Dissertations / Theses: 'Biochemical toxicology'

1

Coleman, M. D. "The biochemical pharmacology and toxicology of anti-parasitic agents." Thesis, Aston University, 2004. http://publications.aston.ac.uk/21356/.

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2

Liu, Yandi. "A study of the biochemical development and toxicology of the seed of Santalum spicatum." Thesis, Curtin University, 1997. http://hdl.handle.net/20.500.11937/2454.

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The seed of Santalum spicatum is rich in a fixed oil (59% by weight), which is characterised by a high percentage of acetylenic, ethylenic ximenynic acid (35% of total fatty acids). A number of important aspects of the seed fixed oil, its composition in developing seeds, its triacylglycerols molecular species in the oil, the nutrition and toxicity of the oil feeding, and the possible bioactivity of ximenynic acid in mice were investigated.The identification of cis and trans isomers of ximenynic acid in the seed oil, and the metabolite of ximenynic acid in mouse liver lipid fractions were achieved using 2-amino-2-methyl-1-propanol to form 2-substituted 4,4-dimethyloxazoline derivatives, which were analysed by gas chromatography with mass spectrometric detection.Changes in proximate and fatty acid composition were investigated in developing seed collected weekly from about seven days after flowering to maturity. It was determined that moisture and carbohydrate contents decreased significantly during the development sequence, while fixed oil content increased from 0.3% to 50% (by weight) with seed development. A corresponding increase in the proportions of both oleic and ximenynic acids occurred suggesting a precursor/product relationship. Mature seed collected from different locations in Western Australia showed minor differences in characteristics and lipid composition, which may have been influenced by geographical origin and harvesting year of samples.The lipid components from the seed oil were separated using thin-layer chromatography and the individual triglyceride bands were characterised by high performance liquid chromatography and gas chromatography using flame ionisation and mass spectrometric detection after removal from the plate. The triximenynin (trisantalbin) band showed no other contaminating fatty acids and was obtained in a relatively pure state.A nutrition and toxicity study was performed by feeding a semi-synthetic diet containing sandalwood seed oil to a level of 15% of total energy content to a group of mice for one month and another group for two months. The most significant effect of sandalwood seed oil ingestion when compared with a standard lab diet (5% fat, by weight) and a canola oil-enriched diet (15% fat, by weight) was an apparent reduction in body weight gain, which may be the effect of ximenynic acid as a growth retardant. Serum aspartate aminotransferase levels were determined in the mice as an indicator of hepatotoxicity. These levels were higher in mice fed the sandalwood seed oil diet than those fed the standard lab diet, suggesting that ximenynic acid may affect liver-specific enzyme activity. Analysis of the total lipid fatty acids of various tissues and organs of mice showed only a low incorporation of ximenynic acid into the general tissues (0.3-3% by weight), and its absence in the brain.This study suggests a few health benefits from consumption of large quantities of sandalwood seed oil in the diet. These include a low lipid content in blood, heart, muscle, increase in the 16:1/16:0 and 18:1/18:0 ratios, production of increased levels of 18:1 (n-9) and docosahexaenoic acid, and decreased levels of arachidonic acid in certain tissues. There were no specific pathological, morphological or mortality changes observed in the mice.Sandalwood seed may be both a food and a medicine.

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3

Jackson, John B. "The biochemical toxicology of serum carboxylesterase in pigeons (Columba livia)." Thesis, University of Reading, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240286.

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4

Tormey, William Patrick. "The provision of biochemical investigations in forensic toxicology for coroners." Thesis, Ulster University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.646399.

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Death certification plays a central role in health service planning therefore identification of specific causes of death is critical. The requirements of biochemical toxicology as set out in the Coroners Acts in Ireland, Northern Ireland and England and Wales will be parsed to facilitate the construction of a modern best practice template for coroners' toxicology. The Royal College of Pathologists (RCPath) provides published standard guidelines for pathologists reporting to coroners. Their adequacy will be critically evaluated to facilitate reform with the intention of maximising the accuracy of death certification. The roles of psychological factors, tobacco smoking, non steroidal anti-inflammatory drugs, and cannabis in cardiac death will be detailed. The potential for adverse drug reactions to prescription medication to cause death by misadventure will be explored. The role for the expert witness in the inquisitorial coroners system to improve the accuracy of the causes of death and thus the verdict will be explored. My experience has shown that misinterpretation of presence of cannabis in autopsy blood and urine samples is common and this underlines the need for true expert guidance for the coroner. The current practice in biochemical toxicology of screening blood, urine and vitreous humor will be critically evaluated and the necessity for a wide ranging screen of potential toxins as a contributor to the cause of death examined. The appropriate analytes on the screening menu will be determined by local cultural factors. Gas and liquid chromatography with mass spectrometry are the methods of choice. The interpretation of isopropanol, ethanol and ketones in post-mortem blood will be considered as will t~e role of alcohol in death. The apparent population exposure to poisons as reported by Poisons Information Services will be used to explore the dichotomy between the usually benign outcome of common poisons and the often lethal consequences of poisoning by prescription and illicit drugs. The aim of this research is to use the template of the current legal requirements and routine laboratory procedures to suggest reforms which will improve the analytical protocol and reporting of biochemical toxicology in the coronial system resulting in greater accuracy in delineating the causes of death The narrative of this thesis travels through the areas of the coroners acts especially in the Republic of Ireland and the United Kingdom where forensic biochemistry plays a role in the specification of the causes of deaths. There is a deconstruction of the place of doctors in the coronial system and in the new arrangements following the passage of the Coroners and Justice Act 2009 in England and Wales and the potential for change in the Coroners Bill in the Republic of Ireland which fell with the dissolution of the Dail in20ll. There is an examination of the autopsy guidelines issued by the RCPath and suggestions for change which have been published. There is an analysis of the place of cannabinoids in coroners ' cases and publications setting out the position are included. A series of recommendations are made regarding improvement in practice for the reporting of biochemical toxicology in the coronial system. Two cases where there appears to be potential misinterpretation of the toxicological evidence, which may result in the review of the causes of death, are detailed as relevant clinical examples. Some laboratory pitfalls in relation to alcohol analysis have been demonstrated and the consequences of a protocol free service have been detailed with a prescription for improvement and practical solutions to improve outcomes. The under-estimation of the impact of tobacco toxicity is also addressed as is the potential for error due to lack of appreciation of drug-drug interactions. The role of biochemistry in the post-mortem diagnosis of alcoholic and diabetic ketoacidosis is discussed. Multidisciplinary reviews of biochemical toxicology for the coroners' court are suggested as the best safeguard of accurate interpretation to assist coronial enquiry. Conclusions suggesting standard operating procedures for post-mortem scenarios are detailed where possible.

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5

Liu, Yandi. "A study of the biochemical development and toxicology of the seed of Santalum spicatum." Curtin University of Technology, School of Pharmacy, 1997. http://espace.library.curtin.edu.au:80/R/?func=dbin-jump-full&object_id=12031.

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Abstract:

The seed of Santalum spicatum is rich in a fixed oil (59% by weight), which is characterised by a high percentage of acetylenic, ethylenic ximenynic acid (35% of total fatty acids). A number of important aspects of the seed fixed oil, its composition in developing seeds, its triacylglycerols molecular species in the oil, the nutrition and toxicity of the oil feeding, and the possible bioactivity of ximenynic acid in mice were investigated.The identification of cis and trans isomers of ximenynic acid in the seed oil, and the metabolite of ximenynic acid in mouse liver lipid fractions were achieved using 2-amino-2-methyl-1-propanol to form 2-substituted 4,4-dimethyloxazoline derivatives, which were analysed by gas chromatography with mass spectrometric detection.Changes in proximate and fatty acid composition were investigated in developing seed collected weekly from about seven days after flowering to maturity. It was determined that moisture and carbohydrate contents decreased significantly during the development sequence, while fixed oil content increased from 0.3% to 50% (by weight) with seed development. A corresponding increase in the proportions of both oleic and ximenynic acids occurred suggesting a precursor/product relationship. Mature seed collected from different locations in Western Australia showed minor differences in characteristics and lipid composition, which may have been influenced by geographical origin and harvesting year of samples.The lipid components from the seed oil were separated using thin-layer chromatography and the individual triglyceride bands were characterised by high performance liquid chromatography and gas chromatography using flame ionisation and mass spectrometric detection after removal from the plate. The triximenynin (trisantalbin) band showed no other contaminating fatty acids and was obtained in a relatively pure state.A ++
nutrition and toxicity study was performed by feeding a semi-synthetic diet containing sandalwood seed oil to a level of 15% of total energy content to a group of mice for one month and another group for two months. The most significant effect of sandalwood seed oil ingestion when compared with a standard lab diet (5% fat, by weight) and a canola oil-enriched diet (15% fat, by weight) was an apparent reduction in body weight gain, which may be the effect of ximenynic acid as a growth retardant. Serum aspartate aminotransferase levels were determined in the mice as an indicator of hepatotoxicity. These levels were higher in mice fed the sandalwood seed oil diet than those fed the standard lab diet, suggesting that ximenynic acid may affect liver-specific enzyme activity. Analysis of the total lipid fatty acids of various tissues and organs of mice showed only a low incorporation of ximenynic acid into the general tissues (0.3-3% by weight), and its absence in the brain.This study suggests a few health benefits from consumption of large quantities of sandalwood seed oil in the diet. These include a low lipid content in blood, heart, muscle, increase in the 16:1/16:0 and 18:1/18:0 ratios, production of increased levels of 18:1 (n-9) and docosahexaenoic acid, and decreased levels of arachidonic acid in certain tissues. There were no specific pathological, morphological or mortality changes observed in the mice.Sandalwood seed may be both a food and a medicine.

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6

Dahl, Ulrika. "Integrating biochemical and growth responses in ecotoxicological assays with copepods." Doctoral thesis, Stockholm University, Department of Applied Environmental Science (ITM), 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8218.

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The understanding of effects of chemical exposure in nature is lagging behind. Predictions of harmful effects of chemicals on aquatic organisms rely mainly on ecotoxicity tests. To improve the understanding of the biological linkage between the cellular and organismal responses to a chemical in an ecotoxicological test, the major aim of this doctoral thesis was to investigate the usefulness of two biochemical endpoints, contents of RNA and ecdysteroids, by incorporating them with life-history traits of copepods (Crustacea). To do so, the two methods needed to be established at our laboratory. Both biochemical methods are more commonly used in basic biological research, but I here present its usefulness in ecotoxicological testing. It was found that individual RNA content as a biochemical endpoint was significantly altered in the brackish water harpacticoid copepod Nitocra spinipes when exposed to the pesticide Lindane (paper IV) and low concentrations (0.16

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7

Bazara, Salem Mohammed. "Biochemical studies on the toxicity and carcinogenicity of PCBs and related compounds." Thesis, Brunel University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235935.

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8

Shipp, Nancy Gillett. "Characterization of mitoxantrone cardiotoxicity in cultured heart cells." Diss., The University of Arizona, 1991. http://hdl.handle.net/10150/185453.

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The use of the anthracenedione mitoxantrone as an antitumor agent is steadily increasing. While the toxicities associated with its use are significantly less than those observed following treatment with the widely used doxorubicin, mitoxantrone cardiotoxicity is clearly a substantial clinical problem. Current information on the mechanism by which mitoxantrone causes toxicity in heart tissue is limited. Thus, the goal of these studies was to describe a model system in which mitoxantrone cardiotoxicity can be studied, and begin to describe the mechanism by which mitoxantrone exerts its cardiotoxic effect. These experiments have shown that cultured neonatal rat heart cells are an effective model system for studying mitoxantrone-induced cytotoxicity and biochemical changes in heart tissue. Cultured heart cells develop dose- and time-dependent toxicity following a short exposure to near-pharmacologically achievable drug concentrations. Furthermore, histologic changes characteristic of this drug are also observed at the light and electron microscopic level. Initial experiments aimed at defining mitoxantrone mechanism of action showed that mitoxantrone likely does not stimulate a significant production of active oxygen species, or have a specific effect on mitochondrial function. However, there is evidence to support the possibility that mitoxantrone can form a reactive intermediate in vitro. These studies have shown that covalent binding of mitoxantrone to proteins can occur under certain conditions. Mitoxantrone toxicity is lowered with the addition of ICRF-187, a metal chelating agent. Protection is not due to inactivation of mitoxantrone, decreased mitoxantrone uptake, or a delayed increase in cytosolic calcium. Similar protection is observed against doxorubicin and the oxidized form of mitoxantrone, but not against the non-hydroxylated analog of mitoxantrone, ametantrone. Furthermore, in a cell-free system, mitoxantrone can form complexes with both copper (II) and iron (III). Mitoxantrone metal binding is reversible as ICRF-187 as well as other chelators can remove the metals from these complexes. These data suggests that metal chelation is involved in the enhancement of mitoxantrone toxicity in vitro.

