In -utero and lactational exposure of humans to polychlorinated biphenyls (PCBs) is associated with cognitive dysfunctions while developmental exposure of laboratory animals to PCBs induces changes in neurotransmitter and cognitive function. Because most laboratory-based and epidemiological studies have investigated the effects of developmental exposure to either mixtures of PCBs or complex environmental samples, it is necessary, in order to understand the mechanisms by which PCBs alter the development and function of the central nervous system, to study the developmental effects of exposure to individual congeners. We propose to determine the neurochemical, neurobehavioral and endocrine effects of in-utero and lactational exposure of the laboratory rat to individual coplanar, di- ortho-substituted and mono-ortho-substituted PCB congeners that we hypothesize will alter neurochemical and second messenger systems and the development of key endocrine systems needed for normal brain development. We will determine; (i) biogenic amine neurotransmitter concentrations in striatal brain slices following in-vitro exposure to these congeners; (ii) regional brain biogenic amine concentrations, circulating concentrations of T3, T4, TSH and circulating gonadotropins in offspring exposed during gestation and lactation to these congeners; (iii) neurochemical, neurobehavioral and endocrine responses in offspring exposed during development to pharmacologic agents and in-vivo generated metabolites (alpha-methyl paratyrosine, NSD-1015, propylthiouracil, catecholestrogens and hydroxybiphenyls) and (iv) changes in cognitive function in animals exposed to PCB congeners and the above agents. These experiments, using a number of prototypical PCB congeners, will allow us to determine which congeners directly affect the development of important neurotransmitters; which congeners indirectly affect brain development by altering key endocrine systems during development and the behavioral consequences of developmental exposure to these congeners. In turn, these data will allow a more complete understanding of the action of complex mixtures of congeners, the risk to the developing human and suggest pharmacologic and behavioral strategies that may ameliorate some of the cognitive dysfunctions observed in developmentally-exposed human infants.
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