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THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY

CURRAN, CHRISTINE PERDAN
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087

Abstract Details

2007, PhD, University of Cincinnati, Medicine : Toxicology (Environmental Health).
Polychlorinated biphenyls (PCBs) are persistent organic pollutants linked to numerous human health problems, including learning and memory deficits in children of exposed mothers. PCBs exist in the environment as complex mixtures. Both coplanar and non-coplanar PCBs are reported to have neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. We used a mixture of eight PCBs to model human exposures based on their reported concentrations in human tissue, breast milk, and the human food supply. Individual risk to PCBs varies by genetic makeup. We developed a mouse model to explore the role of two genes that may be responsible for some of the reported inter-individual differences: the aryl hydrocarbon receptor (AHR) and CYP1A2. There are >12-fold differences between humans with regard to AHR affinity and >60-fold differences in hepatic basal CYP1A2 levels. Our mouse model used Cyp1a2(+/+)wild-type and Cyp1a2(-/-)knockout mice with either a high-affinity or poor-affinity Ahrgene. We hypothesized that high-affinity Ahr bCyp1a2(-/-)would be most susceptible and poor-affinity dCyp1a2(+/+)most resistant to PCB-induced developmental neurotoxicity. Using GC-ECD, we determined that offspring of Cyp1a2(-/-)mothers were exposed to higher levels of coplanar PCBs during development and that Ahr bmice metabolized all PCB congeners more quickly. Differences in PCB exposure were closely correlated with changes in CYP1A1 and CYP1A2 mRNA and protein levels and with well-known endpoints of AHR-mediated toxicity: immunosuppression and hepatotoxicity. In addition, we conducted behavioral phenotyping of exposed offspring. We found significant deficits in learning and memory in Ahr bCyp1a2(-/-)mice, including impairments in novel object recognition and an increased failure rate in the Morris water maze. However, all PCB-treated groups and all genotypes showed significant differences in at least one measure of learning or behavior. We conclude that both the high-affinity AHR and CYP1A2 play a role in protecting offspring from PCB exposure during gestation and lactation. These findings also implicate coplanar PCBs as an essential element in PCB-induced neurotoxicity. The genetic differences uncovered in our studies suggest further study is warranted to elucidate the role of CYP1A2 and the AHR in normal central nervous system development.
Dr. Daniel Nebert (Advisor)
176 p.
toxicology; environmental genetics; PCBs; polychlorinated biphenyls; genetic susceptibility; AHR; aryl hydrocarbon receptor; learning and memory; behavior; neurotoxicity; immunosuppression

Recommended Citations

Citations

  • CURRAN, C. P. (2007). THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087

    APA Style (7th edition)

  • CURRAN, CHRISTINE. THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY. 2007. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087.

    MLA Style (8th edition)

  • CURRAN, CHRISTINE. "THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.