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9

Subhahar, Michael. "Pharmacokinetics and pharmacodynamics of some NSAIDs in horses : a pharmacological, biochemical and forensic study." Thesis, University of Central Lancashire, 2013. http://clok.uclan.ac.uk/9244/.

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Non-steroidal anti- inflammatory drugs (NSAIDs) have been in use for over 100 years to treat pain, exerting their analgesic effect by inhibiting prostaglandin (PG) synthesis via the COX pathway. Some of the NSAIDs have adverse side effects including ulceration of the stomach and cardiovascular events which are associated with bleeding. Search is still going on to find a safe NSAID. Two new coxib NSAIDs, namely celecoxib and etoricoxib have been developed and they exert marked beneficial effects in reducing pain in humans and other small animals with little or no side effects. No such study has been done on horses to see if they can tolerate the drug as an analgesic pain killer. This study was designed to investigate the effects of the two coxib NSAIDs, celecoxib and etoricoxib in six retired race horses to determine any adverse side effects of the drugs, the time course changes in their metabolism and elimination once administered orally in known physiological doses and the metabolites produced by each drug over time. The study employed well established clinical and biochemical techniques to measure blood-borne parameters and the metabolism of each drug. The results show that either etoricoxib or celecoxib had no adverse side effects on blood borne parameters and the stomach of the horses. Pharmacokinetic study following oral administration of 2 mg/kg b wt of either celecoxib or etoricoxib to the six race horses showed a Cmax of 1.15 ± 0.3 µg/ml, tmax, to be 4.09 ± 1.60 hr and a terminal half- life of 15.52 ± 1.99hr for celecoxib and a Cmax of 1.0± 0.09 µg/ml, tmax of 0.79 ± 0.1 hr and, terminal half- life of 11.51 ± 1.56 hr, respectively for etoricoxib. The results also show that each coxib is metabolized in the horse and both the parent drug and its metabolites are found in the urine, plasma and faeces. The results have also shown that even small traces of either drug or its metabolites can be measured in urine samples even 120 hours following oral administration. The main metabolites found in plasma, urine and faeces are hydroxyl celecoxib and carboxycelecoxib when celecoxib was administered orally to the 6 retired race horses. Similarly, hydroxymethyletoricoxib, carboxylic etoricoxib, hydroxymethyl-1-N-oxide metabolite of etoricoxib and hydroxymethyletoricoxib glucuronide were also found in plasma, urine and faeces following oral administration etoricoxib .to the animals. The results for either horse haeptocytes or camel liver show to some extend similar metabolites. In conclusion, the results show that both drugs have no adverse side effects in the horse and their metabolites are completely eliminated within 120 hours following oral administration.

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10

Linderoth, Maria. "Biochemical characterisation of landfill leachate toxicity in fish." Doctoral thesis, Stockholm : Department of Applied Environmental Science (ITM), Stockholm university, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-951.

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11

Webb, Diane. "Assessment of the health of the Swan-Canning river system using biochemical markers of exposure of fish." Thesis, Curtin University, 2005. http://hdl.handle.net/20.500.11937/62.

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Most environmental studies concerning the environmental health of the Swan- Canning River system have focussed on nutrient inputs from both rural and urban catchments that are the cause of algal blooms. On occasions these algal blooms have resulted in fish deaths attributed to oxygen starvation. Relatively few studies have examined whether non-nutrient contamination is affecting the health of the riverine environment. Those studies that have, have concentrated on measuring the levels of heavy metals, organochlorines, organophosphates, and hydrocarbons in the sediments and water of the river system, and in the flesh of the biota. However, chemical analysis often fails to detect chemicals of concern due to high laboratory detection limits. In addition, analysis of the body burden of contaminants within biota does not necessarily convey if exposure is inducing adverse effects at the individual or ecosystem levels. The use of biochemical markers as a tool for the assessment of the health of the Swan-Canning River system was examined under a collaborative research project with the Waters and Rivers Commission, established in response to the recognition of the paucity of information from chemical analyses. The present study focussed on the estuarine portion of the Swan-Canning River system, using the black bream (Acanthopagrus butcheri), an estuarine dependent fish species, as a biomonitoring tool. Prior to the commencement of this study it had been determined that the black bream was a suitable fish species for use as a biomonitoring tool when using mixed function oxygenase (MFO) activity induction under laboratory conditions.Biopsies taken from feral black bream collected from eight sites during the period 2000 to 2002 from the estuary confirmed that the use of MFO induction in this fish species as a biomarker of exposure to organic contaminants is a reliable biomarker. Fish gender was a confounding factor in the interpretation of MFO induction when using the enzyme ethoxyresorufin-O-deethylase (EROD) as EROD activity was suppressed in both pre- and post-spawning female black bream. No such suppression was identified when using the MFO enzyme ethoxycoumarin-O-deethylase (ECOD). However, due to differences in the pattern and intensity of the induction of EROD and ECOD activities it was concluded that ECOD activity was not a substitute for EROD activity to detect certain chemical as ECOD activity represents a different cytochrome P450 pattern to EROD activity. No spatial, seasonal or interannual differences in the level of the enzyme sorbitol dehydrogenase (SDH) in the blood of the black bream were measured indicating that the interpretation of MFO activity induction was not compromised by hepatocellular damage. This study has shown that the black bream in the Swan-Canning Estuary are exposed to, and are metabolising polycyclic aromatic hydrocarbons (PAHs), notwithstanding that the chemical analysis of the contaminant load of these substances in the estuarine waters is consistently below laboratory detection limits. In addition, biomarker responses such as ECOD activity indicate that various other organic pollutants are present and are being metabolised by the black bream.The measurement of biliary metabolites clearly show that, under winter conditions, the comprehensive drainage system of the Swan Coastal Plain contributes PAHs from pyrogenic sources such as burnt fuels into the estuary although the onset and intensity of rainfall events notably impacts on the volume of stormwater inflow. During the summer months, when freshwater flow is minimal, petrogenic sources of PAHs are dominant. Metabolic enzyme analysis points to the black bream being challenged in their aerobic capacities during summer, and that gill tissue was the most suitable tissue to evaluate the aerobic and anaerobic capacity of this fish species. Furthermore, there was a significant negative correlation between stress protein (hsp70) expression and DNA integrity in field-collected fish suggesting that the black bream within the estuary are highly stressed. No gradient of response in biomarker levels was identified in the Swan-Canning Estuary under either winter or summer conditions indicating there are multiple sources of inputs of potential pollutants along the length of the estuary. Stormwater and road runoff are the primary source of pollutant input into the estuary in the winter months, while summer biomarker levels, particularly PAH, appear to reflect the high usage of the estuary for recreational purposes and runoff from poorly irrigated parks and gardens. Significant rainfall events at any time of the year have the potential to adversely impact the biota of the estuary, particularly when these events result in a flush of water from the drains following long dry periods.The study shows that the black bream is a suitable fish species to use under field conditions to detect the presence of bioavailable non-nutrient contamination within the Swan-Canning Estuary. A suite of biomarkers in black bream have been tested seasonally and annually but only a small number of biomarkers have proven suitable for routine monitoring of the health of the Swan-Canning Estuary. This treatise concludes with several recommendations for further investigations into biomarkers of fish health for the purpose of increasing our understanding on the sources and type of contamination entering the estuary, and potential effects on the aquatic biota of the Swan-Canning River system. These recommendations include, but are not limited to: (1) the need to determine baseline levels for the different biomarkers investigated in this study, (2) the examination of the Moore River or the Warren River estuaries as potential reference sites for biomarker studies in the Swan- Canning Estuary, (3) the advantage of identifying a second estuarine-dependent indigenous fish as a biomonitoring tool, (4) the requirement for a targeted study aimed at clarifying the relationship between major drain discharges, biomarker levels and impacts on river biota, and (5) a study of estuarine waters utilising SPMDs be undertaken in tandem with biomarker analysis of field captured fish would be beneficial.

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12

Healy, Charles E. "Immunologic, Hematologic, and Endocrine Responses to Subacute and Subchronic Exposures to Graded, Subanesthetic Levels of Nitrous Oxide in CD-1 Mice." DigitalCommons@USU, 1989. https://digitalcommons.usu.edu/etd/4651.

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Nitrous oxide (N2O) oxidizes vitamin B12. disrupting deoxyribonucleic acid (DNA) synthesis. Occupational exposures to subanesthetic levels of the gas have been documented that may result in suppressed proliferative cell activities. Male CD-I mice were exposed to 0, 50, 500, and 5000 parts of N2O per million parts of air (ppm) for 6 hr/day, 5 days/week for 2 and 13 weeks. Splenic lymphocytes were assayed for responsiveness to mitogens and for the ability to produce interleukin-2 (lL-2) . Tritiated-thymidine ([3H]-TdR) uptake was measured in CD-I splenic lymphocytes cultured in a mixed-lymphocyte culture (MLC). Cytolytic cell activity was measured by 51chromium release assay. Antibody-mediated immunocompetency was determined for sheep red blood cell (SRBC)-sensitized animals by plaque-forming cell (PFC) assay and sera anti-SRBC antibody titer. Deoxyuridine suppression tests (dUdRST) were performed on bone marrow cells. Serum adrenocorticotropic hormone and corticosterone levels were determined. There was significantly decreased splenic lymphocyte uptake of [3H)-TdR by cells cultured with mitogenic substances and in MLC following 2-week animal exposures to 5000 ppm. After 13-week exposures, the animals' splenic lymphocytes showed decreased [3H]-TdR uptake following low N20 dosing and nonsignificantly increased responsiveness at the higher gas exposures in both the blastogenic and MLC assays. Compared to control animals, the 5000- ppm-exposure group had significantly depressed PFC activity and circulating anti-SRBC immunoglobulin M levels following 13-week gas exposures, and all three subchronic exposure groups demonstrated both decreased liver weights and leukopenia. Bone marrow activity at these dosing levels was dose-responsively depressed following subchronic gas exposures.No hormonal effect appears to be attributable to N20 exposure.

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13

Tian, Lei. "BIOCHEMICAL CHARACTERIZATION OF HUMAN MISMATCH RECOGNITION PROTEINS MUTSα AND MUTSβ." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_diss/43.

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The integrity of an organism's genome depends on the fidelity of DNA replication and the efficiency of DNA repair. The DNA mismatch repair (MMR) system, which is highly conserved from prokaryotes to eukaryotes, plays an important role in maintaining genome stability by correcting base-base mismatches and insertion/deletion (ID) mispairs generated during DNA replication and other DNA transactions. Mismatch recognition is a critical step in MMR. Two mismatch recognition proteins, MutSα (MSH2-MSH6 heterodimer) and MutSβ (MSH2-MSH3 heterodimer), have been identified in eukaryotic cells. MutSα and MutSβ have partially overlapping functions, with MutSα recognizing primarily base-base mismatches and 1-2 nt ID mispairs and MutSβ recognizing 2-16-nt ID heteroduplexes. The goal of this dissertation research was to understand the mechanism underlying differential mismatch recognition by human MutSα and MutSβ and to characterize the unique functions of human MutSα and MutSβ in MMR. In this study, recombinant human MutSα and MutSβ were purified. Binding of the proteins to a T-G mispair and a 2-nt ID mispair was analyzed by gel-mobility assay; ATP/ADP binding was characterized using a UV cross-linking assay; ATPase activity was measured using an ATPase assay; MutSα amd MutSβ’s mismatch repair activity was evaluated using a reconstituted in vitro MMR assay. Our studies revealed that the preferential processing of base-base and ID heteroduplexes by MutSα and MutSβ respectively, is determined by the significant differences in the ATPase and ADP binding activities of MutSα and MutSβ, and the high ratio of MutSα:MutSβ in human cells. Our studies also demonstrated that MutSβ interacts similarly with a (CAG)n hairpin and a mismatch, and that excess MutSβ does not inhibit (CAG)n hairpin repair in vitro. These studies provide insight into the determinants of the differential DNA repair specificity of MutSα and MutSβ, the mechanism of mismatch repair initiation, and the mechanism of (CAG)n hairpin processing and repair, which plays a role in the etiology and progression of several human neurological diseases.

