Cd sur la fonction barrière intestinale et l'expression des gènes ont été évalués. Sur la perméabilité des monocouches de Caco-2, le DON et le mélange DON / Cd ont montré un effet dose-dépendant tandis qu'aucun effet n'a été observé pour le Cd. Le DON a induit une altération significative des cytokines inflammatoires alors que le Cd a montré une surexpression des gènes de la métallothionéine. Dans le milieu supplémenté avec 1% de FCS, nos résultats préliminaires ont montré des effets du Cd sur la fonction de barrière intestinale. Les effets combinés du DON et du Cd sur l'intégrité de barrière des cellules Caco-2 différentiées variait d'un antagonisme modéré à presque additif. En conclusion, notre étude indique que l'exposition combinée au DON et au Cd est spécifique à l'organe cible et au stade de développement de la cellule. De plus, les interactions entre le DON et le Cd devront être étudiées dans des expériences ex vivo et in vivo pour confirmer ces résultats
Cadmium (Cd) is a common and widespread toxic heavy metal. Human can be exposed to this environmental contaminant through smoke, food and water. Deoxynivalenol (DON) is one of the most prevalent mycotoxins in cereals. If numerous studies investigated the toxicity of DON and Cd individually, very little is known about their combined toxicity. However, consumers can be exposed to a cocktail DON and Cd. In the present study, we focused on the effects of DON and Cd, alone or in the mixture using in vitro approach. Different human cell lines from kidney (HEK-293), intestine (Caco-2), blood (HL-60) and liver (HepG2) were exposed to a range of doses of DON and Cd alone and in combination. The induced toxicity was evaluated with CellTiter-Glo(r) Luminescent Assay, based on the measure of ATP content, proportional to the number of viable cells. Interactions between DON and Cd were analyzed with isobologram-combination index method derived from the Median-Effect Equation of the Mass Action Law of Chou and Talalay (1984). HEK-293 cells were exposed to increasing doses of DON, Cd and their combinations at different ratios (DON/Cd of 2/1; 1/1; 1/2 and 1/8). Regardless of the ratio, the type of interaction observed in HEK-293 cells ranged from moderate antagonism to nearly additive. In Caco-2 cells, the interactions ranged from slight synergy to antagonism whatever the ratio. At ratio 1/1, in HL-60 and HepG2 cells, interactions ranged from synergy to antagonism depending on the cytotoxicity level. In the medium supplemented with 1% Fetal Calf Serum (FCS), the interaction of DON and Cd on HEK-293 and Caco-2 cells did not show a significant difference compared to medium with 10% FCS. Then, the effects of DON and Cd on the barrier function and gene expression were evaluated. On Caco-2 monolayers permeability, DON and DON/Cd mixture showed a dose- dependent effect while no effect was observed with Cd. DON-induced a significant alteration of inflammatory cytokines whereas Cd showed overexpression of metallothionein genes. In medium supplemented with 1% FCS, our preliminary results showed effects of Cd on intestinal barrier function. The combined effects of DON and Cd on Caco-2 cells barrier function ranged from moderate antagonism to nearly additive. In conclusion, our study indicates that the combined exposure to DON and Cd is specific to the target organ and development stage of the cells. Moreover, the interactions between DON and Cd will have to be investigated in ex vivo and in vivo experiments to confirm these results

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Jonsson, Karl. « Are nAChRs and NMDA receptors involved in low dose ethanol-nicotine toxicity in SH-SY5Y cells ? » Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-193048.

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Consumption of alcohol and tobacco is common all around the world and these drugs are frequently consumed concomitantly. It has been estimated that 70-80 % of alcoholics are smokers and non-alcoholic drinkers are more often smokers than teetotallers. Alcohol and tobacco may affect the risk of developing neurological diseases and might influence this risk differently when combined compared to when only one of these compounds is consumed. Some in vitro-research have shown that non-toxic concentrations of ethanol and nicotine, in combination, can exert toxicity, and might do so in a synergistic way. In this work, investigations were made to see if the neuronal nicotinic acetylcholine receptors (nAChRs) and NMDA receptors are involved in this interactive behaviour between ethanol and nicotine. A human neuroblastoma SH-SY5Y cell line was treated with ethanol and nicotine at different concentrations and cell viability was measured through an MTT-assay. A significant reduction in cell viability was induced by chronic treatment with a low-dose combination of ethanol and nicotine. The cell viability reduction was completely inhibited by pretreatment with the non-specific nAChR antagonist mecamylamine. This suggests that nAChRs are involved in low-dose ethanol-nicotine interactions. The NMDA receptor antagonist memantine did not affect the ethanol-nicotine effect, which implies that NMDA receptors are not involved in low-dose ethanol-nicotine interactions in SH-SY5Y cells. However, it is unclear if the SH-SY5Y cell line expresses fully functional NMDA receptors. The expression of NMDA receptors might vary with cell passage number. Further research has to be done to uncover the contribution of specific nAChR subtypes to the ethanol-nicotine interaction. There also remains to be revealed if human neuroblastoma SH-SY5Y cells express fully functional NMDA receptors and how cell passage number affects the expression of these receptors.

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HUBERT, NOELLA. « Interaction fer et hepatocytes en culture : regulation des proteines du metabolisme du fer et toxicite cellulaire ». Rennes 1, 1992. http://www.theses.fr/1992REN10144.

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De nombreuses inconnues subsistent dans le cadre de l'hemochromatose genetique (hg) ou une surcharge hepatocytaire en fer est observee. En effet, le gene responsable de cette maladie n'est toujours pas caracterise, les modifications de l'expression des proteines du metabolisme du fer lors de la surcharge ne sont pas clairement definies et enfin, les mecanismes impliques dans le developpement du carcinome hepatocellulaire restent a preciser. Afin d'apporter des elements de reponse a certaines de ces inconnues, nous avons developpe des modeles cellulaires de surcharge en fer faisant appel a des cultures primaires d'hepatocytes et a une lignee d'hepatome differenciee. Nous avons ainsi montre que les hepatocytes humains normaux et les cellules d'hepatome humain hepg2 repondent au fer de maniere similaire a celle observee in vivo au cours de l'hg en augmentant l'expression de la ferritine et en diminuant l'expression du recepteur de la transferrine. Dans les cellules hepg2, la regulation de l'expression de la ferritine s'exerce au niveau traductionnel alors que dans les hepatocytes humains, cette proteine est regulee transcriptionnellement et/ou post-transcriptionnellement. La regulation de l'expression du recepteur de la transferrine se situe au niveau transcriptionnel et/ou post-transcriptionnel dans les deux modeles de culture. Le fer entraine une diminution de l'affinite de l'iron regulatory factor (irf) pour l'iron responsive element (ire). Alors que dans les cellules hepg2, l'irf est regule post-traductionnellement par une modification de son affinite, le mecanisme de regulation semble plus complexe dans les hepatocytes humains et s'exercerait au niveau traductionnel et/ou post-traductionnel. Nous avons egalement demontre que le fer entraine une induction de l'oncogene c-myc dans les hepatocytes en culture primaire et pourrait jouer un role dans la carcinogenese hepatique. Enfin, nous avons mis en evidence l'effet protecteur d'une chelateur du fer, la pyoverdine pf, vis-a-vis de la surcharge en fer dans des cultures d'hepatocytes de rat. Il apparait donc que les hepatocytes en culture primaire constituent un modele tout a fait approprie pour l'etude des mecanismes impliques au niveau hepatocytaire dans la physiopathologie de l'hg

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Taylor, Cameron S. « Characterisation of engineered nanoparticles and their interaction with natural biological and non-biological material ». Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:03810528-de65-4094-907c-8c0d4e0386c8.

