Hepatic toxicity and polychlorinated biphenyls : toxicogenomic examination of single congener and mixture effects in C57BL/6 mice
Human exposures to persistent organic pollutants rarely occur in isolation but rather as complex mixtures. Interactions between environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) can produce additive, synergistic or antagonistic interactions, which may influence risk assessment. Therefore, scientifically based risk and health hazard evaluation requires toxicological data from chemical mixture studies, in addition to traditional studies involving single chemical exposure.Dioxins and PCBs are ubiquitous toxicants that persist in the environment due to their lipophilicity and propensity to bioaccumulate in biological tissues. These chemicals elicit tissue- and species-specific effects including hepatotoxicity, immune suppression, endocrine disruption, and carcinogenicity. Structural similarity to the most toxic coplanar dioxin, TCDD, determines the dioxin-like effects of individual PCBs and the spectrum of aryl hydrocarbon receptor (AhR)-mediated biochemical and toxic responses. In contrast, non-coplanar PCB congeners are more abundant in the environment and elicit responses that are unique and non-AhR-mediated. The main objective of this research was to evaluate how mixture interactions between these structurally different, dioxin and non-dioxin-like chemicals affect the gene expression responses underlying the hepatic toxicity in the immature C57BL/6 mouse model.Comprehensive time course and dose-response hepatic gene expression analyses were performed for dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB126) and non-dioxin-like 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) relative to TCDD, and differentially expressed genes were phenotypically anchored to changes in physiological endpoints to establish a quantitative baseline of toxic responses. Assessment of the toxic effects exerted by a mixture of TCDD and PCB153 was performed using a 1 to 10,000 ratio, respectively, to reflect relative environmental concentrations of each of the chemicals and to compare obtained results to previous literature reports examining non-additive AhR interactions.In summary, the single chemical studies demonstrated that each compound elicited a complex and unique temporal and dose-dependent gene expression profile that could be linked to the physiological outcomes. In the mixture studies, microarray profiling and statistical dose-response modeling identified a small subset of non-additive, synergistically induced gene expression responses, which were consistent with effects on relative liver weights, histopathology, hepatocellular lipid accumulation and tissue level pharmacokinetics.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Kopec, Anna Katarzyna
- Thesis Advisors
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Zacharewski, Timothy R.
- Committee Members
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Dewitt, David
Kaminski, Norbert
Wang, John
Hegg, Eric
- Date
- 2010
- Subjects
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Gene expression
Hepatotoxicology
Polychlorinated biphenyls
Genetic toxicology
Mice as laboratory animals
- Program of Study
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Biochemistry and Molecular Biology - Environmental Toxicology
- Degree Level
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Doctoral
- Language
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English
- Pages
- xvii, 224 pages
- ISBN
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9781124371382
1124371389
- Permalink
- https://doi.org/doi:10.25335/wssd-3809