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14

Webb, Diane. "Assessment of the health of the Swan-Canning river system using biochemical markers of exposure of fish." Curtin University of Technology, Department of Environmental Biology, 2005. http://espace.library.curtin.edu.au:80/R/?func=dbin-jump-full&object_id=16725.

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Most environmental studies concerning the environmental health of the Swan- Canning River system have focussed on nutrient inputs from both rural and urban catchments that are the cause of algal blooms. On occasions these algal blooms have resulted in fish deaths attributed to oxygen starvation. Relatively few studies have examined whether non-nutrient contamination is affecting the health of the riverine environment. Those studies that have, have concentrated on measuring the levels of heavy metals, organochlorines, organophosphates, and hydrocarbons in the sediments and water of the river system, and in the flesh of the biota. However, chemical analysis often fails to detect chemicals of concern due to high laboratory detection limits. In addition, analysis of the body burden of contaminants within biota does not necessarily convey if exposure is inducing adverse effects at the individual or ecosystem levels. The use of biochemical markers as a tool for the assessment of the health of the Swan-Canning River system was examined under a collaborative research project with the Waters and Rivers Commission, established in response to the recognition of the paucity of information from chemical analyses. The present study focussed on the estuarine portion of the Swan-Canning River system, using the black bream (Acanthopagrus butcheri), an estuarine dependent fish species, as a biomonitoring tool. Prior to the commencement of this study it had been determined that the black bream was a suitable fish species for use as a biomonitoring tool when using mixed function oxygenase (MFO) activity induction under laboratory conditions.
Biopsies taken from feral black bream collected from eight sites during the period 2000 to 2002 from the estuary confirmed that the use of MFO induction in this fish species as a biomarker of exposure to organic contaminants is a reliable biomarker. Fish gender was a confounding factor in the interpretation of MFO induction when using the enzyme ethoxyresorufin-O-deethylase (EROD) as EROD activity was suppressed in both pre- and post-spawning female black bream. No such suppression was identified when using the MFO enzyme ethoxycoumarin-O-deethylase (ECOD). However, due to differences in the pattern and intensity of the induction of EROD and ECOD activities it was concluded that ECOD activity was not a substitute for EROD activity to detect certain chemical as ECOD activity represents a different cytochrome P450 pattern to EROD activity. No spatial, seasonal or interannual differences in the level of the enzyme sorbitol dehydrogenase (SDH) in the blood of the black bream were measured indicating that the interpretation of MFO activity induction was not compromised by hepatocellular damage. This study has shown that the black bream in the Swan-Canning Estuary are exposed to, and are metabolising polycyclic aromatic hydrocarbons (PAHs), notwithstanding that the chemical analysis of the contaminant load of these substances in the estuarine waters is consistently below laboratory detection limits. In addition, biomarker responses such as ECOD activity indicate that various other organic pollutants are present and are being metabolised by the black bream.
The measurement of biliary metabolites clearly show that, under winter conditions, the comprehensive drainage system of the Swan Coastal Plain contributes PAHs from pyrogenic sources such as burnt fuels into the estuary although the onset and intensity of rainfall events notably impacts on the volume of stormwater inflow. During the summer months, when freshwater flow is minimal, petrogenic sources of PAHs are dominant. Metabolic enzyme analysis points to the black bream being challenged in their aerobic capacities during summer, and that gill tissue was the most suitable tissue to evaluate the aerobic and anaerobic capacity of this fish species. Furthermore, there was a significant negative correlation between stress protein (hsp70) expression and DNA integrity in field-collected fish suggesting that the black bream within the estuary are highly stressed. No gradient of response in biomarker levels was identified in the Swan-Canning Estuary under either winter or summer conditions indicating there are multiple sources of inputs of potential pollutants along the length of the estuary. Stormwater and road runoff are the primary source of pollutant input into the estuary in the winter months, while summer biomarker levels, particularly PAH, appear to reflect the high usage of the estuary for recreational purposes and runoff from poorly irrigated parks and gardens. Significant rainfall events at any time of the year have the potential to adversely impact the biota of the estuary, particularly when these events result in a flush of water from the drains following long dry periods.
The study shows that the black bream is a suitable fish species to use under field conditions to detect the presence of bioavailable non-nutrient contamination within the Swan-Canning Estuary. A suite of biomarkers in black bream have been tested seasonally and annually but only a small number of biomarkers have proven suitable for routine monitoring of the health of the Swan-Canning Estuary. This treatise concludes with several recommendations for further investigations into biomarkers of fish health for the purpose of increasing our understanding on the sources and type of contamination entering the estuary, and potential effects on the aquatic biota of the Swan-Canning River system. These recommendations include, but are not limited to: (1) the need to determine baseline levels for the different biomarkers investigated in this study, (2) the examination of the Moore River or the Warren River estuaries as potential reference sites for biomarker studies in the Swan- Canning Estuary, (3) the advantage of identifying a second estuarine-dependent indigenous fish as a biomonitoring tool, (4) the requirement for a targeted study aimed at clarifying the relationship between major drain discharges, biomarker levels and impacts on river biota, and (5) a study of estuarine waters utilising SPMDs be undertaken in tandem with biomarker analysis of field captured fish would be beneficial.

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15

Nair, Madhavan Nair Gopalakrishnan. "Comparison of the biochemical and pathological effects of aflatoxin Bâ†1 and fumonisin Bâ†1 in mice and assessment of chemoprotective effect of oltipraz." Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307616.

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16

Ethridge, Victoria Taryn. "Measuring Acute Effects of Aluminum Chloride Exposures on the Adult Male Rat Hippocampus Using Neuro-electrophysiology and Biochemical Assays." Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1560168124743024.

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Arnolds, Judith Lize. "Oxidative stress responses in the aquatic macrophyte, Ceratophyllum Demersum L., as biomarkers of metal exposure." Thesis, Cape Peninsula University of Technology, 2017. http://hdl.handle.net/20.500.11838/2649.

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Thesis (DTech (Environmental Health))--Cape Peninsula University of Technology, 2017.
Metal pollution in aquatic environments is considered a major environmental concern because of variation in several abiotic factors that impose severe restrictions on organisms living in these areas. Ceratophyllum demersum L. (family Ceratophyllaceae), a hornwort or coontail, free floating rootless macrophyte has been suggested a suitable model for investigating metal stress and was used in the current study. This study assessed the use of selected biological responses, namely antioxidant responses and changes in chlorophyll concentration in Ceratophyllum demersum L., as biomarkers of metal exposure, and also investigated the field application of these responses in the Diep River. The ultimate aim was also to determine the usefulness of C. demersum as model of metal contamination and as phytoremediator after a pollution event. An investigation of metal bioaccumulation in this macrophyte exposed to different concentrations of a combination of metals over a five-week exposure period in a greenhouse, was undertaken, as well as a field study in the Diep River, Milnerton, Cape Town and a pond (reference site) at the Cape Peninsula University of Technology, Cape Town, to validate experimental results. In the laboratory study the water was contaminated once off at the beginning of the study, to simulate a pollution event. The metal concentrations in the water and plants were measured in the four treatments and the control every week over a five-week exposure period. The samples were acid-digested and analysed with an Inductively-Coupled Plasma-Mass Spectrophotometer (ICP-MS). The results showed that concentrations of the metals in the water varied in all treatments over time with no specific patterns amongst the treatment groups. This macrophyte proved highly effective in the bioaccumulation of these metals at all four exposure concentrations. The metals bioaccumulated rapidly in the plants after the water was spiked. The main focus of the study was to investigate the possible use of biochemical responses in C. demersum as possible biomarkers for metal exposure. A range of antioxidant/oxidative stress parameters were measured in the plant exposed to a combination of metals (Al, Cu, Fe, Zn) in four different treatments over the five week exposure period. Total antioxidant capacity (TAC) was measured using Total Polyphenols (TP), Ferric Reducing Antioxidant Power (FRAP) and Oxygen Radical Absorbance Capacity assay (ORAC), enzyme activity was determined using Catalase (CAT), Superoxide Dismutase (SOD), Ascorbate Acid (AsA) and Total Glutathione (GSHt) and lipid peroxidation was measured by using Thiobarbituric Acid Reactive Substances (TBARS) and Conjugated Dienes (CDs). The cocktail of the four metals induced significant changes in the antioxidant defence system of C. demersum, including the antioxidant enzyme activities. The different metal exposures disturbed the cellular redox status in the plant. The current study has demonstrated that this macrophyte shows tolerance to metal-induced oxidative stress and that it can survive under relatively high concentrations of these metals by adapting its antioxidant defence strategies. Chlorophyll was extracted in 80% chilled acetone in the dark and the absorbance values were determined using a spectrophotometer. Chlorophyll a (chl a), chlorophyll b (chl b) and total chlorophyll (chl t) contents were measured under different exposure concentrations of metals in the macrophyte. The results of this study indicated that chlorophyll contents were variable over the exposure period and no significant differences in chlorophyll concentrations were found between weeks. A field study in the Diep River and the pond located at the CPUT campus (reference site) was conducted to validate experimental results. Plants in a polluted section of the Diep River were shown to bioaccumulate metals to high concentrations. Bioaccumulation of metals in C. demersum might have induced oxidative stress, and other environmental factors such as temperature- and chemical stress might have caused chlorophyll degradation. The chlorophyll concentrations in the plants of the pond (reference site) might also have been affected by temperature and chemical stress of the water. Significantly higher AsA, CAT, ORAC, SOD and TBARS concentrations in the Diep River plants might be an indication that the plants in the river might be well adapted to the constant exposure to metals and that the plants might have developed a tolerance mechanism to cope with oxidative stress compared to those of the pond. The results show that metals are bioaccumulated quickly by C. demersum after the water is contaminated with metals, i.e. after the "pollution event". However, over time, metals are continuously exchanged between the plants and the water, accounting for the fluctuations in metal concentrations observed over time. This study has shown that C. demersum has phytoremediation potential because it was able to remove high concentrations of metals from the contaminated water. Therefore, C. demersum, can be applied as a model for metal contamination and a phytoremediator after a pollution event. The potential to antioxidant responses and chlorophyll content as biomarkers of metal exposure in C. demersum have been demonstrated.

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Cregger, S. S., and Phillip R. Scheuerman. "A Rapid Biochemical Test Using Cell Lines for Measuring Chemical Toxicity in Aquatic Systems." Digital Commons @ East Tennessee State University, 1993. https://dc.etsu.edu/etsu-works/2896.

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19

Lin, Shuhai. "Mass spectrometry-based metabolomics delineates biochemical changes in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity, high-fructose diet effect, Alzheimer's disease and viral infection." HKBU Institutional Repository, 2011. http://repository.hkbu.edu.hk/etd_ra/1248.

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20

Bermúdez, Mei-Ling. "Carnosine as a Mechanism-based Intervention in the Thy1-aSyn Mouse Model of Parkinson’s Disease: Neurobehavioral, Biochemical, and Bioinformatic Analyses." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543839362404126.

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21

Holloway, Jennifer C. "Investigation of white blood cell phagocytosis as a potential bio-marker of mercury immunotoxicity in birds." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33002.

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White blood cell phagocytosis was investigated and used with avian blood, and assessed as a potential biomarker for mercury immunotoxicity in free ranging birds (common loons). Phagocytosis is an essential immunological function and can be measured using flow cytometry. The assay was assessed with in vitro exposure using whole blood and isolated white blood cells (WBC) from domestic chickens, and with in vivo exposure using whole blood from captive doves and wild loons. McHg at 0.1ppm significantly depressed phagocytic capacity of isolated WBCs without affecting their viability, but did not affect phagocytic activity when added to whole blood up to 50ppm. Also, no significant relationship between blood-Hg level and phagocytic capacity of WBCs was observed in ringed turtle doves fed McHg in their diets, nor in wild common loons having a range of blood-Hg concentrations. The phagocytosis assay is a convenient assay for use in field studies of free-living birds, but is not responsive to McHg exposure in birds, and so is not recommended as a biomarker of immunotoxicity in Hg-exposed loons.