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Form, mobility, toxicity and the eventual fate of engineered nanomaterials in environmental ecosystems are currently not well defined and are needed to improve risk assessment and legislation. The present study subjected uncoated zinc oxide (ZnO) nanoparticles (30nm and 200nm) and coated silver (Ag) nanoparticles (Paraffin: 3-8nm and citrate/PVP: 50nm) to different ionic strength media and different types of algal/bacterial extracellular-polymeric species (EPS) at long (6 months) and short (2 weeks) timescales. Changes in particle size distribution and stability were examined using a multi-method approach. Sample concentration and sample polydispersity are important factors when selecting techniques. Uncoated ZnO nanoparticles aggregated heavily in water at high concentrations (1000mg/L). However silver nanoparticles (1-10mg/L) remained stable at all ionic strengths and EPS in this study due to the steric component of their coatings. Nano-toxicological experiments involving cyanobacteria S.leopoliensis and green algae C.reinhardtii showed size-dependent toxicity from coated nanosilver particles. Smaller nanoparticles (3-8nm) showed greater dissolution over 72h and greater toxicity to both species than 50nm particles indicating silver ions are an important toxicity mechanism. Nanoparticle coatings were likely important in controlling dissolution levels. Cell viability and production of reactive oxygen species (ROS) were shown to be important mechanisms of toxicity to phycological species. Species specific effects were noted for both silver nanoparticles. EPS from S.leopoliensis were noted to remove ionic silver from suspension and different types of C.reinhardtii EPS were produced when particles underwent different levels of toxic stress indicating that EPS could both affect particle toxicity and be affected by it. This work has demonstrated that coated nanoparticles could remain stable under various ionic strengths and with exposure to algal organic matter for timescales up to 6 months. This could result in adverse effects to aquatic organisms were they to reach environmental systems and is of concern to nanomaterial risk assessors.

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Yang, Zhongbao [Verfasser]. « The interaction between aluminium toxicity and drought stress in common bean (Phaseolus vulgaris L.) : physiological and molecular aspects / Zhongbao Yang ». Hannover : Technische Informationsbibliothek und Universitätsbibliothek Hannover (TIB), 2011. http://d-nb.info/1015447910/34.

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Potdevin, Sophie. « Interaction des derives du platine avec les systemes de transport de la cellule tubulaire proximale renale ». Paris 5, 1998. http://www.theses.fr/1998PA05N136.

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Le, Quang Dieu. « Métabolisme de la cyclosporine A et propriétés toxicopharmacologiques de ses métabolites ». Paris 5, 1998. http://www.theses.fr/1998PA05P250.

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Bounab, Yacine. « CRMP1 protein complexes modulate polyQ-mediated Htt aggregation and toxicity in neurons ». Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16185.

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Chorea Huntington (HD) ist eine neurodegenerative Erkrankung, die durch Ablagerungen von N-terminal Polyglutamin-reichen Huntingtin (Htt) -Fragmenten in den betroffenen Neuronen charakterisiert ist. Das mutierte Htt (mHtt) Protein wird ubiquitär exprimiert. Das zellspezifische Absterben von „medium-sized spiny neurons“ (MSN) wird jedoch im Striatum von HD Patienten verursacht (Albin, 1995). Es wird angenommen, dass Striatum-spezifische Proteine, die mit Htt interagieren, eine wichtige Rolle in der Pathogenese von HD spielen (Ross, 1995). Protein-Protein-Interaktionsstudien haben gezeigt, dass einige der Htt-Interaktionspartner mit unlöslichen Htt-Ablagerungen in den Gehirnen von HD-Patienten kolokalisieren und die Bildung von Protein-Aggregaten beeinflussen (Goehler, 2004). Kürzlich wurde durch die Integration von Genexpressions- und Interaktionsdaten ein Striatum-spezifisches Protein-Interaktionsnetzwerk erstellt (Chaurasia, unveröffentlichte Daten). Eines der identifizierten Proteine ist CRMP1 (collapsin response mediator protein 1), das spezifisch in Neuronen exprimiert wird und möglicherweise eine wichtige Rolle bei der Pathogenese von HD spielt. Experimentelle Untersuchungen mithilfe eines Filter-Retardationsassays zeigten, dass CRMP1 die Anordnung von Htt zu fibrillären, SDS-unlöslichen Aggregaten verringert. Durch Rasterkraftmikroskopie wurde der direkte Effekt von CRMP1 auf den Aggregationsprozess von Htt bestätigt. Ko-Immunopräzipitationsstudien zeigten, dass CRMP1 und Htt in Säugerzellen unter physiologischen Bedingungen miteinander interagieren. Es wurde nachgewiesen, dass CRMP1 die Polyglutamin-abhängige Aggregation und Toxizität von Htt in Zell- und Drosophila-Modellen von HD moduliert. Außerdem konnte CRMP1 in neuronalen Ablagerungen in R6/2 Mäusegehirnen und dessen selektive Spaltung durch Calpaine gezeigt werden. Diese Ergebnisse deuten darauf hin, dass die Lokalisation und Funktion von CRMP1 bei der Krankheitsentstehung verändert werden.
Huntington’s disease (HD) is a neurodegenerative disorder characterized by the accumulation of N-terminal polyglutamine (polyQ)-containing huntingtin (Htt) fragments in affected neurons. The mutant Htt (mHtt) protein is ubiquitously expressed but causes specific dysfunction and death of striatal medium-sized spiny neurons (MSNs) (Albin, 1995). It is assumed that striatum specific proteins interacting with Htt might play an important role in HD pathogenesis (Ross, 1995). Previous protein-protein interaction (PPI) studies demonstrated that many Htt-interacting proteins colocalize with insoluble Htt inclusions in HD brains and modulate the mHtt phenotype (Goehler 2004). A striatum-specific, dysregulated PPI network has been created recently by integrating PPI networks with information from gene expression profiling data (Chaurasia, unpublished data). One of the identified dysregulated proteins potentially involved in HD pathogenesis was the neuron-specific collapsin response-mediator protein 1 (CRMP1). Here, I show that CRMP1 reduces the self-assembly of SDS-insoluble mHtt protein aggregates in vitro, indicating a direct role of CRMP1 on the mHtt aggregation process. Coimmunoprecipitation studies showed that CRMP1 and Htt associate in mammalian cells under physiological conditions. In addition, CRMP1 localizes to abnormal neuronal inclusions and efficiently modulates polyQ-mediated Htt aggregation and toxicity in cell and Drosophila models of HD. This suggests that dysfunction of the protein is crucial for disease pathogenesis. Finally, I observed that CRMP1 localizes to neuronal inclusions and is selectively cleaved by calpains in R6/2 mouse brains, indicating that its distribution and function are altered in pathogenesis. In conclusion, this study presents new findings on the function of CRMP1 and its role in the pathogenesis of HD. The protein interacts with Htt and modulates its aggregation and toxicity, in this way influencing the molecular course of the disease.

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Ferrec, Romain, et Petrus Oskam. « Building Relationships : Assessing the quality of the relationship between leaders and followers as an indication of authenticity vs. toxicity ». Thesis, Linnéuniversitetet, Institutionen för organisation och entreprenörskap (OE), 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-34708.

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Relationships are so entrenched in the social interaction between individuals that most people do not pay attention to them until they experience trouble in their relationship. Humans create new relationships and end old ones all the time in conscious and unconscious processes. This thesis will give a theoretical and practical overview to reveal the process of social interaction which shapes relationships between a leader and a follower. We focus on the necessary components as well as on the process in which the relationship is built. We approach the process of social interaction from both the side of the leader and the side of the follower to create a balanced picture that will provide systematic explanation of this complicated and multidimensional phenomenon. The primary focus of this thesis will be on the origin and development of an authentic, healthy relationship between a leader and a follower.

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Russ, Jenny. « Systematic interaction mapping reveals novel modifiers of neurodegenerative disease processes ». Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16631.

