The overall goal of the FRIENDS Children's Environmental Health Center is to understand the impact of prenatal exposure to contaminants found in fish-including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and methyl mercury (MeHg)-on cognitive, motor and auditory function of children. The animal studies described in this proposal will complement a parallel prospective birth cohort study (Project 2) in which children born to women consuming fish contaminated with these chemicals will be followed longitudinally from birth. The animal studies will'use an experimental PCB mixture that mimics the PCB congener profile in the fish consumed by women in the epidemiological study. One major goal is to elucidate the effects of PCBs and PBDEs on important executive processes including attention and inhibitory control. Drug challenges with methylphenidate and amphetamine will determine if commonly prescribed ADHD pharmacotherapies improve the performance of PCB- or PBDE-exposed rats on tests of attention and response inhibition, and measures of DA D4 and DA D1 receptor expresion and drug challenges using specific DA D4 and DA D1 receptor agonists will indicate whether these receptor pathways are involved in mediating the behavioral effects. These studies will be conducted in parallel with another laboratory study (Project 4) which will investigate the effects of PCB and PBDE exposure on central catecholamine function and the extent to which these effects are mediated indirectly through PCB or PBDE effects on circulating thyroid hormones. A second major goal is to understand the mechanisms through which PCBs damage the cohclea and produce hearing loss. Histological examinations of the cochlea will confirm whether hearing deficits are due to outer hair cell damage. The contribution of reductions in circulating thyroid hormones or alterations in ryanodine receptor expression in the cochlea to PCB-induced hearing loss will be investigated by utilizing two specific PCB congeners having opposing effects on thyroid hormones and ryanodine channel activity. Because the outer hair cells are believed to protect against noise induced hearing loss, studies will also be conducted to determine if early PCB exposure increases susceptibility to noise-induced hearing loss later in life. As in the past, findings from these animal studies will guide the selection of outcome measures for use in the birth cohort.
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