THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY
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University of Cincinnati / OhioLINK
2007
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin11962540872021-08-03T06:12:23Z THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY CURRAN, CHRISTINE PERDAN toxicology environmental genetics PCBs polychlorinated biphenyls genetic susceptibility AHR aryl hydrocarbon receptor learning and memory behavior neurotoxicity immunosuppression 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 <i>Cyp1a2(+/+)</i>wild-type and <i>Cyp1a2(-/-)</i>knockout mice with either a high-affinity or poor-affinity <i>Ahr</i>gene. We hypothesized that high-affinity <i>Ahr <sup>b</sup>Cyp1a2(-/-)</i>would be most susceptible and poor-affinity <i Ahr=""> <sup>d</sup>Cyp1a2(+/+)</i>most resistant to PCB-induced developmental neurotoxicity. Using GC-ECD, we determined that offspring of <i>Cyp1a2(-/-)</i>mothers were exposed to higher levels of coplanar PCBs during development and that <i>Ahr <sup>b</sup></i>mice 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 <i>Ahr <sup>b</sup>Cyp1a2(-/-)</i>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. 2007 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
toxicology environmental genetics PCBs polychlorinated biphenyls genetic susceptibility AHR aryl hydrocarbon receptor learning and memory behavior neurotoxicity immunosuppression |
| spellingShingle |
toxicology environmental genetics PCBs polychlorinated biphenyls genetic susceptibility AHR aryl hydrocarbon receptor learning and memory behavior neurotoxicity immunosuppression CURRAN, CHRISTINE PERDAN THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY |
| author |
CURRAN, CHRISTINE PERDAN |
| author_facet |
CURRAN, CHRISTINE PERDAN |
| author_sort |
CURRAN, CHRISTINE PERDAN |
| title |
THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY |
| title_short |
THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY |
| title_full |
THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY |
| title_fullStr |
THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY |
| title_full_unstemmed |
THE ROLE OF ARYL HYDROCARBON RECEPTOR AND CYP1A2 IN PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY |
| title_sort |
role of aryl hydrocarbon receptor and cyp1a2 in pcb-induced developmental neurotoxicity |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2007 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1196254087 |
| work_keys_str_mv |
AT curranchristineperdan theroleofarylhydrocarbonreceptorandcyp1a2inpcbinduceddevelopmentalneurotoxicity AT curranchristineperdan roleofarylhydrocarbonreceptorandcyp1a2inpcbinduceddevelopmentalneurotoxicity |
| _version_ |
1719432704070516736 |