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Neurodegenerative Erkrankungen (NDs) wie Alzheimer (AD), Parkinson (PD), und amyotrophe lateral Sklerose (ALS) sind Hirnerkrankungen, die durch unlösliche Proteinaggregate in Neuronen oder im Extrazellularraum charakterisiert sind. In dieser Arbeit habe ich für verschiede bekannte und vorhergesagte neurodegenerative Krankheitsproteine (NDPs) Proteininteraktionsnetzwerke erstellt, um mögliche gemeinsame Krankheitsmechanismen genauer zu studieren. Mit Hilfe eines automatisierten Hefe-Zwei-Hybrid-Systems (Y2H) konnte ich 18.663 Protein-Protein-Interaktionen (PPIs) für 449 wildtyp und 22 mutierte Proteine identifizieren. Eine genaue funktionelle Analyse der Interaktionspartner von korrespondierenden wildtyp und mutierten Proteinen ergab deutliche Unterschiede zum einen im Fall von allen untersuchten Proteinen und insbesondere im Fall vom ALS Krankheitsprotein TDP-43. Die identifizierten PPIs wurden außerdem verwendet um krankheitsspezifische Netzwerke zu erstellen und um Proteine zu identifizieren, die mit mehreren NDPs verbunden sind. Ich habe auf diese Weise vier Proteine (APP, IQSEC1, ZNF179 und ZMAT2) gefunden, die mit bekannten NDPs with Huntingtin, TDP-43, Parkin und Ataxin-1 interagieren und so fünf verschiedene NDs miteinander verbinden. Die Reduktion der mRNA Expression von IQSEC1, ZNF179 oder ZMAT2 mit Hilfe von siRNA führte zu einer Verstärkung von pathogenen Mechanismen wie der Aggregation von mutiertem Huntingtin und TDP-43 sowie der Hyperphosphorylierung des Proteins Tau. Außerdem habe ich 22 Proteine entdeckt, die die Aggregation von TDP-43 deutlich verändern und außerdem Mitglieder in sieben vorhergesagten Proteinkomplexen sind. Die Proteinkomplexe habe ich durch Kombination von Interaktionsdaten und Daten eines siRNA Screenings vorhergesagt. Zusätzlich habe ich herausgefunden, dass die Proteine eines vorhergesagten Komplexes, nämlich HDAC1, pRB, HP1, BRG1 und c-MYC, die Aggregation von TDP-43 durch Veränderung von dessen Genexpression beeinflussen.
Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD) or amyotrophic lateral sclerosis (ALS) are progressive brain disorders characterized by the accumulation of insoluble protein aggregates in neuronal cells or the extracellular space of patient brains. To elucidate potential common pathological mechanisms in different NDs, I created comprehensive interaction networks for various known and predicted neurodegenerative disease proteins (NDPs). I identified 18,663 protein-protein interactions (PPIs) for 449 bioinformatically selected wild-type target proteins and 22 mutant variants of 11 known NDPs by using an automated yeast two-hybrid (Y2H) system. The functional analysis of the interaction partners of corresponding wild-type and mutant NDPs revealed strong differences in the case of all 11 NDPs and especially for the ALS protein TDP-43. The identified PPIs were used to generate networks for individual NDs such as AD or PD and to identify proteins that are connected to multiple NDPs. For example, I found that five neurodegenerative diseases are connected by four proteins (APP, ZMAT2, ZNF179 and IQSEC1) that link known NDPs such as huntingtin, TDP-43, parkin, ataxin-1 and SOD1. Analysis of publicly available gene expression data suggested that the mRNA expression of the four proteins is abnormally altered in brains of ND patients. Moreover, the knock-down of IQSEC1, ZNF179 or ZMAT2 aggravates pathogenic disease mechanisms such as aggregation of mutant huntingtin or TDP-43 as well as hyperphosphorylation of tau. Additionally, I identified 22 modifiers of TDP-43 aggregation, which are members in 7 protein complexes. These complexes were predicted based on combined data from PPI as well as siRNA screenings. Finally, I found that the proteins HDAC1, pRB, HP1, BRG1 and c-MYC, which form one of the predicted complexes, influence TDP-43 aggregation by altering its mRNA expression.

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Renzi, Maria Teresa. « Effects of pesticides on honey bees (Apis mellifera L.) : study of a specific route of exposure and evaluation of biochemical-physiological changes in the assessment of the pesticides toxicity ». Phd thesis, Université d'Avignon, 2013. http://tel.archives-ouvertes.fr/tel-01002986.

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In this study, some important aspects of the relationship between honey bees (Apis mellifera L.) and pesticides have been investigated. In the first part of the research, the effects of the exposure of honey bees to neonicotinoids and fipronil contaminated dusts were analyzed. In fact, considerable amounts of these pesticides, employed for maize seed dressing treatments, may be dispersed during the sowing operations, thus representing a way of intoxication for honey bees. In particular, a specific way of exposure to this pesticides formulation, the indirect contact, was taken into account. To this aim, we conducted different experimentations, in laboratory, in semi-field and in open field conditions in order to assess the effects on mortality, foraging behaviour, colony development and capacity of orientation. The real dispersal of contaminated dusts was previously assessed in specific filed trials. The results showed a significant effect on mortality of neonicotinoids and fipronil contaminated dusts, both in laboratory and in semi-field trials. However, no effects were evidenced in honey bees orientation capacity.In the second part, the impact of various pesticides (chemical and biological) on honey bee biochemical-physiological changes, was evaluated. Different ways and durations of exposure to the tested products were also employed. Three experimentations were performed, combining Bt spores and deltamethrin, Bt spores and fipronil, difenoconazole and deltamethrin. Several important enzymes (GST, ALP, SOD, CAT, G6PDH, GAPDH) were selected in order to test the pesticides induced variations in their activity. In particular, these enzymes are involved in different pathways of detoxification, oxidative stress defence and energetic metabolism. The analysis of different biochemical indicators highlighted some interesting physiological variations that can be linked to the pesticide exposure. We therefore stress the attention on the possibility of using such a methodology as a novel toxicity endpoint in environmental risk assessment.

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Fresneau, Brice. « Analyses pronostiques en oncologie pédiatrique : Identification de facteurs de susceptibilité tumorale ou individuelle à l’efficacité et/ou à la toxicité des traitements anticancéreux utilisés chez l’enfant Investigating the Heterogeneity of Alkylating Agents' Efficacy and Toxicity Between Sexes : A Systematic Review and Meta-Analysis of Randomized Trials Comparing Cyclophosphamide and Ifosfamide (MAIAGE Study) Is Alpha-Fetoprotein Decline a Prognostic Factor of Childhood Non-Seminomatous Germ Cell Tumours ? Results of the French TGM95 Study New Insight into Severe Ototoxicity after Childhood Cancer. Is there an Impact of Melphalan and Busulfan ? A French Childhood Cancer Survivor Study A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated with High-Dose Methotrexate : Data from the OS2006/Sarcoma-09 Trial ». Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS034.

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Les progrès thérapeutiques en oncologie pédiatrique ont permis une amélioration des taux de survie qui dépassent aujourd’hui 80%. De façon à augmenter les taux de guérison et diminuer les complications et séquelles des traitements, des efforts collaboratifs internationaux ont permis le développement de protocoles thérapeutiques stratifiés sur les facteurs pronostiques majeurs incluant des facteurs biologiques tumoraux issus des analyses moléculaires et notamment génomiques. Cependant, si les traitements utilisés prennent de plus en plus en compte la biologie tumorale, leur adaptation aux facteurs individuels reste marginale. La thèse ici présentée cherche à mieux comprendre comment les caractéristiques tumorales et individuelles des patients modifient l’efficacité et la toxicité des thérapeutiques anticancéreuses utilisées en oncologie pédiatrique.Plusieurs travaux ont été réalisés :1- Etude de l’impact pronostique des facteurs tumoraux : évaluation de l’impact pronostique de la décroissance du marqueur tumoral alphafoetoprotéine (AFP) dans les tumeurs germinales malignes de l’enfant et de l’adolescent traitées par chimiothérapie ; 2- Etude de l’impact pronostique des facteurs constitutionnels : (i) évaluation de l’effet du sexe sur l’efficacité et la toxicité des agents alkylants ; (ii) évaluation de l’impact pronostique de polymorphismes génétiques de gènes impliqués dans le métabolisme du méthotrexate sur l’efficacité et/ou la toxicité du méthotrexate haute dose dans le traitement de l’ostéosarcome ;3- Etude des facteurs de risque de toxicité tardive : analyse de la de toxicité auditive sévère dans la cohorte des survivants à long terme de cancers pédiatriques (FCCSS)
Therapeutic advances in pediatric oncology have improved survival rates reaching over 80%. In order to increase cure rates and decrease complications and treatment sequelae, international collaborative efforts led to the development of therapeutic trials stratified on major prognostic factors including biological factors. However, treatment adaptation to individual patient characteristics remains marginal.In this thesis, our objective was to better understand how somatic (tumor-related) and constitutional (patient-related) characteristics could modify efficacy and toxicity of anticancer therapies used in pediatric oncology. Several works were performed: 1- Prognostic analysis of tumor markers: assessment of the alpha-foetoprotéine (AFP) decline prognostic value in childhood malignant germ cell tumors; 2- Prognostic analysis of constitutional factors: (i) assessment of the interaction between gender and type of alkylating agents on efficacy and acute toxicity; (ii) assessment of the efficacy and toxicity impact of genetic polymorphisms in patients with osteosarcoma treated with high-dose methotrexate; 3- Risk factors analysis of long-term toxicities: analysis of severe ototoxicity in the French Childhood Cancer Survivors Study (FCCSS)

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Oudin, Philippe. « Interactions entre polychlorobiphényles et micro-organismes : modification expérimentale de la paroi de deux souches de levure Rhodotorula glutinis et Saccharomyces cerevisiae en vue de l'optimisation du phénomène de bioaccumulation ». Nancy 1, 1998. http://www.theses.fr/1998NAN10361.

