Year of Award

2013

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Erica Woodahl

Commitee Members

Fernando Cardozo-Pelaez, Elizabeth A. Putnam, David Poulsen, Scott Wetzel, Leslie Dickman

Keywords

PARKINSON'S DISEASE, PESTICIDE, P-GLYCOPROTEIN TRANSPORT, PHARMACOKINETICS, TOXICITY

Abstract

Variation in the gene that encodes P-glycoprotein (P-gp), ABCB1, has been associated with Parkinson's disease risk. The aim of my research was to evaluate P-gp transport of pesticides that have been associated with Parkinson's disease as a mechanism for the pharmacogenomic association. To facilitate this aim, a combination of models was utilized to determine P-gp transport of the pesticides diazinon, dieldrin, endosulfan, maneb, MPP+, paraquat, and rotenone. Paraquat pharmacokinetics and brain accumulation were measured in both FVB wildtype and mdr1a(-/-)/1b(-/-) mice. P-gp deficient mice displayed no changes in paraquat brain accumulation, indicating that P-gp does not mediate paraquat disposition. I confirmed this observation in vitro using ATPase activity, cytotoxic sensitivity, transepithelial transport, and rhodamine-123 inhibition assays, in which I observed no interaction between P-gp and paraquat. There has been recent controversy regarding paraquat induction of Parkinson's disease in mice. I evaluated paraquat toxicity in both C57BL/6J and FVB wild-type mice. I observed no differences in any of the neurological endpoints in C57BL/6J and FVB mice. I next evaluated diazinon, dieldrin, endosulfan, maneb, MPP+, and rotenone as P-gp substrates or inhibitors. None of the pesticides inhibited P-gp. Only rotenone stimulated ATPase activity, suggesting that rotenone is a P-gp substrate. It is possible that exposure to rotenone may confer differential Parkinson's disease risk in individuals with genetic variation in ABCB1. Collectively, I screened the pesticides associated with Parkinson's disease as P-gp substrates and inhibitors. Indentifying rotenone as a P-gp substrate has provided the first piece of evidence towards identifying a potential mechanism for the association between genetic variation in ABCB1 and Parkinson's disease. The observations gathered from the models of P-gp transport and pesticide toxicity evaluated herein will be pivotal in further evaluation of the association of genetic variation in ABCB1 and Parkinson's disease risk. It is possible that this association may be a result of another exposure or endogenous molecule, however, the role of genetic variation in ABCB1 and Parkinson's disease remains unclear. Further, the use of paraquat as a reproducible method to induce Parkinson's disease in mice is an unreliable model of Parkinson's disease and requires further investigation.

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© Copyright 2013 Sarah Elizabeth Lacher