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Hoffman, Jessie Baldwin. "PCB DISRUPTION OF GUT AND HOST HEALTH: IMPLICATIONS OF PREBIOTIC NUTRITIONAL INTERVENTION." UKnowledge, 2018. https://uknowledge.uky.edu/pharmacol_etds/25.

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Exposure to environmental pollutants poses numerous risk factors for human health, including increasing incidence of cardiovascular disease and diabetes. Persistent organic pollutants, such as polychlorinated biphenyls (PCBs) have been strongly linked to the development of these chronic inflammatory diseases and the primary route of exposure is through consumption of contaminated food products. Thus, the gastrointestinal tract is susceptible to the greatest levels of these pollutants and is an important facet to study. The first two hypotheses of this dissertation tested that exposure to PCBs disrupts gut microbiota directly (in vitro) and within a whole body system. PCB exposure disrupted microbial metabolism and production of metabolites (i.e. short chain fatty acids) in vitro. These disruptions in microbial populations were consistent in our mouse model of cardiometabolic disease, where we observed reductions in microbial diversity, an increase in the putative pro-inflammatory ratio of Firmicutes to Bacteroidetes, and reductions in beneficial microbial populations in exposed mice. Furthermore, observed greater inflammation was observed both within the intestines and peripherally in PCB exposed mice as well as disruptions in circulating markers associated with glucose homeostasis. Nutritional interventions high in prebiotic dietary fiber such as inulin may be able to attenuate the toxic effects of pollutant exposure. To test the hypothesis that consumption of the prebiotic inulin can decrease PCB-induced disruption in gut microbial and metabolic homeostasis, LDLr-\- mice were fed a diet containing inulin and exposed to PCB 126. Mice fed an inulin-containing diet and exposed to PCBs exhibited improved glucose tolerance, lower hepatic inflammation and steatosis, and distinct differences in gut microbial populations. Overall, these data suggests that nutritional intervention, specifically prebiotic consumption, may reduce pollutant-induced disease risk.

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Nair, Manoj Sadasivan. "Mechanism of Action of Insecticidal Crystal Toxins from Bacillus thuringiensis: Biophysical and Biochemical Analyses of the Insertion of Cry1A Toxins into Insect Midgut Membranes." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1218558470.

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24

Miller, Lana L., and University of Lethbridge Faculty of Arts and Science. "Species differences in selenium toxicity : linking cellular responses to population effects." Thesis, Lethbridge, Alta. : University of Lethbridge, Dept. of Biological Sciences, c2011, 2011. http://hdl.handle.net/10133/2622.

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Model organisms are often used in ecotoxicological studies and environmental risk assessments; however, species differences in responses to toxicants exist. A meta-analysis identified normal biomarker ranges for rainbow trout (RT) and brook trout (BT), and showed that RT had greater whole-body lipids and plasma T4 levels than BT. Exposure to selenium inhibited cortisol secretion of trout adrenocortical cells; however, RT were more sensitive than BT. To investigate species vulnerability at the individual level, RT and BT were stocked into reference and selenium-contaminated pit lakes. Fish accumulated more Se from selenium-contaminated than reference lakes, and selenium accumulation was similar between species. Chronic selenium exposure had a greater energetic cost for RT than BT, but this was mitigated by food availability. Chronic selenium exposure decreased plasma T3 and T4 levels, but did not alter other endocrine or oxidative stress biomarkers. This project highlights the need for both species- and site-specific risk assessments.
xiv, 171 leaves : ill., maps ; 29 cm

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25

Sanchez, Chardi Alejandro. "La musaranya comuna, Crocidura russula (Hermann, 1780), com a bioindicador en estudis ecotoxicologics." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/129847.

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En aquesta memòria de tesi es detalla la quantificació de biomarcadors d’exposició (acumulació de Pb, Hg, Cd, Tl, Fe, Mg, Zn, Cu, Mn, Mo, Co, Ni, Cr, Sr, Ba i B a teixits tous i durs) i d’efecte (morfometria, hematologia, activitat enzimàtica, genotoxicitat i histopatologia) en un total de 243 exemplars de musaranya comuna, Crocidura russula (Hermann, 1780). En el present estudi, es va tenir en compte la importància de l’edat i el sexe en els paràmetres quantificats ja que són dos factors biòtics que expliquen part de la variabilitat observada. Les zones d’estudi van ser 4 zones contaminades i 4 zones de referència triades per la seva importància tant mediambiental (6 de les 8 zones estudiades tenen estatus de protecció parcial o total) com d’interès per la societat: l’abocador de Garraf, el més gran de la península Ibèrica, la mina abandonada d’Aljustrel a la zona portuguesa de la faixa piritosa ibèrica, el Parc Nacional de Doñana afectat pel vessament de la mina de pirita d’Aznalcóllar, situada a la part espanyola de la faixa piritosa ibèrica i el Delta de l’Ebre afectat diverses activitats humanes incloent caça, industria i residus domèstics. Dels exemplars analitzats, 138 van ser capturats pròpiament per estudis ecotoxicològics a 3 de les zones contaminades (Garraf, Aljustrel i Doñana) i 105 eren mostres de col•lecció procedents d’altres estudis ecològics (Delta de l’Ebre). Especialment en les zones contaminades estudiades, es van observar marcades diferències en la bioacumulació entre elements essencials i no essencials per diferències en biodisponibilitat, toxicitat, i capacitat de transferència i biomagnificació al llarg de les cadenes tròfiques entre ambdós grups d'elements. Els majors augments detectats als teixits de les musaranyes de les zones contaminades es van donar entre els metalls pesants no essencials (Pb, Cd, Hg, Tl i Ni), els nivells tissulars dels quals no estan metabòlicament regulats a mamífers, donant com a resultat alts increments a teixits durs i tous quan augmenta la biodisponibilitat al medi ambient. Dels elements quantificats només Pb, Hg, Cd, i, possiblement Tl, Ni, B, Ba i Sr, van acumular-se fins a nivells que poden ser tòxics en mamífers. Ja que hi ha escassa informació sobre com afecta l’exposició crònica a les poblacions naturals d’insectívors, les dades conjuntes dels biomarcadors d’efecte obtingudes serveixen com valors de referència per a l’espècie i poden contribuir a estimar els efectes tòxics sobre els organismes. Es van detectar disminucions en la massa corporal i l'activitat de GST, i increments de massa i patologies atribuïbles a la contaminació a fetge i ronyó i freqüència de micronuclis en les musaranyes de les zones contaminades. Dels dos factors biòtics estudiats, l'edat va ser el més important ja que 10 dels elements, amb especial rellevància en el cas del Cd, van presentar patrons d’acumulació diferencials entre joves i adults. Per contra, mascles i femelles de musaranya comuna només van presentar petites diferències en l'acumulació de Pb, Hg, Ni, Mo, Mn, Co i Fe. Com amb els marcadors d’exposició, la rellevància de edat en els biomarcadors d’efecte va ser també major que la del sexe per explicar la variabilitat observada. L’ús de diversos biomarcadors d’exposició d’efecte permeten d’una banda obtenir una millor idea del conjunt d'efectes tòxics de la contaminació sobre el normal desenvolupament dels sistemes biològics, així com indiquen la idoneïtat de la musaranya comuna com a bioindicador de contaminació ambiental especialment per l’avaluació de risc ambiental a zones protegides i per les poblacions humanes.
In this report, a quantification of biomarkers of exposition (accumulation of Pb, Hg, Cd, Tl, Fe, Mg, Zn, Cu, Mn, Mo, Co, Ni, Cr, Sr, Ba and B in soft and hard tissues) and effect (morfometry, haematology, enzymatic activity, genotoxicity and histopathology) in a total of 243 specimens of the greater white-toothed shrew, Crocidura russula (Hermann, 1780) was found. In the present study, the age- and sex-dependent variations were also considered in order to explain the variability due to these important biotic factors. The study sites were 4 polluted sites and 4 reference sites selected both for their environmental relevance (6 out the 8 sites have granted partial or total protection status) and for the interest for the society: the landfill of Garraf, the bigger dump site in the Iberian Peninsula; the abandoned mine of Aljustrel in the Portuguese part of the Iberian Pyrite Belt (IPB); the National Park of Doñana affected by the wastes of the mine of Aznalcóllar, sited in the Spanish part of the IPB; and the Ebro Delta disturbed during decades by several human activities including hunting, industries and domestic wastes. A total of 138 shrews were captured for ecotoxicological studies in 3 polluted sites (Garraf, Aljustrel, and Doñana) and 105 specimens were captured for other ecological studies and stored in a zoological collection (Ebro Delta). Especially in the polluted sites studied, there were marked differences between the bioaccumulation patterns of essential and non-essential elements due to differences in the bioavailability, toxicity, and transfer and bioaccumulation throughout the food chains between the two groups of elements. The highest increases in the tissues of shrews from the polluted sites were on non-essential heavy metals (Pb, Cd, Hg, Tl, and Ni), without metabolic regulation of tissular levels in mammals that ends in high burdens in soft and hard tissues when bioavailability increase in the environment. Among elements quantified, only Pb, Hg, Cd, and, probably Tl, Ni, B, Ba and Sr, were accumulated till levels that may produce toxic effects in mammals. The scarce information of the effects of chronic exposure in natural populations of insectivores render more relevant the use of a battery of biomarkers of effect, that serve as reference values for the species and as assessment of toxic effects in organism. Decreases of body mass and GST activity and increases of mass and pathologies attributable to pollution in liver and kidneys were detected in shrews from the polluted sites. Among biotic factors, age was important because 10 of the elements quantified, with special remark on Cd, showed differential bioaccumulation patterns in juveniles and adults. In contrast, only slight differences in bioaccumulation of Pb, Hg, Ni, Mo, Mn, Co, and Fe were found between males and females. The same pattern of importance of age and sex as in the biomarker of exposure was found in the biomarkers of effect. The use of several biomarkers of exposure and effect provide information of the whole toxic effects of pollution in the normal function of biological systems and point out C. russula as a suitable bioindicator of environmental pollution, specially to evaluate environmental risk both in protected sites and human populations.

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Larian, Nika. "PYOCYANIN, A VIRULENCE FACTOR PRODUCED BY SEPSIS-CAUSING PSEUDOMONAS AERUGINOSA, PROMOTES ADIPOSE WASTING AND CACHEXIA." UKnowledge, 2019. https://uknowledge.uky.edu/pharmacol_etds/31.

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Sepsis is a leading cause of death among critically ill patients that results in metabolic alterations including hypercatabolism, lipoatrophy, and muscle wasting, contributing to the development of cachexia. Septic cachexia is associated with loss of body weight, fat mass, and lean mass and dysregulated immune function. There are currently no efficacious treatment strategies for septic cachexia, and nutritional interventions have limited success in preventing hypercatabolic wasting. Pyocyanin is a virulence factor produced by sepsis-causing Pseudomonas aeruginosa that has been shown to activate the aryl hydrocarbon receptor (AhR), increase inflammation, and produce reactive oxygen species. Thus, pyocyanin represents a novel mechanistic target in the development of septic cachexia. In Aim 1, we hypothesized that pyocyanin reduces adipocyte differentiation and activates AhR in vitro and in vivo. In vitro, pyocyanin reduced differentiation of 3T3-L1 cells to adipocytes and promoted expression of proinflammatory cytokines. These effects were associated with activation of AhR. We established an in vivo model of pyocyanin-induced cachexia using repeat intraperitoneal exposure to pyocyanin in male and female C57BL/6J mice. Acutely, pyocyanin reduced differentiation of stem cells isolated from adipose stromal vascular tissue and augmented expression of proinflammatory cytokines. Chronically, pyocyanin reduced body weight and fat mass, which was associated with adipose-specific AhR activation. Pyocyanin had sexually dimorphic effects on lipolysis and adipocyte inflammation. These data suggest a role of pyocyanin in adipose cachexia associated with sepsis. In Aim 2, we hypothesized that pyocyanin activates adipocyte AhR to promote adipose tissue wasting and cachexia. To test this hypothesis, we used a mouse model of adipocyte-specific deficiency of AhR and chronically administered pyocyanin to male and female mice. In male mice with adipocyte AhR deficiency, effects of pyocyanin to promote adipose wasting and cachexia were attenuated. In contrast, female adipocyte AhR deficient mice had an augmented response to pyocyanin to decrease body weight. Results suggest divergent mechanisms of pyocyanin to regulate adiposity and body weight through adipocyte AhR between male and female mice. These data support a role for pyocyanin in the development of adipose cachexia associated with Pseudomonas aeruginosa sepsis that is partially regulated by adipocyte AhR. Targeting pyocyanin’s effects on adipocytes represents a potentially novel therapeutic approach for septic cachexia that could mitigate septic cachexia, a condition associated with increased risk of mortality in this population.