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Clift, Martin James David. « Quantum dots : an investigation into how differing surface characteristics affect their interaction with macrophages in vitro ». Thesis, Edinburgh Napier University, 2009. http://researchrepository.napier.ac.uk/Output/2557.

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Quantum dots (QDs) are potentially advantageous tools for both diagnostics and therapeutics due to their light emitting characteristics. The impact of QDs on biological systems however, is not fully understood. The aim of this project therefore, was to investigate the interaction of a series of different surface modifies QDs with macrophages and their subsequent toxicity. CdTe/CdSe (core), ZnS (shell) QDs with either an organic, COOH or NH2 polyethylene glycol (PEG) surface coatings were used. Fluorescent COOH polystyrene beads (PBs) at (Ø) 20nm and 200nm were also studied. J774.A1 murine ‘macrophage-like' cells were treated for two hours with QDs (40nM) of PBs ($50μg.ml^{-1}$) in the presence of 10% FCS prior to assessment of cellular uptake via confocal microscopy and flow cytometry. COOH and $NH_{2}$ (PEG) QDs, as well as 20nm and 200nm PBs entered macrophages within 30 minutes, and were found to locate within endosomes, lysosomes and the mitochondria. T.E.M. also illustrated particles, including organic QDs, to be present inside J774.A1 cells within membrane- bound vesicles at two hours. Organic QDs were unable to be visualised via fixed cell confocal microscopy. Live cell confocal microscopy (without 10% FCS) did suggest however, that organic QDs entered cells in low quantities up to 30 minutes, after which fluorescence declined. Particle toxicity was determined over 48 hours via the MTT, LDH and GSH assays, as well as via assessment of their potential to produce the pro-inflammatory cytokine (TNF-α) and effect cytosolic $Ca^{2+}$ signalling in the J774.A1 cells. Organic QDs were found to be highly toxic at all time points and concentrations used. Both COOH and $NH_{2 }$ (PEG) QDs induced significant (p<0.0001) cytotoxicity (MTT and LDH assays) at 80nM after 48 hours, as well as significant (p<0.01) GSH depletion over 24 hours at all doses, as well as increasing the level of cytosolic $Ca^{2+}$ at 40nM when assessed over 30 minutes. Organic and NH2 (PEG) QDs were found to significantly increase TNF-α production after 24 hours at 80nM. The findings of this study demonstrate that QDs differ in their uptake by macrophages according to their surface coating, with the organic surface coated QDs being the most toxic. At sub-lethal concentrations, in the presence of 10% FCS, the COOH and $NH_{2}$ (PEG) QDs are taken up resulting in GSH depletion and modulated $Ca^{2+}$ signalling, with $NH_{2}$ (PEG) QDs and organic QDs only eliciting limited TNF-α production. Interestingly however, despite these observations, QD surface coating does not affect the intracellular fate of these NPs, with all of the different surface coated QDs observed to be present in endosomes, lysosomes and the mitochondria within J774.A1 macrophage cells. Therefore, in conclusion, the surface coating of QDs plays a significant role in their interaction with macrophages, their uptake and their subsequent toxicity.

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CHAHINE, RAMEZ. « Recherches toxicologiques et pharmacologiques sur les effets de la metabolisation de la nicotine ». Toulouse 3, 1989. http://www.theses.fr/1989TOU30008.

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Deon, Magnus Dall'Igna. « Crescimento e nutrição mineral da soja submetida a excesso de P, S, K, Ca e Mg em solução nutritiva ». Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/11/11140/tde-19072007-094401/.

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Um sistema de cultivo eficiente depende do correto manejo da nutrição das plantas. Desordens nutricionais podem ser induzidas por manejo da fertilização inadequada e excessiva, dentre elas toxidez e deficiência induzida de um nutriente por outro. Com o objetivo de avaliar o comportamento da soja cultivar CD-208 ao excesso de cinco macronutrientes em solução nutritiva, foi realizado um experimento em casa de vegetação. Os tratamentos constituíram-se de um controle baseado na solução nutritiva de Hoagland e Arnon (1950) e soluções nutritivas iguais a essa, com a adição de 1,5; 3,0; 4,5 e 6,0 mmolc L-1 de um dos dois ânions (H2PO4 - e SO4 -2) acompanhado da mesma molaridade de carga de cada um dos três cátions (K+, Ca+2 e Mg+2). O único nutriente que provocou toxidez às plantas foi o fósforo, acumulando-se nas folhas diagnósticas em concentrações de até 12,8 g kg-1. Sob essa condição de toxidez, as plantas apresentaram clorose amarelo-amarronzada internerval nas folhas velhas que progrediu para necrose e abscisão, e acumularam menos massa seca, sofrendo alteração da relação entre parte aérea e raízes. Também apresentaram teores maiores de nitrogênio, enxofre e potássio, resultante da concentração destes nutrientes com a diminuição da massa seca e diminuição do teor de magnésio. Potássio e magnésio tiveram a concentração foliar aumentada pela sua maior concentração na solução, diferentemente do cálcio. A concentração foliar de cálcio foi menor com maiores concentrações de potássio e magnésio na solução nutritiva, mas potássio e magnésio não sofreram redução na concentração foliar com o aumento de outros cátions na solução. As mais altas concentrações de potássio na solução resultaram em menor concentração de ferro nos tecidos. O aumento na concentração de fósforo na solução nutritiva resultou na diminuição da concentração de cobre, mas não da concentração de zinco nas folhas diagnósticas.
An effective cultivation system depends on the adequate management of plant nutrition. Nutritional disorders may be induced by inadequate and excessive fertilization, and toxicity and deficiency may be induced by one nutrient on another. A greenhouse experiment was performed aiming to evaluate the behavior of the soybean cultivar CD- 208 to excess of five macronutrients in nutrient solution. Treatments were a control based on the Hoagland and Arnon (1950) nutrient solution and similar solutions with the addition of 1.5, 3.0, 4.5 and 6.0 mmolc L-1 of the anions H2PO4 -or SO4 -2 and the same molarity charge of each of the cations K+, Ca+2 and Mg+2. The only nutrient that caused toxicity to the plants was phosphorus, which accumulated in the diagnostic leaves in concentrations up to 12.8 g kg-1. Under this condition of toxicity, plants presented a yellow-brownish interveinal chlorosis in the old leaves which progressed to necrosis and abscission, and accumulated less dry mass, modifying the shoot:root ratio. The leaves also presented higher nitrogen, sulfur and potassium content due to concentration effect as dry matter diminished, and lower magnesium content than the control plants. Potassium and magnesium had their leaf concentration increased by its higher concentration in the solution; the same doesn't happen with calcium. High magnesium and potassium rates significantly decreased calcium content in the leaves. However, potassium and magnesium concentrations were not influenced by increasing concentration of others cations in the nutrient solution. There was a decrease in the content of iron with increasing potassium concentration in the solution culture. High phosphorus rates in nutrient solution decreased copper content in leaves, but did not decrease zinc content.

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Rima, Wael. « Apport de la microscopie electronique dans la compréhension des mécanismes d’interactions entre nanoparticules et cellules biologiques ». Thesis, Lyon, INSA, 2012. http://www.theses.fr/2012ISAL0131/document.

