Genetic susceptibility to PCB-induced developmental neurotoxicity.
Curran-CP; Williams-MT; Vorhees-CV; Patel-KV; Nebert-DW
Birth Defects Research Part A 2008 May; 82(5):290
Polychlorinated biphenyls (PCBs) are widcspread 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 (209 possible congeners). Both coplanar and non-coplanar PCBs are reported to have neurotoxic effects in animal studies, but individual congeners do not, always produce the same eftects as PCB mixtures. We developed a mixture of 3 planar and 5 non-coplanar PCBs to model developmental human exposures. Using a mouse model that mirrors human variation in two genes associated with PCB metabolism (the aryl hydrocarbon receptor and CYP1A2), we hypothesized that genetic differences would lead to differential susceptibility and resistance following developmental PCB exposure. Specifically, we tested the hypothesis that Ahr(d)Cyp1a2(+/+) mice with a poor-affinity AHR and a functioning CYP1A2 enzyme would be most resistant while Ahr(b)Cypa2(-/-) mice with a high-affinity AHR and no CYP1A2 enzymc would be most susceptiblc to PCB-induced developmental neurotoxicity. We predicted that a third line of mice, Ahr(b)Cyp1a2(+/+), would show an intermediat phenotype. Pregnant dams were treated at gestational day 10 (GD10) and again at postnatal day 5 (PND5) with either the PCB mixture or the corn oil vehicle to insure exposure during early central nervous system development. We tested hippocampal-dependent spatial and non-spatial learning and memory in exposed offspring at PND60. We found the most striking deficits in learning and memory in Ahr(b)Cypa2(-/-) mice with significant impairments in Novel Object Recognition, significantly increased latency in Morris Water Maze Cued Platform tests, and a significantly increased failure rate in three phases of Morris Water Maze Hidden Platform testing. Ahr(d)Cyp1a2(+/+) mice showed no deficits in learning and memory compared with corn oil-treated control animals. We conclude that hepatic CYP1A2 is protective against learning and memory deficits in offspring exposed to a mixture of coplanar and non-coplanar PCBs. Because CYP1A2 sequesters planar, but not non-coplanar congeners, these findings also implicate coplanar PCBs as an essential element of PCB-induced neurotoxicity.
Health-hazards; Reproductive-hazards; Reproductive-system-disorders; Reproductive-effects; Hormones; Hormone-activity; Pollution; Polychlorinated-aromatic-hydrocarbons; Mental-disorders; Mental-processes; Neurotoxicity; Neurotoxins; Laboratory-animals; Laboratory-testing; Genetic-disorders
Birth Defects Research Part A-Clinical and Molecular Teratology