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27

Helsley, Robert N. "THE ROLE OF PXR AND IKKβ SIGNALING IN CARDIOMETABOLIC DISEASE." UKnowledge, 2016. http://uknowledge.uky.edu/pharmacol_etds/14.

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Cardiovascular disease (CVD) is the leading cause of death worldwide and is partially attributed to perturbations in lipid metabolism. Xenobiotics, such as pharmaceutical drugs and environmental chemicals, have been associated with increased risk of CVD in multiple large-scale human population studies, but the underlying mechanisms remain poorly defined. We and others have identified several xenobiotics as potent agonists for the pregnane X receptor (PXR), a nuclear receptor that can be activated by numerous drugs as well as environmental and dietary chemicals. However, the role of PXR in mediating the pathophysiological effects of xenobiotic exposure in humans and animals remains elusive. The work herein identified several widely used pharmaceutical agents and endocrine disrupting chemicals as PXR-selective agonists such as drugs involved in HIV therapy and phthalates/phthalate substitutes, respectively. We investigated the role of amprenavir, an HIV protease inhibitor, and tributyl citrate, a phthalate substitute, on PXR-dependent alterations in lipoprotein metabolism. Acute exposure with either xenobiotic in mice elicited increases in the proatherogenic LDL-cholesterol levels in a PXR-dependent manner. PXR activation significantly induced expression of genes involved in intestinal lipid metabolism. Further, we went on to identify the intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), as a direct PXR-target gene. PXR activation also stimulated cholesterol uptake in both murine and human intestinal cells. Moreover, we provide evidence that the microsomal triglyceride transfer protein (MTP) may be a direct PXR-target gene. Taken together, these findings provide critical mechanistic insight into the role of xenobiotic-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating adverse effects of xenobiotics on CVD risk in humans. In addition to PXR signaling, we investigated the role of IκB kinase β (IKKβ), a central coordinator of inflammation, in adipocyte progenitor cells. Targeting IKKβ in adipose progenitor cells resulted in decreased high fat diet (HFD)-elicited adipogenesis, while protecting mice from inflammation and associated insulin resistance. Consistently, we discovered that IKKβ inhibition by antisense oligonucleotides ablated HFD-induced adiposity, while protecting mice against associated metabolic disorders. In conclusion, targeting IKKβ with antisense therapy may present as a novel therapeutic approach to combat obesity and metabolic dysfunctions.

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28

Vallaster, Markus Parzival. "Intergenerational Effects of Nicotine in an Animal Model of Paternal Nicotine Exposure." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/913.

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Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends on short-term environmental challenges with low doses of nicotine prior to the LD50 application. The observed survival phenotype is not restricted to nicotine as drug of abuse, but also presents itself, when NIC offspring is challenged with a cocaine LD50 after acclimatization to low doses of either nicotine or cocaine. Functionally, NIC offspring metabolizes nicotine faster than control. Mechanistically, NIC offspring livers show global up-regulation of xenobiotic processing genes (XPG), an effect that is even more pronounced in primary hepatocyte cultures. Being known targets of Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR), these XPGs show higher baseline expression in naïve NIC offspring livers. Nicotine’s action on the brain’s reward circuitry does not appear to be of biological significance in our model system. Taken together, paternal nicotine exposure leads to a non-specific and conditional phenotype in male NIC offspring that may provide a general survival advantage against xenobiotic challenges.

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29

Vallaster, Markus Parzival. "Intergenerational Effects of Nicotine in an Animal Model of Paternal Nicotine Exposure." eScholarship@UMMS, 2008. http://escholarship.umassmed.edu/gsbs_diss/913.

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Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends on short-term environmental challenges with low doses of nicotine prior to the LD50 application. The observed survival phenotype is not restricted to nicotine as drug of abuse, but also presents itself, when NIC offspring is challenged with a cocaine LD50 after acclimatization to low doses of either nicotine or cocaine. Functionally, NIC offspring metabolizes nicotine faster than control. Mechanistically, NIC offspring livers show global up-regulation of xenobiotic processing genes (XPG), an effect that is even more pronounced in primary hepatocyte cultures. Being known targets of Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR), these XPGs show higher baseline expression in naïve NIC offspring livers. Nicotine’s action on the brain’s reward circuitry does not appear to be of biological significance in our model system. Taken together, paternal nicotine exposure leads to a non-specific and conditional phenotype in male NIC offspring that may provide a general survival advantage against xenobiotic challenges.

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30

Newsome, Bradley J. "Addressing Public Health Risks of Persistent Pollutants Through Nutritional Modulation and Biomimetic Nanocomposite Remediation Platforms." UKnowledge, 2014. http://uknowledge.uky.edu/chemistry_etds/38.

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Due to their relative chemical stability and ubiquity in the environment, chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) pose significant health risks and enduring remediation challenges. Engineered nanoparticles (NPs) provide a novel platform for sensing/remediation of these toxicants, in addition to the growing use of NPs in many industrial and biomedical applications, but there remains concern for their potential long-term health effects. Research highlighted herein also represents a transdisciplinary approach to address human health challenges associated with exposure to PCBs and NPs. The objectives of this dissertation research are two-fold, 1) to develop effective methods for capture/sensing and remediation of environmental toxicants, and 2) to better understand associated risks and to elucidate relevant protective mechanisms, such as lifestyle-related modulators of environmental disease. Prevalent engineered nanoparticles, including aluminum oxide and titanium dioxide, have been studied to better understand effective nanoparticle dispersion methods for in vitro nanotoxicology studies. This work has served both to effectively stabilize these nanoparticles under physiological conditions and to better understand the associated mechanisms of toxicity, which links these metal nanoparticles to endothelial oxidative stress and inflammation through phosphorylation of key cellular signaling molecules and increased DNA binding of pro-inflammatory NFκB. Surface functionalization, though, is being found to limit potential toxicity and has been utilized in subsequent research. A novel polyphenol-functionalized, NP-based system has been developed which combines the biomimetic binding capabilities of nutrient polyphenols with the separation and heating capabilities of superparamagnetic iron oxide NPs for the capture/sensing of organic contaminants in polluted water sources. Magnetic nanocomposite microparticles (MNMs) incorporating the fluorescent polyphenols quercetin and curcumin exhibit high affinity for model organic pollutants followed by rapid magnetic separation, addressing the need for sustainable pollutant remediation. Further work has been performed to both better understand health concerns associated with environmental toxicants such as PCBs and to determine effective methods for modulating their toxicity. This research has shown that PCB remediation through dechlorination is a viable technique for decreasing endothelial inflammation, although complete dechlorination to biphenyl is necessary to effectively eliminate superoxide production, NFκB activation, and induction of inflammatory markers. Additionally, the nutrient polyphenol EGCG, found in green tea, has been shown to serve as a biomedical modulator of in vivo PCB toxicity by up-regulating a battery of antioxidant enzymes transcriptionally controlled by AhR and Nrf2 proteins.

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Sampaio, Mariana Neiva. "The role of personality in fish response to Carbamazepine: from biochemical responses to learning." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22022.

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Mestrado em Biologia Molecular e Celular
A personalidade animal está ligada aos processos fisiológicos e bioquímicos do organismo. É definida como um conjunto individual de padrões comportamentais que se mantêm ao longo de um determinado período de vida. Estudos recentes mostraram a capacidade de muitos compostos, incluindo fármacos, interferirem no comportamento e em traços da personalidade. No entanto, o conhecimento sobre este fenómeno é ainda limitado. Sabendo-se que os fármacos podem interferir na personalidade, coloca-se a questão: qual será o papel da personalidade no efeito dos fármacos? Neste trabalho foi utilizado o peixe zebra (Danio rerio) como modelo biológico. Os organismos foram avaliados segundo parâmetros comportamentais e classificados e separados em dois grupos (bold e shy), com base no seu estilo de coping face a um novo ambiente. Como fármaco foi selecionada a carbamazepina, medicamento com elevada taxa de prescrição, detetado no ambiente e com uma reduzida taxa de degradação. Os organismos com os dois estilos de coping foram submetidos durante 96h a diferentes concentrações de carbamazepina (0.0044, 0.067, 1 e 15 mg/L). O estudo avaliou parâmetros comportamentais (e.g., distância total nadada e tigmotaxia) face a estímulos de luz (ciclos de luz e escuro) e biomarcadores bioquímicos. A aprendizagem e memória foram igualmente avaliadas com recurso a medições comportamentais diárias. Os dados obtidos revelaram diferenças nas respostas dos dois grupos de peixes, havendo um maior nível de atividade nos peixes reativos. As respostas aos períodos de luz/escuro foram diferenciadas. No escuro, a distância total nadada e a percentagem de distância nadada na área de fora são mais elevadas e a percentagem de tempo passado na área de fora foi menor. A carbamazepina por si só não influenciou as respostas analisadas. No entanto, as respostas dos peixes de diferentes personalidades dependeram das concentrações de carbamazepina a que estiveram expostos e do estímulo luz/escuro aplicado. Dos biomarcadores bioquímicos avaliados, LPO (peroxidação lipídica) variou de acordo com a personalidade, tendo os peixes proativos níveis mais elevados, e GST (glutationa-s-transferase) foi significativamente inibida nos peixes reativos pela maior concentração de carbamazepina. De uma forma geral os resultados mostram que estilos de coping influenciam a resposta a fármacos.
Animal personality is linked to physiological and biochemical processes of the organism. It is defined as individual behavioural patterns that are constant throughout a certain phase of life. Recent studies have shown compounds capacity, including pharmaceuticals, to interfere with behaviour and personality traits. However, knowledge about this phenomenon is still limited. Knowing that pharmaceuticals can interfere with personality, one question arises: what may be personality’s role on pharmaceutical’s effects? In this experiment, zebrafish (Danio rerio) was chosen as biological model. Individuals were evaluated by behavioural patterns and classified and separated in two groups (bold and shy) based on their stress coping strategy as a reaction to a novel environment. Carbamazepine was selected as pharmaceutical to study, due to its high prescription rate, detection in the environment and reduced degradation rate. Individuals with both coping styles were exposed for 96h to different concentrations of carbamazepine (0.0044, 0.067, 1 e 15 mg/L). The experiment evaluated behavioural parameters (e.g., total distance swam and thigmotaxis) in response to light stimuli (light and dark cycles) and biochemical biomarkers. Learning and memory were also evaluated resorting to daily behavioural measures. Data obtained revealed differences in responses between both groups of individuals. Behavioural data showed a higher activity level in shy fish. Responses to light and dark were also differentiated. In darkness, total distance swam and percentage of distance swam in the outside area increased comparing to light periods, whilst percentage of time spent in the outside area decreased. Carbamazepine alone did not influence responses analysed. However, responses from bold and shy fish depended on the concentration of carbamazepine and stimulus light/dark. From the biochemical biomarkers assessed, LPO (lipid peroxidation) varied according to personality, with bold fish having higher levels, and GST’s (glutathione-s-transferase) levels were significantly inhibited in shy fish exposed to the highest concentration of carbamazepine. Overall, results showed that coping styles influence response to pharmaceuticals.

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Nogueira, Ana Filipa Ferreira. "Developmental, behavioral, biochemical and epigenetic effect of pharmaceuticals in larvae and embryos of Danio rerio." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22024.

