The long-term goals of this research are to determine the mechanisms by which polychlorinated biphenyls (PCBs) disrupt thyroid hormone action during brain development, and to define the neurological consequences of this disruption. PCBs are widespread and persistent environmental contaminants, and incidental exposure to PCBs have been associated with reduced circulating levels of thyroid hormones in pregnant women, lower birth weight and early growth rate, and neurological deficits. There is general speculation that the polyhalogenated biphenyl is similar enough in structure to thyroid hormone that it interacts with the thyroid hormone receptor and functions as a hormone agonist, antagonist or mixed agonist/antagonist. However, this speculation has been largely untested either in vivo or in vitro. Work proposed in this application will test this hypothesis directly. Representative coplanar (PCB 77 and PCB 126), and non-coplanar (PCB 105, 118, 153, and 138) congeners will be evaluated both in vivo and in vitro for their ability to act as thyroid hormone analogues. In vivo experiments will determine the ability of individual PCB congeners to regulate the expression of specific thyroid hormone-responsive genes in the developing brain, including RC3/Neurogranin and myelin basic protein (MBP), and will identify the pattern of halogen substitution associated with this activity. In addition, thyroid hormone-responsive developmental processes will be evaluated including cerebellar granule cell proliferation and apoptosis. A second series of experiments will determine whether these effects are independent of endogenous thyroid hormone, precluding the possibility that PCBs influence thyroid hormone metabolism. In vitro experiments will determine whether individual congeners can bind to the thyroid hormone receptor, whether binding characteristics differ between the TR 1 and TR 1 thyroid hormone receptor and whether the binding mediates agonist or antagonist activity. This in vivo activity will be correlated with the in vivo activity to confirm the mechanism by which these individual congeners affect brain development. Previous work indicates that perinatal exposure to PCBs affects the sensitivity of the hypothalamic-pituitary-thyroid axis to the negative feedback action of thyroid hormone of the adult. Studies are designed to test this hypothesis directly. These studies have the potential to identify individual PCB congeners with thyroid hormone agonist or antagonist actions. In addition, these studies will identify adverse neurological effects and the doses required for these effects.
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