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Parmi les nanoparticules aptes à accompagner la radiothérapie en clinique, les nanoparticules à base d’oxyde de gadolinium paraissent pertinentes, de part leur multimodalité en imagerie et leur effet radiosensibilisant prouvé in vitro et in vivo. Cet effet de radiosensibilisation est exceptionnel notamment sur des cellules cancéreuses radiorésistantes de la lignée SQ20B (carcinome squameux tête et cou) et uniquement pour des doses modérées de nanoparticules (aux alentours de 0.6 mM en Gd). Les clichés de microscopie électronique ont montré que ce maximum de radiosensibilisation est dû à une internalisation maximale des particules dans le cytoplasme, notamment par macropinocytose. Ce mécanisme d’internalisation est caractérisé par la formation de vésicules de grandes tailles, ou macropinosomes. Il se produit suivant deux étapes : la formation d’agglomérats de nanoparticules à proximité de la membrane cellulaire puis la récupération de ceux-ci par les lamellipodes de la cellule. La première étape est fortement dépendante des caractéristiques physicochimiques des particules, plus particulièrement leur potentiel zêta qui détermine la taille de l’agglomérat, et de la distance les séparant de la cellule. Dans des gammes de taille et de distance à la membrane optimales aux concentrations modérées, l’agglomérat peut être récupéré par les lamellipodes de la cellule. Il s’en suit une protubérance sur la membrane plasmique formant un macropinosome contenant les agglomérats de nanoparticules. Cet endosome précoce suivra ensuite le schéma d’endocytose classique dans le cytoplasme en fusionnant avec des corps multivésiculaires, uniquement visible en microscopie électronique à transmission, pouvant contenir des enzymes de dégradation détruisant leur contenu. Ces enzymes rendent le pH acide à l’intérieur de la vésicule. Plus les nanoparticules sont proches du noyau cellulaire plus leur effet radiosensibilisant sera efficace. Les espèces oxygénées réactives (ROS) et les électrons Auger et secondaires peuvent atteindre l’ADN du noyau plus facilement. A faibles doses (<0.4 mM) très peu de nanoparticules sont internalisées et un effet linéaire de la radiosensibilisation est observé jusqu'à 0.6 mM. A fortes doses (> 0.7 mM) les nanoparticules forment une couronne autour de la membrane cellulaire agissant comme écran, empêchant ainsi les ROS et les électrons générés de pouvoir atteindre l’ADN et induire des cassures, le noyau étant situé à quelques micromètres de la membrane cellulaire. Les résultats obtenus ouvrent la voie sur la nécessité de contrôler l'internalisation cellulaire des nanoparticules en contrôlant leur chimie, laissant envisager ainsi des opportunités prometteuses dans le domaine de la radiothérapie assistée par nanoparticules délivrant de faibles doses de radiation aux patients
Over the last few decades, nanoparticles have been studied in theranostic field with the objective of exhibiting a long circulation time through the body coupled to major accumulation in tumor tissues, rapid elimination, therapeutic potential and contrast properties. In this context, we developed sub-5 nm gadolinium-based nanoparticles that possess in vitro efficient radiosensitizing effects at moderate concentration when incubated with head and neck squamous cell carcinoma cells (SQ20B). Two main cellular internalization mechanisms were evidenced and quantified: passive diffusion and macro- pinocytosis. Whereas the amount of particles internalized by passive diffusion is not sufficient to induce in vitro a significant radiosensitizing effect, the cellular uptake by macropinocytosis leads to a successful radiotherapy in a limited range of particles incubation concentration. Macropinocytosis processes in two steps: formation of agglomerates at vicinity of the cell followed by their collect via the lamellipodia (i.e. the “arms”) of the cell. The first step is strongly dependent on the physicochemical characteristics of the particles, especially their zeta potential that determines the size of the agglomerates and their distance from the cell. These results should permit to control the quantity of particles internalized in the cell cytoplasm, promising ambitious opportunities towards a particle-assisted radiotherapy using lower radiation doses

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Torres, Arias Marbel. « Signalisation de l'immunité innée et Apicomplexes : Rôle de la protéine adaptatrice MyD88 et de l'inflammasome dans le contrôle de l'infection à Toxoplasma gondii ou à Cryptosporidium parvum ». Thesis, Tours, 2013. http://www.theses.fr/2013TOUR3807.

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Les Apicomplexes constituent une vaste famille de parasites protozoaires responsables de nombreuses maladies chez l’Homme et chez les animaux. C’est le cas de Toxoplasma gondii, agent de la toxoplasmose et de Cryptosporidium parvum, responsable de la cryptosporidiose. Ces pathogènes représentent un réel problème de santé publique et vétérinaire. A l’heure actuelle, les seuls moyens de lutte contre ces parasites demeurent la chimiothérapie car il n’existe aucune stratégie prophylactique efficace. L’identification de cibles vaccinales repose sur le décryptage des mécanismes de défense mis en jeux vis-à-vis de ces agents infectieux. Dans le cadre de cette thèse, nos recherches se sont tournées vers l’étude du bras inné de la réponse immunitaire et plus particulièrement vers les voies de signalisation intracellulaires conséquentes de la reconnaissance de ces parasites
No summary available

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40

Rima, Wael. « Apport de la microscopie electronique dans la compréhension des mécanismes d'interactions entre nanoparticules et cellules biologiques ». Phd thesis, INSA de Lyon, 2012. http://tel.archives-ouvertes.fr/tel-00876351.

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Parmi les nanoparticules aptes à accompagner la radiothérapie en clinique, les nanoparticules à base d'oxyde de gadolinium paraissent pertinentes, de part leur multimodalité en imagerie et leur effet radiosensibilisant prouvé in vitro et in vivo. Cet effet de radiosensibilisation est exceptionnel notamment sur des cellules cancéreuses radiorésistantes de la lignée SQ20B (carcinome squameux tête et cou) et uniquement pour des doses modérées de nanoparticules (aux alentours de 0.6 mM en Gd). Les clichés de microscopie électronique ont montré que ce maximum de radiosensibilisation est dû à une internalisation maximale des particules dans le cytoplasme, notamment par macropinocytose. Ce mécanisme d'internalisation est caractérisé par la formation de vésicules de grandes tailles, ou macropinosomes. Il se produit suivant deux étapes : la formation d'agglomérats de nanoparticules à proximité de la membrane cellulaire puis la récupération de ceux-ci par les lamellipodes de la cellule. La première étape est fortement dépendante des caractéristiques physicochimiques des particules, plus particulièrement leur potentiel zêta qui détermine la taille de l'agglomérat, et de la distance les séparant de la cellule. Dans des gammes de taille et de distance à la membrane optimales aux concentrations modérées, l'agglomérat peut être récupéré par les lamellipodes de la cellule. Il s'en suit une protubérance sur la membrane plasmique formant un macropinosome contenant les agglomérats de nanoparticules. Cet endosome précoce suivra ensuite le schéma d'endocytose classique dans le cytoplasme en fusionnant avec des corps multivésiculaires, uniquement visible en microscopie électronique à transmission, pouvant contenir des enzymes de dégradation détruisant leur contenu. Ces enzymes rendent le pH acide à l'intérieur de la vésicule. Plus les nanoparticules sont proches du noyau cellulaire plus leur effet radiosensibilisant sera efficace. Les espèces oxygénées réactives (ROS) et les électrons Auger et secondaires peuvent atteindre l'ADN du noyau plus facilement. A faibles doses (<0.4 mM) très peu de nanoparticules sont internalisées et un effet linéaire de la radiosensibilisation est observé jusqu'à 0.6 mM. A fortes doses (> 0.7 mM) les nanoparticules forment une couronne autour de la membrane cellulaire agissant comme écran, empêchant ainsi les ROS et les électrons générés de pouvoir atteindre l'ADN et induire des cassures, le noyau étant situé à quelques micromètres de la membrane cellulaire. Les résultats obtenus ouvrent la voie sur la nécessité de contrôler l'internalisation cellulaire des nanoparticules en contrôlant leur chimie, laissant envisager ainsi des opportunités prometteuses dans le domaine de la radiothérapie assistée par nanoparticules délivrant de faibles doses de radiation aux patients.