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Abstract:

Mestrado em Biologia Molecular e Celular
The scientific community has been concerned for several years about the presence of pharmaceuticals in the wild, since these compounds may have deleterious or unpredictable effects on living organisms. The scientific knowledge on the fate and effect of drug residues in the environment has evolved considerably in recent years, revealing that drug residues do indeed pose a threat to the aquatic ecosystem. Two examples of widely used pharmaceuticals that are present in the environment are paracetamol (acetaminophen) and ciprofloxacin, Paracetamol is a drug with analgesic properties, used for the temporary relief of mild to moderate pain associated with common colds, and in the reduction of fever. Ciprofloxacin is an antibiotic from the chemical class of the fluoroquinolones which presents a broad antibacterial spectrum. Firstly we decided the range of concentrations for each drug. In the case of paracetamol, the tested concentrations were 0.005 mg/L, 0.025 mg/L, 0.125 mg/L, 0.625 mg/L, and 3.125 mg/L, plus a control treatment with water from the facility system. And for ciprofloxacin, the tested concentrations were 0.005 μg/L, 0.013 μg/L, 0.031 μg/L, 0.078 μg/L, 0.195 μg/L, and 0.488 μg/L. These concentrations were chosen as for their environmental relevance since they are close to the real concentrations of these pharmaceuticals found in surface waters and effluents. This work aims to characterize the effects of both drugs in zebrafish embryos and larvae, not only in developmental and behaviour parameters, but also using a biomarker-based approach, namely by quantifying the activities of catalase (CAT), glutathione-S-transferase (GST’s), cholinesterases (ChE’s), glutathione peroxidase (GPx), and determining the TBARS level. Exposure to paracetamol caused an increase in the percentage of organisms with morphological deformations, but no morphological deformations were observed in organisms exposed to ciprofloxacin. Concerning larvae behavioural tests, significant differences were observed for larvae exposed to paracetamol but not for larvae exposed to ciprofloxacin. In the biomarker determination, both drugs caused a statistically significant increase in ChE activity; in CAT only ciprofloxacin caused a significant difference, a decrease in its activity. Paracetamol induced an increase in activity for total GPx and in GST’s. The TBARS levels significantly increased in the exposure to paracetamol, but they significantly decreased in the exposure to ciprofloxacin. In this work, we also prepared an immunohistochemical detection of global methylation, which allowed to observe that, in embryos, the highest concentration of paracetamol caused a slight increase in the intensity of the 5- mdC signal, which can be translated into a slight increase in the DNA methylation. On the other hand, the embryos exposed to ciprofloxacin did not appear to have any difference from control. The comparison of the here-obtained results for the two different drugs allows observing that zebrafish larvae were more sensitive to the exposure to paracetamol, being the most sensitive methodology the biomarker determination. We can also conclude that oxidative stress occurred as a consequence of the exposure to both pharmaceuticals, being more evident in the case of paracetamol. We also showed that the oxidative stress created by the two pharmaceuticals may be the cause of all the other observations.
A presença de produtos farmacêuticos na natureza é uma questão emergente para a comunidade científica uma vez que estes compostos podem ter efeitos deletérios ou imprevisíveis sobre os organismos vivos. O estudo dos efeitos dos resíduos de medicamentos no ambiente evoluiu consideravelmente nos últimos anos, revelando que estes resíduos são uma ameaça para o ecossistema aquático. Dois exemplos de produtos farmacêuticos amplamente utilizados por humanos e presentes no meio ambiente são o paracetamol (acetaminofeno) e a ciprofloxacina. O paracetamol é um medicamento com propriedades analgésicas, utilizado para o alívio temporário da dor leve a moderada associada a gripes comuns, e na redução da febre. A ciprofloxacina é um antibiótico da classe química das fluoroquinolonas que apresenta um amplo espectro antibacteriano. Este trabalho tem como objetivo utilizar larvas de peixe-zebra e caracterizar os efeitos de ambos os medicamentos, não apenas nos parâmetros de desenvolvimento e comportamento, mas também usando com uma abordagem baseada em biomarcadores, nomeadamente quantificando as atividades de catalase (CAT), glutationa-S-transferase (GST), colinesterases (ChE's), glutationa peroxidase (GPx) e determinação do nível TBARS, bem como uma abordagem epigenética. Neste trabalho, também avaliamos por técnicas histoquímicas a metilação global do ADN. No caso do paracetamol, as concentrações testadas foram 0.005 mg/L, 0.025 mg/L, 0.125 mg/L, 0.625 mg/L, e 3.125 mg/L, juntamente com o controlo que apenas continha água do sistema. Para a ciprofloxacina, as concentrações testadas foram 0.005 μg/L, 0.013 μg/L, 0.031 μg/L, 0.078 μg/L, 0.195 μg/L, e 0.488 μg/L. Estas concentrações foram escolhidas pela sua relevância ambiental, uma vez que são muito próximas às concentrações destes fármacos no ambiente. A exposição ao paracetamol causou um aumento na percentagem de organismos com deformações morfológicas, mas não foram observadas deformações morfológicas em organismos expostos à ciprofloxacina. Quanto aos testes comportamentais com larvas de peixe-zebra, observaram-se diferenças significativas nas larvas expostas ao paracetamol, que demonstraram uma maior distância de natação, mas o mesmo efeito não foi observado para as larvas expostas à ciprofloxacina. Os dados obtidos para os diferentes biomarcadores demonstraram que ambos os fármacos causaram um aumento estatisticamente significativo na atividade de ChE. Na actividade da CAT, apenas a ciprofloxacina causou diferença significativa, mais propriamente uma descida na atividade da CAT. O paracetamol induziu um aumento na atividade da GPx total e das GSTs. Os níveis de TBARS aumentaram significativamente após exposição ao paracetamol, mas diminuíram significativamente em organismos expostos à ciprofloxacina. Os dados relativos à quantificação da metilação global do ADN permitiram observar que, em embriões, a maior concentração de paracetamol causou um ligeiro aumento na intensidade do sinal do marcador de metilação de ADN (5- mdC,) quando observado por miscroscopia de confocal. Por outro lado, os embriões expostos à ciprofloxacina não aparentavam ter qualquer diferença no perfil deste marcador de epigenética comparativamente ao controlo. A comparação dos resultados aqui obtidos para os dois fármacos diferentes permite observar que as larvas de peixe zebra eram mais sensíveis à exposição ao paracetamol, sendo a metodologia mais sensível a determinação do biomarcador. Também podemos concluir que o estresse oxidativo ocorreu como conseqüência da exposição a ambos os produtos farmacêuticos, sendo mais evidente no caso do paracetamol. Também mostramos que o estresse oxidativo criado pelos dois produtos farmacêuticos pode ser a causa de todas as outras observações.

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Santos, Tiago André Azevedo dos. "Fish personality, memory and learning hability: the effect of pharmaceuticals and abiotic factors." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22023.

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Abstract:

Mestrado em Biologia Molecular e Celular
Over the last years, animal personality has been gaining a lot of attention from the scientific community, and, at the moment, it is being questioned its importance in survival and the evolution of species in stress situation. Between all of potential stress agents, there are emerging environmental contaminants, such as, pharmaceuticals. However, there are not many behavior and personality studies in fish. The present work aims to increase the knowledge of how factors associated with personality can influence the response to pharmaceuticals detected in the environment. For model organism, the zebrafish (Danio rerio) was chosen, and 8 months old organism were selected. Animals were separated, based on behavior responses, in two classes, bold and shy. After the selection, organisms were exposed, during 96h to a human drug, gemfibrozil, used as a lipid regulator. During the experimental assay, behavior parameters that allowed to evaluate the capacity of response to stimuli, and memory to adaptation were assessed. After 96h of exposure, associated parameters and oxidative stress were equally assessed. Bold fish traveled a bigger distance than shy fish. Furthermore, shy fish expressed higher LPO levels than bold fish, and fish from the control group, as well as, shy fish exposed to the lowest concentration of gemfibrozil expressed more LPO than shy fish exposed to the higher concentrations of gemfibrozil
Nos últimos anos, a personalidade animal tem vindo a atrair a atenção da comunidade científica, estando neste momento a ser questionada a hipótese de da sua importância na sobrevivência e a evolução das espécies em situação de stress. De entre os diferentes potenciais agentes causadores de stress estão os contaminantes ambientais emergentes como, por exemplo, os fármacos. No entanto não existem muitos estudos de comportamento e personalidade dos peixes. Este trabalho visou aumentar o conhecimento de como fatores associados a personalidade podem influenciar a resposta a fármacos detetados no ambiente. Como organismo modelo foi escolhido o peixe zebra (Danio rerio), tendo sido selecionado organismos com 8 meses. Os animais foram separados, com base em resposta comportamentais, em duas classes, proativos e reativos. Após a separação, os organismos foram expostos, durante 96h a um fármaco humano, gemfibrozil, utilizado como regulador lipídico. Ao longo do ensaio experimental foram avaliados parâmetros comportamentais que permitiram avaliar a capacidade de resposta a estímulo, memória a adaptação. Ao fim de 96 h de exposição, parâmetros associados e stress oxidativo foram igualmente avaliados. Os peixes proativos percorreram uma maior distância que os peixes retroativos. Para além disso, os peixes retroativos expressaram níveis maiores de LPO que os peixes proativos, e os peixes retroativos do controlo e expostos à menor concentração de gemfibrozil expressaram mais LPO que os peixes retroativos expostos às concentrações maiores de gemfibrozil.

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bhardwaj, vinay. "Label-free surface-enhanced Raman spectroscopy-linked immunosensor assay (SLISA) for environmental surveillance." FIU Digital Commons, 2015. http://digitalcommons.fiu.edu/etd/2321.

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The contamination of the environment, accidental or intentional, in particular with chemical toxins such as industrial chemicals and chemical warfare agents has increased public fear. There is a critical requirement for the continuous detection of toxins present at very low levels in the environment. Indeed, some ultra-sensitive analytical techniques already exist, for example chromatography and mass spectroscopy, which are approved by the US Environmental Protection Agency for the detection of toxins. However, these techniques are limited to the detection of known toxins. Cellular expression of genomic and proteomic biomarkers in response to toxins allows monitoring of known as well as unknown toxins using Polymerase Chain Reaction and Enzyme Linked Immunosensor Assays. However, these molecular assays allow only the endpoint (extracellular) detection and use labels such as fluorometric, colorimetric and radioactive, which increase chances of uncertainty in detection. Additionally, they are time, labor and cost intensive. These technical limitations are unfavorable towards the development of a biosensor technology for continuous detection of toxins. Federal agencies including the Departments of Homeland Security, Agriculture, Defense and others have urged the development of a detect-to-protect class of advanced biosensors, which enable environmental surveillance of toxins in resource-limited settings. In this study a Surface-Enhanced Raman Spectroscopy (SERS) immunosensor, aka a SERS-linked immunosensor assay (SLISA), has been developed. Colloidal silver nanoparticles (Ag NPs) were used to design a flexible SERS immunosensor. The SLISA proof-of-concept biosensor was validated by the measurement of a dose dependent expression of RAD54 and HSP70 proteins in response to H2O2 and UV. A prototype microchip, best suited for SERS acquisition, was fabricated using an on-chip SLISA to detect RAD54 expression in response to H2O2. A dose-response relationship between H2O2 and RAD54 is established and correlated with EPA databases, which are established for human health risk assessment in the events of chemical exposure. SLISA outperformed ELISA by allowing RISE (rapid, inexpensive, simple and effective) detection of proteins within 2 hours and 3 steps. It did not require any label and provided qualitative information on antigen-antibody binding. SLISA can easily be translated to a portable assay using a handheld Raman spectrometer and it can be used in resource-limited settings. Additionally, this is the first report to deliver Ag NPs using TATHA2, a fusogenic peptide with cell permeability and endosomal rupture release properties, for rapid and high levels of Ag NPs uptake into yeast without significant toxicity, prerequisites for the development of the first intracellular SERS immunosensor.

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Chalghmi, Houssem. "Etude de la pollution marine par les hydrocarbures et caractérisation de leurs effets biochimiques et moléculaires sur la palourde de Ruditapes sp." Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0175/document.

