Predictive Modeling of Thyroid Hormone Disruption and Investigation of Potential Biomarkers of Chemical Exposure

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Title: Predictive Modeling of Thyroid Hormone Disruption and Investigation of Potential Biomarkers of Chemical Exposure
Author: Flippin, Jennifer Lynn
Advisors: Andrew D. Wallace, Committee Member
Gerald A. LeBlanc, Committee Co-Chair
Kevin M. Crofton, Committee Co-Chair
Mike J. DeVito, Committee Member
Abstract: Humans and wildlife are exposed to thyroid hormone disrupting chemicals in their environments. These exposures often occur as complex mixtures of xenobiotics with similar and dissimilar modes of action. This research tested the hypothesis that serum thyroxine (T4) concentrations in rodents exposed to a mixture of chemicals with two distinct modes of action (enhancers of T4 hepatic metabolism and inhibitors of thyroidal hormone synthesis) could be best predicted by a model of integrated addition. Female Long-Evans rats, 23 days of age, were dosed with dilutions of a mixture of 18 polyhalogenated aromatic hydrocarbons (dioxins, dibenzofurans, and polychlorinated biphenyls) and a mixture of three pesticides (pronamide, mancozeb, and thiram) for four consecutive days. Serum was collected 24 hours after the last exposure and T4 concentrations were measured by RIA. Animals exposed to the highest dose of the mixture experienced a 45% decrease in serum T4. Three additivity model predictions (dose addition, effect addition, and integrated addition) were generated and compared. The response to the mixture was best modeled by integrated addition in which responses to the pesticides and polyhalogenated aromatic hydrocarbons were separately evaluated according to dose additivity, and the response of the two groups of chemicals were summed according to effect additivity. The response to the mixture was also well-predicted by a dose addition model. These results lead to a clearer understanding of thyroid hormone disruption by a complex mixture and show that models are able to accurately predict the response of T4 to a mixture of endocrine disruptors. Thiram, mancozeb, and pronamide inhibit thyroid hormone production in the thyroid gland. These hormone decreases may be associated with altered expression of thyroidal genes. It was hypothesized that exposure to TH synthesis inhibitors would result in altered expression of mRNA of PAX-8, Hex, Tg, NIS, and/or TPO in the thyroid gland. Female Long-Evans rats were exposed for four days to two dilutions of each of the following mixtures: three pesticides (thiram, mancozeb, and pronamide); 18 PHAHs (dioxins, furans, and PCBs); a combination of the three pesticides and 18 PHAHs. Thyroids were collected and rtPCR was used determine if alteration of key thyroid genes occurred as a result of TH synthesis inhibition. Thyroidal expression of PAX-8, Hex, Tg, NIS, and TPO mRNA was not significantly different than corn oil treated control animals. The expression patterns of the genes tested in this study do not provide a useful biomarker of short term exposure to the tested doses of TH synthesis inhibiting pesticides.
Date: 2008-12-07
Degree: MS
Discipline: Toxicology

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