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Al-Zebari, Nawar. « Production and characterisation of self-crosslinked chitosan-carrageenan polyelectrolyte complexes ». Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/267918.

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Macromolecular biomaterials often require covalent crosslinking to achieve adequate stability and mechanical strength for their given application. However, the use of auxiliary chemicals may be associated with long-term toxicity in the body. Oppositely-charged polyelectrolytes (PEs) have the advantage that they can self-crosslink electrostatically and those derived from marine organisms are an inexpensive alternative to glycosaminoglycans present in the extracellular matrix of human tissues. A range of different combinations of PEs and preparation conditions have been reported in the literature. However, although there has been some work on complex formation between chitosan (CS) and carrageenan (CRG), much of the work undertaken has ignored the effect of pH on the consequent physicochemical properties of self-crosslinked polyelectrolyte complex (PEC) gels, films and scaffolds. Chitosan is a positively-charged polysaccharide with NH3+ side groups derived from shrimp shells and, carrageenan is a negatively-charged polysaccharide with OSO3- side groups derived from red seaweed. These abundant polysaccharides possess advantageous properties such as biodegradability and low toxicity. However, at present, there is no clear consensus on the cell binding properties of CS and CRG or CS-CRG PEC materials. The aim of this study was to explore the properties of crosslinker-free PEC gels, solvent-cast PEC films and freeze-dried PEC scaffolds based on CS and CRG precursors for medical applications. The objective was to characterise the effect of pH of the production conditions on the physicochemical and biological properties of CS-CRG PECs. Experimental work focused on the interaction between PEs, the composition of PECs, the rheological properties of PEC gels and the mechanical properties of PEC films and scaffolds. In addition, cell and protein attachment to the PEC films was assessed to determine their interactions in a biological environment. For biomedical applications, these materials should ideally be stable when produced such that they can be processed to form either a film or a scaffold and have mechanical properties comparable to those of collagenous soft tissues. FTIR was used to confirm PEC formation. Zeta potential measurements indicated that the PECs produced at pH 2-6 had a high strength of electrostatic interaction with the highest occurring at pH 4-5. This resulted in stronger intra-crosslinking in the PEC gels which led to the formation of higher yield, solid content, viscosity and fibre content in PEC gels. The weaker interaction at pH 7-12 resulted in higher levels of CS incorporated into the complex and the formation of inter-crosslinking through entanglements between PEC units. This resulted in the production of strong and stiff PEC films and scaffolds appropriate for soft tissue implants. The PECs prepared at pH 7.4 and 9 also exhibited low swelling and mass loss, which was thought to be due to the high CS content and entanglements. From the range of samples tested, the PECs produced at pH 7.4 appeared to show the optimum combination of yield, stability and homogeneity for soft tissue implants. Biological studies were performed on CS, CRG and PECs prepared at pH 3, 5, 7.4 and 9. All of the PE and PEC films were found to be non-cytotoxic. When the response of three different cell types and a high binding affinity protein (tropoelastin) was evaluated; it was found that the CS-CRG PEC films displayed anti-adhesive properties. Based on these experimental observations and previous studies, a mechanistic model of the anti-adhesive behaviour of PEC surfaces was proposed. It was therefore concluded that the CS-CRG PECs produced might be suitable for non-biofouling applications.

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Willemin, Marie-Émilie. « Modélisation de la toxicocinétique des isomères cis et trans de la perméthrine et de ses métabolites chez le rat et de leur métabolisme sur hépatocytes humains ». Thesis, Compiègne, 2014. http://www.theses.fr/2014COMP2149/document.

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Les pyréthrinoïdes sont des insecticides auxquels la population est quotidiennement exposée. Le composé parent est suspecté d’induire des perturbations neuronales et hormonales chez l’homme. Au sein de cette famille, la perméthrine (mélange d’isomère cis et trans) est le composé le plus utilisé dans le traitement des intérieurs de maison. Dans ce travail de thèse, nous proposons de développer un modèle PBPK pour la perméthrine et certains de ses métabolites urinaires, utilisés comme biomarqueurs d’exposition, et d’évaluer les interactions métaboliques des deux isomères. Trois étapes ont été suivies. Une méthode analytique par GC-MS/MS a été développée pour doser simultanément les composés dans les différentes matrices. Un modèle PBPK de la perméthrine chez le rat a été associé à un modèles PBPK réduit du DCCA et empirique du 4’-OH-PBA et du 3-PBA. Les paramètres toxicocinétiques de chaque composé ont été estimés dans un cadre Bayésien à partir d’expériences in vivo menées à la dose orale de 25 mg/kg de cis- ou trans-perméthrine chez le rat. Le modèle PBPK de la perméthrine a été vérifié sur des données de cinétique d’un mélange cis/trans. Le métabolisme hépatique de chaque composé a été quantifié chez l’homme sur des hépatocytes primaires dans des conditions optimales pour l’extrapolation in vitro-in vivo, en incubant les isomères séparément et en mélange. Ce travail de thèse souligne la possibilité d’établir un modèle PBPK générique pour les pyréthrinoïdes. L’absence d’interaction entre les isomères au niveau in vitro et lors de la vérification du modèle PBPK de la perméthrine pourrait simplifier la caractérisation de l’exposition à un mélange de pyréthrinoïdes
Population is largely exposed to pyrethroids, an insecticide family. The parent compound is suspected to induce neuronal and hormonal modifications in humans. Among this family, permethrin, a mixture of isomers cis/trans, is mainly used in house tratments. In this PhD project, we developed a PBK model of permethrin and some urinary metabolites uses as biomarkers of exposure. The matabolic interactions between the two isomers were also evaluated. A three steps strategy was followed. An analytical method by GC-MS/MS was developed to measure these compounds simultaneously in the different matrices. A PBPK of permethrin in rat was associated to a reduced PBPK model of DCCA and a 2-compartment model of 4'-OH-PBA and 3-PBA. The toxicokinetics parameters of each compound were estimated in a Bayesian framework from in vivo experiments in rats orally dosed with 25 mg/kg of cis- or trans permethrin. The PBPK model of permethrin was validated on the kinetic data of a mixture of permethrin. The hepatic metabolism was quantified in humans in primary hepatocytes in optimal conditions for in vitro-in vivo extrapolation, by incubating the isomers separately and as a mixture. This work underlines that a general PBPK model for Type 2 pyrethroids can be considered for the parent compound The lack of interaction between isomers during in vitro experiments and the validation of the PBPK model of permethrin could simplify the characterization of the exposure to a mixture of pyrethroids

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Almasri, Hanine. « Toxicologie des mélanges de pesticides chez des abeilles exposées à un agent pathogène : action combinée de l'agent pathogène Nosema ceranae, de l'insecticide imidaclopride, du fongicide difénoconazole et de l'herbicide glyphosate Mixtures of an insecticide, a fungicide and a herbicide induce high toxicities and systemic physiological disturbances in winter Apis mellifera honey bees Toxicity of the pesticides imidacloprid, difenoconazole and glyphosate alone and in binary and ternary mixtures to winter honey bees : effects on survival and antioxidative defenses Toxicological status changes the susceptibility of the honey bee Apis mellifera to a single fungicidal spray application Physiological effects of the interaction between Nosema ceranae and sequential and overlapping exposure to glyphosate and difenoconazole in the honey bee Apis mellifera ». Thesis, Avignon, 2020. http://www.theses.fr/2020AVIG0722.