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Dans notre étude, la biosurveillance de la lagune de Tunis a été réalisée durant une année enemployant une approche combinant les analyses chimiques et biologiques et en utilisant lapalourde Ruditapes decussatus comme espèce bioindicatrice. Cette approche a permis demettre en évidence la forte contamination de la lagune de Tunis par les métaux traces et leshydrocarbures aromatiques polycycliques (HAPs). La variation saisonnière des niveaux debioaccumulation de ces contaminant par la palourde s’avère être fortement associée auxchangements des paramètres physico-chimiques du milieu et aux processus physiologiques del’animal. L’étude de la réponse biologique basée sur l’utilisation d’une batterie debiomarqueurs d’exposition et d’effet situés à différents niveaux de l’organisation biologique :moléculaire (l’expression de cinq gènes d’intérêt), biochimique (les activités benzo(a)pyrènehydroxylase, glutathion S-transférase, acétylcholinestérase, catalase et taux demalondialdéhyde) et tissulaire (altérations histopathologiques), a permis de mettre enévidence une modulation des processus de défense contre les perturbations induites par lapollution et l’identification des altérations histopathologiques (structurales) au niveau desbranchies et de la glande digestive impliquant un impact sévère des contaminants sur l’état desanté de la palourde. L’étude des interactions spatio-temporelles entre les facteurs abiotiqueset biotiques a permis d’identifier la température et la reproduction comme paramètresprincipaux affectant la réponse biochimique de défense et d’effet. L’analyse en composanteprincipale (ACP), regroupant tous les paramètres analysés pendant le printemps, nous apermis d’identifié le site Z2 comme le site le plus affecté par la pollution. Dans un secondtemps, le benzo(a)pyrène (BaP), déjà identifié dans la lagune de Tunis, a été employé dansdes conditions contrôlées au laboratoire afin de caractériser les réponses moléculaires etbiochimiques chez les bivalves (Ruditapes philippinarum et Crassostrea gigas) face à desexpositions subaiguës et aiguës à ce contaminant. Cette étude nous a permis d’identifier unemodulation des biomarqueurs biochimiques de métabolisation, de stress oxydant et deneurotoxicité et de l’expression des gènes impliqués dans les processus de métabolisation, derespiration mitochondriale, de défense antioxydante, de reproduction et de défenseimmunitaire. L’analyse de l’altération de l’ADN a révélé un pouvoir génotoxique précoce etélevé du BaP chez les deux bivalves
Firstly, biomonitoring of Tunis lagoon was conducted during one year using an approach combining chemicals and biological analyses and the bioindicator species Ruditapesdecussatus. This approach high lighted the high contamination of the Tunis lagoon by tracemetals and polycyclic aromatic hydrocarbons (PAHs). Seasonal variation of contaminant bioaccumulation levels in clam was found to be strongly associated with physico chemical changes in surrounding environment and physiological processes in organism. Biological responses investigated through a battery of exposure and effect biomarkers located at differentlevels of biological organisation: molecular (expression of five genes), biochemical(benzo(a)pyrene hydroxylase, glutathione S-transferase, acetylcholinesterase and catalase activities and malondialdehyde concentration) and tissular (histopathological damages),demonstrated a defense process modulation by pollution and showed histopathological alterations in gills and digestive gland involving severe impact of contaminants on health stateof clam. The study of spatio temporal interactions between abiotic and biotic factors identified temperature and reproduction as main parameters affecting defense and effect biochemical response. The principal component analysis (PCA), using all analyzed parameters during thespring, allowed to identify site Z2 as the most affected by pollution. Secondly,benzo(a)pyrene (BaP), already identified in Tunis lagoon, was used in controlled conditions at the laboratory in order to characterize the molecular and biochemical responses in bivalves(Ruditapes philippinarum and Crassostrea gigas) facing a subacute and acute exposures tothis contaminant. This study showed a modulation of biochemical biomarkers of metabolism,oxidative stress and neurotoxicity and expression of genes involved in process of metabolisation, mitochondrial respiration, antioxidant defense, reproduction and immune defense. The analysis of DNA damages revealed a high and early genotoxicity effect of BaPin both bivalves

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Reddy, Dayananda R. "Biochemical toxicology of dimethoate (organophosphorus pesticide) in silkworm bombyx mori." Thesis, 1994. http://hdl.handle.net/2009/2472.

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Sasso, Alan F. "Development and application of a generalized physiologically-based toxicokinetic model for environmental risk assessment." 2010. http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000052148.

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Truong, Don H. "The biochemical basis of hepatocyte cytotoxicity induced by hydrogen sulfide or allyl sulfide /." 2008. http://proquest.umi.com/pqdlink?did=1659961701&sid=11&Fmt=2&clientId=12520&RQT=309&VName=PQD.

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Van, Wyk Erika. "Biochemical genetics, physiology and ecotoxicology of Southern African vulture species." Thesis, 2012. http://hdl.handle.net/10210/7463.

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D.Phil.
The main objective of this study was to describe the population genetic structure of African Whitebacked Vultures (Pseudogyps africanus) and to compare values to those previously documented for the Cape Griffon Vulture (Gyps coprotheres). The percentage of polymorphic .loci (P = 34.15%, 0.99 criterion) and average heterozygosity (17 = 0.108, ±0.032) calculated for P. africanus, confirm low levels of genetic -variation as reported for G. coprotheres. Blood samples' obtained from Lappetfaced (Torgos, tracheliotos) and Egyptian (Neophron percnopterus) Vultures enabled an evaluation of the genetic differentiation among the four southern African vulture species from allele frequency data assessed at 19 presumptive gene loci. Six (31.58%) of the 19 shared loci were polymorphic. Values of 1.26 (10.1), 26.32% and 0.076 (±0.047) for P.'africanus, 1.21 (±0.1), 21.05% and 0.097 (±0.045) for T. tracheliotos, 1.11 (±0.7), 21.05%. and 0.053 .(±0.053) for N: percnopterus and 1.05 (±0.5), 5.26% and 0.044 (±0.047) for G. coprotheres were obtained for the mean number of alleles per locus, P and Ti respectively. An average between-population fixigion index (FsT) value of 0.322 was obtained, which is indicative of significant (P < 0.01) differentiation between the four accipitrid species studied. Reference values for some haematological and plasma chemical parameters were established in 33 apparently normal, free-living, African Whitebacked Vulture nestlings. This .information can be. used in future ornithological research. A total of 27 variables . were examined, which include: leucocyte and erythrocyte counts, haemoglobin concentration, .haematocrit, haematimetric indices, glucose, creatinine, urea, total prOtein, albumin, globulin, albumin/globulin ratio, cholesterol, total lipids, triglycerides, aspartate aminotransferase, cholinesterase, lactate dehydrogenase, alkaline phosphatase, calcium, phosphorus, chloride, potassium, sodium and osmolarity. Only five parameters exhibited statistically significant (p < 0.05) differences between the two populations assayed. The Sandveld population showed elevated mean corpuscular haemoglobin concentration and alkaline phosphatase levels relative to the Dronfield population, whereas, the latter group displayed higher erythrocyte counts and potassium and sodium values than birds from the Sandveld community. Gaschromatography was used to establish the presence of quantifiable . residues .of 14 persistent chlorinated hydrocarbon pollutants in whole blood, clotted blood, heart, kidney, liver, bone, fat and muscle samples obtained from individual African Whitebacked, Cape. Griffon and Lappetfaced Vultures from different localities in South Africa. Concentrations of seven essential elements (Ca, Co, Cr, Cu, Fe, Mn and Zn) and four toxic metals (Al, Ni, Pb and Sr) were, furthermore, measured. The levels of pollutants measured in whole blood samples of live specimens were compared between nestlings from two natural breeding colonies, adults from a wildlife area and birds held in captivity. Statistically significant differences between populations were detected in geometric means calculated for y-BHC, a-chlordane and a-endosulfan. Five of the organochlorine contaminants displayed significant variations between concentrations detected in the clotted blood, organs and muscles excised from vulture carcasses. This includes residues ofy-BHC, a-chlordane, dieldrin, ,8-endosulfan and heptachlor epoxide. Values of the respective organochlorines obtained in vulture samples were generally low in comparison to results documented for a number of avian species. Levels of the , majority of metals analysed differed significantly- between two or more of the sampling localities, between adults and nestlings, and between captive and wild individuals. Metals which did not occur in such distinctly defining concentrations were Sr, Cu and Fe. Birds from Moholoholo maintained the highest overall blood metal burden, while nestlings from Dronfield were the least contaminated Significant differences were present between two or more tissues types for all the metals. The predominant sites for metal accumulation in vultures were the fatty tissues and bones. Most of the levels of metals measured in vultures compared well with concentrations reported for other avian species, and were generally within the range documented for species devoid of deleterious symptoms induced from heavy metal poisoning. However; certain individuals exhibited potentially toxic concentrations of specific metals such as Cu, Fe, Ni, and Pb. Continual monitoring of breeding colonies is recommended. The suitability of African Whitebacked Vulture nestlings as basic bioindicatori is highly advocated. The genetic data from this study can be used to compare levels of genetic diversity remaining in captive and wild vulture populations. An assessment of the amount and pattern of genetic variation of current populations of vulture species is an essential step towards ensuring the longterm survival of these birds. The phylogenetic conclusions found in. this study through allozyme electrophoresis correspond to results obtained from nucleotide sequence studies of the mitochondrial cytochrome b. gene. This points to an extent of positive corroboration between the two techniques. The haematological profile established for African Whitebacked Vulture nestlings constitutes a set of reference values that was previously unavailable for southern African vulture species. This data can assist in diagnosing and monitoring pathological and clinical' incidents detected in vultures. Values for a number of organochlo?ine pesticides and heavy metals, which have not been analysed in vulture species in the past, are documented. These values can serve as guidelines for future research, as well as control values for monitoring the occurrence and distribution of these contaminants within the habitats of vulture species. This study, therefore, presents information for research fields directly related to the survival of vulture populations. These factors must be included in future vulture management and reintroduction programmes as they will serve to enhance the success of conservation attempts.

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Hull, Rodney. "Stress response to genotoxic agents and to infection." Thesis, 2012. http://hdl.handle.net/10539/12067.

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Insects have evolved various physiological responses to cope with stressors such as pathogens, toxins and environmental factors. It is known that the responses resulting from infection or DNA damage share some of the same pathways. Exposure of Drosophila melanogaster and the dung beetle Euoniticellus intermedius to stress led to changes in the expression of proteins involved in metabolism, development, protein degradation, mRNA processing and stress responses. Stress responses in D. melanogaster are well characterised. However, the role played by Drosophila p53 (Dmp53) and a member of the retinoblastoma binding protein 6 (RBBP6) family, Snama, are unknown. Snama has been proposed to play a role in Dmp53 regulation. Following DNA damage we investigated the role of Dmp53 and Snama. Flies recovering from camptothecin treatment display a glycolytic flux, involving a metabolic shift, different to that observed in cancer cells. Camptothecin treatment leads to an increase in the mortality of both sexes. Furthermore, females show a specific decrease in fecundity which is due to an increase in Dmp53 dependent apoptosis in the ovaries and is accompanied by a depletion of Snama and an increase in Dmp53 transcripts. Expression data indicated that Dmp53 activity may be largely regulated at the protein level. Bypassing glycolysis through methyl pyruvate supplementation led to differential expression of Dmp53 and Snama and improved reproduction and embryonic development. These results highlight differences between the metabolic strategies used by cancerous and non-cancerous cells which may be exploited in future chemotherapies. While immune responses amongst insect orders are evolutionarily conserved, many remain uncharacterised. To investigate the immune system of an organism that lives in a microbe rich environment, E. intermedius was infected with the fungal pathogen Beauveria bassiana. This resulted in decreased lifespan and fecundity. Homologs of proteins involved in the immune response of insects were identified in E. intermedius, including a member of the Toll family of proteins, an insect defensin (present in the hemolymph) as well as a homolog of the serine protease Persephone. These results show that immune signalling pathways are conserved in this dung beetle.

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TREINEN, KIMBERLEY ANNE. "BIOCHEMICAL TOXICOLOGY OF HUMAN PLACENTAL HIGH AFFINITY CALCIUM-STIMULATED ATPASE AND CALCIUM TRANSPORT (UPTAKE, DDT, DOT)." 1986. http://books.google.com/books?id=z8Y9AAAAMAAJ.

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"Toxicological studies of Thallium in the rat with emphasis on biochemical histopathological and ultrastructural changes." 1998. http://library.cuhk.edu.hk/record=b6073096.

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Abstract:

by Ka-ming Leung.
Thesis (Ph.D.)--Chinese University of Hong Kong, 1998.
Includes bibliographical references (p. 178-186).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Mode of access: World Wide Web.
Abstracts also in Chinese.

