GENETIC SUSCEPTIBILITY TO PCB-INDUCED DEVELOPMENTAL NEUROTOXICITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that bio-accumulate in the food supply and resist environmental degradation. In September 2008, Kentucky identified numerous waterways where PCB-contaminated fish remain a human health concern. Recently, new sources of human exposure have been identified including wood treatments and construction materials used in older homes and schools. Studies of human populations near the most polluted sites have found learning, memory and behavioral abnormalities in children exposed during pregnancy and breast-feeding. Not all exposed individuals experience the same level of adverse health effects, indicating that genetic differences are important in determining who is at highest risk. The applicant previously used a novel mouse model to identify two genes which affect susceptibility to PCB exposure during brain development: the aryl hydrocarbon receptor (Ahr) and cytochrome P450 1A2 (Cyp1a2). PCB-treated mice with a high-affinity AHR and lacking CYP1A2 showed deficits in tests of spatial and non-spatial learning and memory and an attenuated startle response. Prenatal stress can produce a similar behavioral phenotype in conjunction with reduced expression of the glucocorticoid receptor and related genes regulated by DNA methylation. AHR activation was recently shown to increase the activity of DNA methylases. Therefore, we hypothesize that persistent activation of the AHR alters normal brain development and the response to stress via epigenetic mechanisms.