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Les données scientifiques actuelles suggèrent un déclin de la diversité et de l’abondance des insectes, y compris les abeilles domestiques Apis mellifera. Ces dernières sont confrontées à de fortes pertes de colonies dans plusieurs régions du monde telles que l’ouest de l’Europe et les États-Unis. De nombreuses études suggèrent que l’origine du déclin des colonies d’abeilles est multicausale et identifient les pesticides et les agents pathogènes comme étant les principaux contributeurs à ce déclin. La co-exposition des abeilles à de multiples pesticides et l’infection par plusieurs pathogènes constituent un phénomène courant. Cependant, les recherches sur les effets des mélanges de pesticides n’ont pas fait l’objet d’un intense développement. Ainsi, les travaux conduits dans le cadre de cette thèse ont été focalisés sur la détermination de la toxicité des mélanges de pesticides, appliqués à des niveaux d’exposition environnementaux, en présence d’un agent pathogène. Le choix s’est porté sur l’étude des interactions entre un insecticide néonicotinoïde, l’imidaclopride, un fongicide azole, le difénoconazole, et un herbicide, le glyphosate, en présence de l’agent pathogène Nosema ceranae. Les résultats des différentes études effectuées durant cette thèse, révèlent la complexité des études sur les mélanges de pesticides. Ces travaux nous ont permis de constater que les effets d’un mélange de pesticides peuvent fortement varier en fonction des concentrations des pesticides constituant le mélange. L’augmentation du nombre de substances et du niveau d’exposition, n’induit pas nécessairement une augmentation de la toxicité du mélange. De plus, les effets du mélange peuvent varier en fonction de la séquence d’exposition aux pesticides et de l’état sanitaire des abeilles. Les mélanges de pesticides affectent l’état physiologique des abeilles suite à une réponse systémique liée à des perturbations de mécanisme généraux tels que le stress oxydant. Cependant, ces trois pesticides, seuls et en mélanges n’ont aucun effet sur l’installation du microbiote intestinal à des niveaux d’exposition environnementaux
Current scientific findings suggest a decline in the diversity and abundance of insects, including the honey bee Apis mellifera. The latter are facing high colony losses in several regions of the world such as Western Europe and the United States. Numerous studies suggest that the origin of bee colony decline is multi-causal and identify pesticides and pathogens as the main contributors to this decline. Co-exposure of honey bees to multiple pesticides and infection by multiple pathogens are common phenomena. However, research on the effects of pesticide mixtures has not been extensively developed. Thus, the thesis work has focused on determining the toxicity of pesticide mixtures, applied at environmental exposure levels, in the presence of pathogens. The choice was made to study the interactions between a neonicotinoid insecticide, imidacloprid, an azole fungicide, difenoconazole, and a herbicide, glyphosate, in the presence of the pathogen Nosema ceranae. The results of the different studies, carried out during this thesis, reveal the complexity of the studies on pesticide mixtures. The work allowed us to notice that the effects of a pesticide mixture can vary according to the concentrations of the pesticides constituting the mixture. The increase of the number of substances and the level of exposure does not necessarily induce an increase of the toxicity of the mixture. Furthermore, the effects of the mixture may vary depending on the sequence of exposure to the different pesticides and the health status of the honey bees. Pesticide mixtures affect the physiological state of individuals as a result of a systemic response related to disturbances of general mechanisms such as oxidative stress. However, these three pesticides, alone and in mixtures, have no effect on the installation of the intestinal microbiota at environmental exposure levels

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Ishac, Nicole. « Comment deux lignées cellulaires stromales mésenchymateuses humaines récapitulent in vitro le microenvironnement hématopoïétique ? : Intérêt en ingénierie ». Thesis, Tours, 2015. http://www.theses.fr/2015TOUR4038/document.

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L’hématopoïèse se déroule dans un microenvironnement spécialisé appelé niche où les cellules souches hématopoïétiques (CSH) sont en contact étroit avec les cellules stromales mésenchymateuses. Cette interaction cellulaire associée à d’autres facteurs environnementaux, comme la présence des espèces réactives à l’oxygène, est cruciale pour la régulation des CSH normales, mais aussi leucémiques. Pour étudier ce microenvironnement, il est donc important de développer un modèle in vitro de niche humaine qui mime la physiologie in vivo. Nous avons choisi comme modèle deux lignées mésenchymateuses stromales humaines HS-27a et HS-5, très peu décrites dans la littérature. Le premier objectif a été de déterminer la qualité de cette niche tant du point de vue cellulaire, moléculaire que fonctionnel. Nos résultats montrent clairement que les cellules HS-27a participent à la formation d’une niche « quiescente » alors que les cellules HS-5 représentent une niche « proliférative ». Le deuxième objectif a été de créer une niche contrôlée pour le métabolisme oxydatif en régulant l’expression d’une protéine antioxydante, la glutathion peroxydase 3 ou GPx3. L’originalité de ce travail repose sur l’utilisation d’une méthode non virale de transfert de gène par le transposon piggyBac. Le plasmide porteur du gène d'intérêt a été apporté sous forme d’ADN et une source de transposase, enzyme catalysant la réaction d'intégration sous forme d’ARNm. Notre travail montre que GPx3 est un régulateur clé de l’homéostasie hématopoïétique favorisant le maintien des progéniteurs immatures. Pour la première fois, nous créons par ingénierie in vitro une niche hématopoïétique « calibrée » capable de mimer le microenvironnement normal et leucémique. Ce modèle permet non seulement d’identifier les acteurs clés de la régulation des cellules médullaires, mais aussi de développer des stratégies thérapeutiques ciblées
Hematopoiesis occurs in a hypoxic microenvironment or niche in which hematopoietic stem cells (HSCs) are in close contact with mesenchymal stromal cells. Cellular interactions as well as microenvironmental factors such as reactive oxygen species are crucial for the maintenance of normal and leukemic HSCs. Developing an in vitro human culture system that closely mimcs marrow physiology is therefore essential to study the niche. Here, we present a model using two human stromal cell lines, HS-27a and HS-5. Previously poorly described in the literature, we have further characterized both of these cell lines. The first objective was to assess the quality of HS-27a and HS-5 niches by investigating their cellular, molecular and functional characteristics. Our results clearly show that HS-27a cells display features of a “quiescent” niche whereas HS-5 cells rather represent a “proliferative” niche. The second objective was to engineer a hematopoietic niche where the oxidative metabolism is optimized for the expression of an antioxidant protein, glutathione peroxidase 3 (GPx3). The originality of this work is the use of a non-viral gene transfer system by using the transposon piggyBac. This strategy was achieved by delivering a DNA plasmid carrying the gene of interest, and an mRNA source of transposase, the enzyme which catalyzes the transgene integration. Functionally, GPx3 was shown to be a key regulator for sustaining hematopoietic homeostasis by maintaining immature progenitor cells. For the first time, an original non-viral gene transfer has been used to create an in vitro hematopoietic niche that recapitulates the complexity of normal and leukemic microenvironment. This niche not only provides a platform to identify regulatory factors controlling medullary cells, but may also help in the development of targeted therapeutic strategies

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LI, BO-LOU, et 李寶樓. « The interaction of manganese toxicity on inorganic nutrition of soybean plants ». Thesis, 1989. http://ndltd.ncl.edu.tw/handle/23005301862998734497.

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Hall, Julie. « The interaction of chronic copper toxicity with nutrient limitation in two chlorophytes ». 1987. http://hdl.handle.net/1993/30043.

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Rider, Cynthia V. « Development and application of an integrated addition and interaction model of mixture toxicity ». 2005. http://www.lib.ncsu.edu/theses/available/etd-01022006-223335/unrestricted/etd.pdf.

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Fischer, Hans Christian. « Investigating the Interaction of Semiconductor Quantum Dots with in vivo and Cellular Environments to Determine Disposition and Risk ». Thesis, 2010. http://hdl.handle.net/1807/26171.

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Nanomaterial toxicity is a major concern and could potentially hamper the progress of biomedical nanotechnology development. Dispelling these concerns requires that the consequences of nanomaterial exposure are evaluated, and the findings will determine whether developmental hurdles can be overcome. This thesis evaluates the both in vivo and in vitro impact of quantum dots (QD , zinc sulphide capped cadmium selenide semiconductor nanocrystals) a fluorescent nanoparticle label with potential as an optical in vivo imaging agent. This work reviews nanoparticle characterization techniques and their importance to biological responses, and surveys QD interactions both in vivo and in vitro. We collected pharmacokinetic and toxicity data by a) quantitatively surveying the in vivo absorption, distribution , metabolism and excretion of QDs, and b) measuring the impacts of QDs on relevant organs (in vivo) and cells (in vitro). Neither of these areas had been explored when this thesis was started. In vivo, intravenous QD dosing in Sprague-Dawley rats showed uptake into reticuloendothelial cells with surface coating dependent kinetics, slow degradation, no excretion detected in feces or urine, and no indications of toxicity. The liver took up the majority of dose after 90 minutes and small amounts of QDs appeared in the spleen, kidney, and bone marrow. After 30 days, the cadmium concentration in the kidneys increased to 3µg/g without a proportional amount of zinc, indicating QD breakdown. In vitro we noted phagocytic capacity comparable to in vivo results, QD breakdown, and a retention of normal macrophage function thereby demonstrating that primary rat liver macrophages (Kupffer cells) are an appropriate in vitro system with which to investigate the cellular responses to quantum dots. Such an in vitro model will facilitate faster evaluation of individual nanotechnologies intended for in vivo use. This dissertation addresses a lack of in vivo background information needed to understand the consequences of QD exposure; though QD fail to demonstrate pharmacokinetics desirable for in vivo imaging agents, they are not toxic. Importantly, we provide in vitro data that will lead to the development of accurate and efficient in vitro primary screening methods that will be central to the further development of biomedical nanotechnologies.

