Project Summary/Abstract Thyroid hormone (TH) is essential for normal brain development in humans and in animals. Thus, it is important that a large number of manufactured chemicals can interfere with TH action, and by a variety of mechanisms. Some chemicals interfere directly with the TH receptor (TR) while others directly affect the thyroid gland, or serum binding proteins, deiodinases or transporters. The long- term goal of our work is to understand the mechanisms of ?thyroid disruption? and apply this to human populations. Our earlier work has demonstrated that specific polychlorinated biphenyls (PCBs) can activate the TR in a cell-based luciferase assay only if the enzyme CYP1A1 was induced and active. This enzyme can hydroxylate parent PCBs, and these OH-PCBs may then act directly on the TR or may act on other proteins that control TH action. Importantly, in animals treated with specific PCB congeners, there is a tight correlation between CYP1A1 induction and measures of TH action in the liver. More recently we have shown this to be true in human placenta as well: CYP1A1 expression was very strongly correlated with the expression of two genes directly regulated by TH ? Placental Lactogen (hPL) and Growth Hormone Variant (GHV). These findings are consistent with the proposition that manufactured chemicals may interfere with TH action during development in the absence of changes in serum TH concentrations. However, we have not identified the chemicals involved or the mechanism by which they may act. We propose now to pursue this work with two Specific Aims: First, to measure PCBs and OH-PCBs in the placental samples (n = 30) that had the highest and lowest CYP1A1 expression in our previous report. This comparison should identify specific congeners and metabolites that we can pursue in Specific Aim 2 to test their ability to the TR using cell-based and biochemical assays.