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43

Loth, Meredith Kyla. "Translocator Protein 18 kDa: from Biomarker to Function." Thesis, 2018. https://doi.org/10.7916/D8K08N6W.

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Abstract:

Translocator Protein 18 kDa (TSPO) is a protein that is expressed at low levels in the brain, but upon brain injury or inflammation, increases its expression in the areas of the brain specific to injury. In this way, TSPO can be used as a biomarker of brain inflammation and injury. TSPO is primarily expressed in two cell types, microglia and astrocytes, and is used as a marker of reactive gliosis in various brain pathologies. Currently, there is a paucity of knowledge on the function(s) of TSPO in glial cells. Recent studies using conditional and global TSPO knockout mice have questioned the role of TSPO in translocating cholesterol across the outer mitochondrial membrane as the first step in steroidogenesis. In the brain, microglia and astrocytes exhibit distinct spatial and temporal patterns of TSPO upregulation. These differential patterns are not well characterized across disease models and in particular, are poorly characterized in the early stages of disease, prior to behavioral and clinical disease manifestations. Importantly, these distinct patterns of TSPO upregulation may indicate different functions of TSPO in microglia and astrocytes. We examined TSPO levels in a neurodegenerative transgenic mouse model of Sandhoff disease (SD) and longitudinally compared TSPO levels to behavioral manifestations of disease and other neuropathological endpoints (neurodegeneration, reactive gliosis, ganglioside accumulation). This study confirmed TSPO upregulation prior to neurodegeneration in a brain region-dependent and disease course-dependent way. In brain regions with increased TSPO levels, there was a differential pattern of glial cell activation with astrocytes being activated earlier than microglia during the progression of disease. Immunofluorescent confocal imaging confirmed that TSPO colocalizes with both microglia and astrocyte markers, but the glial source of the TSPO response differs by brain region and age in SD mice. We next wanted to gain insight into the function of TSPO in microglia. We previously demonstrated that TSPO ligands (TSPO-L) (1-100 nM) induced intracellular ROS production which was abrogated by NADPH oxidase (NOX2) inhibitors, thereby indicating an association between TSPO and NOX2. To further elucidate the relationship between TSPO and NOX, we determined the source of ROS production resulting from microglia exposure to TSPO-L. Intracellular and extracellular ROS production was inhibited by NOX inhibitors, but not by a mitochondria permeability transition pore inhibitor, indicating that the source of ROS production is from NOX and not from mitochondria. These findings were confirmed using the mitochondria specific ROS probe MitoSOX. To further explore the TSPO-NOX2 association, we used 3 molecular approaches to examine protein-protein interactions under unstimulated or stimulated conditions (100 ng/mL lipopolysaccharide (LPS) for 18 hours) in primary microglia. 1) Co-immunoprecipitation (co-IP) revealed that the NOX2 subunits, gp91phox (gp91) and p22phox (p22), co-IP with TSPO supporting a protein-protein interaction. TSPO’s association with gp91 and p22 decreased with activation, but TSPO’s association with VDAC, a mitochondrial protein, remained constant. These findings suggest that microglia activation changes the dynamics of the TSPO-NOX2 interaction. 2) Confocal imaging and colocalization analysis of TSPO/gp91 or TSPO/p22 immunofluorescence confirmed that TSPO colocalizes with both NOX subunits. Under stimulated conditions, TSPO associated with gp91 and TSPO associated with p22, exhibit significantly decreased colocalization with VDAC suggesting a movement from the mitochondria to other cellular compartments. 3) Duolink Proximity Ligation Assay confirmed that TSPO interacts with p22, gp91 and VDAC. Our results suggest a novel TSPO-gp91-p22 interaction with VDAC in primary microglia that is disrupted by microglia activation and may be involved with redox homeostasis with significant implications for a new understanding of TSPO glial cell biology. In summary, the present studies have strengthened the use of TSPO as a preclinical biomarker, confirmed its specific spatiotemporal upregulation in two cell types and have provided a new potential function of TSPO in microglia that has the possibility to revolutionize the TSPO field and to inform neurotoxicity assessments and neurological disease treatments.

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44

"Biochemical responses of juvenile orange-spotted grouper Epinephelus coioides to suspended sediment." 2006. http://library.cuhk.edu.hk/record=b5892757.

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Abstract:

by Tse Ching Yee Carol.
Thesis submitted in: September 2005.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (leaves 75-90).
Abstracts in English and Chinese.
Abstract --- p.ii
摘要 --- p.iv
Acknowledgments --- p.vi
Table of contents --- p.vii
List of tables X
List of figures --- p.xii
Chapter 1.0 --- Introduction --- p.1
Chapter 1.1 --- Sediment pollution in Hong Kong --- p.1
Chapter 1.2 --- Impact of suspended sediment on fish --- p.2
Chapter 1.3 --- Biochemical responses to pollution --- p.3
Chapter 1.3.1 --- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) --- p.4
Chapter 1.3.2 --- Creatine kinase (CK) --- p.5
Chapter 1.3.3 --- Ethoxyresorufin O-deethylase (EROD) --- p.6
Chapter 1.3.4 --- DNA damage --- p.8
Chapter 1.4 --- Study of recovery --- p.10
Chapter 1.5 --- Objectives and significances --- p.11
Chapter 2.0 --- Materials and Methods --- p.13
Chapter 2.1 --- Study sites --- p.13
Chapter 2.2 --- Sediments collection and handling --- p.13
Chapter 2.3 --- Measurement of heavy metals and organic contents of sediment --- p.15
Chapter 2.4 --- Exposure tests --- p.16
Chapter 2.4.1 --- Test organisms --- p.16
Chapter 2.4.2 --- 10- and 30-day exposure experiments --- p.18
Chapter 2.4.3 --- 20-day exposure and recovery experiment --- p.19
Chapter 2.5 --- Biochemical responses --- p.19
Chapter 2.5.1 --- "Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) activities" --- p.19
Chapter 2.5.2 --- Ethoxyresorufin O-deethylase activity (EROD) --- p.20
Chapter 2.5.3 --- DNA damage --- p.21
Chapter 2.5.4 --- Statistical analysis --- p.22
Chapter 3.0 --- Results --- p.24
Chapter 3.1 --- Physical and chemical parameters --- p.24
Chapter 3.2 --- Pollutants in sediment --- p.24
Chapter 3.3 --- Mortality --- p.28
Chapter 3.4 --- Biochemical responses --- p.31
Chapter 3.4.1 --- 10- and 30-day exposure experiments --- p.31
Chapter 3.4.2 --- 20-day exposure and recovery experiments --- p.50
Chapter 4.0 --- Discussion --- p.58
Chapter 4.1 --- "Sediment pollution at Port Shelter, Mirs Bay and Victoria Harbor" --- p.58
Chapter 4.2 --- Biochemical responses --- p.59
Chapter 4.2.1 --- 10- and 30-day exposure experiments --- p.59
Chapter 4.2.1.1 --- "AST, ALT and CK" --- p.59
Chapter 4.2.1.2 --- EROD --- p.63
Chapter 4.2.1.3 --- DNA damage --- p.67
Chapter 4.2.2 --- 20-day exposure and recovery experiments --- p.69
Chapter 5.0 --- Recommendations and conclusions --- p.73
References --- p.75
Appendix --- p.91

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45

Liu, Jiangang. "MOLECULAR PROFILING IN BREAST CANCER AND TOXICOGENOMICS." 2011. http://hdl.handle.net/1805/2636.

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Indiana University-Purdue University Indianapolis (IUPUI)
This dissertation presents a body of research that attempts to tackle the ‘overfitting’ problem for gene signature and biomarker development in two different aspects (mechanistically and computationally). In achievement of a deeper understanding of cancer molecular mechanisms, this study presents new approaches to derive gene signatures for various biological phenotypes, including breast cancer, in the context of well-defined and mechanistically associated biological pathways. We identified the pattern of gene expression in the cell cycle pathway can indeed serve as a powerful biomarker for breast cancer prognosis. We further built a predictive model for prognosis based on the cell cycle gene signature, and found our model to be more accurate than the Amsterdam 70-gene signature when tested with multiple gene expression datasets generated from several patient populations. Aside from demonstrating the effectiveness of dimensionality reduction, phenotypic dissection, and prognostic or diagnostic prediction, this approach also provides an alternative to the current methodology of identifying gene expression markers that links to biological mechanism. This dissertation also presents the development of a novel feature selection algorithm called Predictive Power Estimate Analysis (PPEA) to computationally tackle on overfitting. The algorithm iteratively apply a two-way bootstrapping procedure to estimate predictive power of each individual gene, and make it possible to construct a predictive model from a much smaller set of genes with the highest predictive power. Using DrugMatrix™ rat liver data, we identified genomic biomarkers of hepatic specific injury for inflammation, cell death, and bile duct hyperplasia. We demonstrated that the signature genes were mechanistically related to the phenotype the signature intended to predict (e.g. 17 out of top 20 genes for inflammation selected by PPEA were members of NF-kB pathway, which is a key pre-inflammatory pathway for a xenobiotic response). The top 4 gene signature for BDH has been further validated by QPCR in a toxicology lab. This is important because our results suggest that the PPEA model not largely deters the over-fitting problem, but also has the capability to elucidate mechanism(s) of drug action and / or of toxicity.

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46

Muniz, Juan Fermin. "Biomarkers of oxidative stress and DNA damage in agricultural workers." Thesis, 2009. http://hdl.handle.net/1957/13998.

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Abstract:

Pesticides are among the most pervasive environmental contaminants and they are an important potential risk for human health. Agricultural workers are constantly exposed to pesticide spray, drift and residues in the soil and foliage. Many agricultural pesticides are readily absorbed by the body, through contact with the skin, the respiratory track, the eyes, and the gastrointestinal system. Multiple studies have reported a strong association between pesticide exposure and various health outcomes including cancer. Oxidative stress and DNA damage have been proposed as mechanisms linking pesticide exposure to health effects and neurological diseases. The focus of the present translational study is to examine the relationship between human exposure to the organophosphate pesticide azinphos methyl (AZM) and oxidative stress by measuring biomarkers of oxidative stress in biological fluids (i.e., urine, serum) and peripheral blood lymphocytes (PBLs) of agricultural workers. The findings from these field studies will be validated in vitro by examining cultures of human lymphocytes treated with AZM for similar biomarkers of oxidative stress. Since the collection of PBLs from study participants is highly invasive and not suitable for studies involving younger subjects, we also examined buccal cells for biomarkers of oxidative stress (i.e., DNA damage) as a more universal source of human tissue to assess oxidative stress in pesticide exposed individuals. We demonstrated in this study that AZM induces oxidative stress and causes DNA damage in human tissues. Agricultural workers who had been exposed to AZM showed elevated serum levels of lipid peroxides, increased urinary levels of 8-OH-dG, and lymphocytes from these individuals showed increased DNA damage and associated changes in oxidative DNA repair enzymes. Biomarkers of oxidative stress were also elevated in human lymphocytes treated with physiologically relevant concentrations of AZM. In cultures of human lymphocytes, AZM caused a concentration-dependent loss of viability and associated increases in ROS and a reduction in intracellular GSH. We also demonstrated that viable leukocytes from the oral cavity can be readily obtained from humans and these buccal cells can be used to assess DNA damage following exposure to occupational and environmental genotoxicants. We also noted that oral leukocytes are especially sensitive to cryopreservation with DMSO and thus, these cells must be cryoprotected with 5% DMSO to preserve the viability of these cells for subsequent biochemical studies. In summary, these in vivo and in vitro studies demonstrated that AZM induces oxidative stress in a dose-dependent matter and that oral lymphocytes are a good source of human tissue for assessing DNA damage and possibly other biochemical changes. The possible health implications of the variations in these biomarkers of oxidative stress and DNA damage are undetermined. Yet the findings from these studies have provided a strong foundation for determining the mechanism by which pesticide induce oxidative stress, to explore the putative relationship between pesticide-induced oxidative stress and disease (e.g. cancer, neurodegenerative disorders) and determine whether tissue damage in humans is brought about by direct or by indirect action of organophosphate pesticides.
Graduation date: 2010

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Dissertations / Theses on the topic 'Biochemical toxicology'

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