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Fallon, Aurélie. « Pathological implications of the interaction between neurexins and alpha-synuclein in synucleinopathies ». Thesis, 2020. http://hdl.handle.net/1866/25679.

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La maladie de Parkinson (PD) et la démence à corps de Lewy (DLB) sont les deuxième et troisième maladies neurodégénératives les plus communes et font partie d’une classe de maladies appelées synucléinopathies. Les synucléinopathies sont associées à une pathologie liée à l’α-synucléine (α-syn) laquelle se caractérise par une accumulation de cette protéine dans les neurones, formant ainsi les corps de Lewy. L’α-syn pathologique se retrouve aussi sous forme d’oligomères et de fibrilles, qui sont toxiques pour les neurones et leurs synapses. L’une des premières anomalies observables chez les patients atteints de synucléinopathies est la dysfonction synaptique, souvent combinée à une perte de synapses. Il a été rapporté que les oligomères d’α-syn retrouvés au niveau des synapses précèdent la formation de corps de Lewy dans les neurones et leur transmission semble être associée à la progression des symptômes. Pourtant, les mécanismes moléculaires sous-jacents la dysfonction synaptique causée par l’α-syn restent inconnus. D’autre part, le fonctionnement normal des synapses est fortement régulé par une famille de protéines appelées organisateurs synaptiques. Les organisateurs synaptiques, incluant la protéine neurexine, sont des molécules d’adhésion cellulaire qui régulent la synaptogenèse, la plasticité, la libération des neurotransmetteurs et les fonctions cognitives. De plus, nous avons préliminairement montré que l’α-syn interagit avec l’isoforme β des neurexines (NRXs) (β-NRXs). Mon projet avait donc pour but de caractériser l’interaction α-syn/β-NRX et d’évaluer comment celle-ci contribue à la pathologie liée à l’α-syn. Nous avons émis l’hypothèse que cette interaction affecte la fonction synaptogénique liée aux NRXs et son trafic. Dans un premier temps, pour tester notre hypothèse, l’interaction α-syn/β-NRX a été évaluée grâce à des analyses de liaison à la surface cellulaire. Il a été constaté que les oligomères d’α-syn se lient fortement à NRX1,2β de manière dépendante du domaine riche en histidine (HRD), caractéristique de l’isoforme β, et cela sans perturber sa liaison à ses ligands endogènes postsynaptiques, neuroligine 1 (NLG1) et « leucine rich repeat transmembrane neuronal 2 » (LRRTM2). De plus, à travers des essais d’internalisation, nous avons observé que les oligomères d’α-syn altèrent le trafic de NRX1β en augmentant son internalisation de façon dépendante au HRD et altèrent également la différenciation NRX-dépendante de la synapse en synapse inhibitrice. Par conséquent, nous suggérons que cette internalisation accrue pourrait affecter la fonction synaptogénique associée aux NRXs. Ce travail contribue à une meilleure compréhension sur la façon dont l’α-syn provoque un dysfonctionnement synaptique, fournissant de nouvelles perspectives moléculaires et pharmacologiques sur les synucléinopathies.
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are the second and the third most common neurodegenerative disorders and are part of a class of diseases called synucleinopathies. Synucleinopathies are associated with an α-synuclein (α-syn) pathology which shows an accumulation of α-syn in neurons, forming Lewy bodies. This pathological α-syn can form oligomers and fibrils, which are toxic for neurons and their synapses. One of the first changes to occur in patients’ brain with synucleinopathies is synaptic dysfunction often combined with synapse loss. Synaptic α-syn oligomers were revealed to precede the formation of Lewy bodies, and their transmission to other neurons to correlate with the progression of the symptoms. Yet, the molecular mechanisms underlying how α-syn leads to synaptic dysfunction are unknown. Synaptic function is highly regulated by a protein family called synaptic organizers. Synaptic organizers are cell adhesion molecules that regulate synaptogenesis, plasticity, neurotransmitter release, synaptic plasticity and cognitive functions. Of this family, we have found that α-syn interacts with the β-isoforms of the neurexins (NRXs) family members (β-NRXs). My project aimed to characterize α-syn/β-NRX interaction and to evaluate how this interaction contributes to α-syn pathology. We hypothesized that this interaction affects NRX trafficking and its synaptic function. Firstly, to test our hypothesis, the α-syn/β-NRX interaction was characterized by performing cell surface binding assays. I found that α-syn oligomers strongly bind to NRX1,2β in a histidine rich domain (HRD)-dependent manner, without disrupting NRX binding to its postsynaptic binding partners, neuroligin 1 (NLG1) and leucine rich repeat transmembrane neuronal 2 (LRRTM2). Moreover, using internalization assays, we discovered that α-syn oligomers impair NRX trafficking by increasing NRX1β internalization in an HRD-dependent manner and impair NRX-dependent inhibitory presynaptic differentiation. Thereby, we suggest that this increased internalization affects the inhibitory synaptogenic function of NRX-based synaptic organizing complexes. This work contributes to a better understanding of how α-syn causes synaptic dysfunction, providing promising new molecular mechanisms and pharmacological insights into synucleinopathies.

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Lee, Chia-Hua, et 李佳樺. « Assessing copper and lead interaction in contaminated sediments and their bioavailability and toxicity to larvae and embryos of medaka ». Thesis, 2019. http://ndltd.ncl.edu.tw/handle/sr9nfh.

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碩士
國立臺灣大學
農業化學研究所
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In the river system, sediment is considered as a long-term source of contaminants for aquatic organisms due to its high accumulating capacity. Among all contaminants, heavy metals are of high concern because of their non-biodegradable nature. The bioavailability of these metals may be affected by sediment properties, transportation behavior between sediment-water system and physiology of aquatic organisms. To understand the chemical and biological interaction of sediment-bound contaminants to the aquatic life, this study used the whole-sediment exposure method with intermittent water renewal system to evaluate the bioavailability and toxicity of two heavy metals [i.e. lead (Pb) and copper (Cu)]. Medaka (Oryzias latipes) embryos and larvae, which were used as model organisms, were exposed to a variety of Pb- and Cu-spiked sediments with different physicochemical properties for 7 days to evaluate the toxicity and bioavailability. Moreover, this study discussed the transportation and effect in the sediment between these two metals. The physiochemical properties of four sediments were totally different. ZZ sediment and WS sediment were sand, TS sediment was loamy sand and WB was loam. In these sediments, WB had the highest CEC, as well as ZZ and WS has lower OC. pH value from high to low were TS > WS > ZZ > WB. Survival rates of both treated embryos and larvae from TS were the highest, and those from ZZ were the lowest. As such, we believed that metals in lower pH, CEC, OC and more sandy sediment were more releasable, and larvae were more sensitive to metal toxicity than embryos. Moreover, the larval morphology i.e. body length and body weight in dual metal spiked sediments groups were significantly inhibited in very low concentrations. The trend of larval mortality spiked with single Cu into ZZ sediment was similar to that with dual metal at in same Cu concentration. Based on the results, the lethal toxicity was mainly affected by Cu, as the bioavailability of Pb was low. In this study, we also used several analytical approaches to assess the bioavailability of these two metals and the correlation (log-logistic model and linear regression) with observed toxic effects. The resuls showed that Chelex-100 resin extraction method can be an effective method for predicting and evaluating bioavailability of sedimental Cu and Pb to medaka no matter in single or dual metal polluted sediment.

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