The long-range goal of the proposed research is to better understand mechanisms whereby foreign organic chemicals produce malformations and other forms of toxicity in developing embryos. Because recent research as indicated that embryonic enzyme systems can catalyze conversion of environmental chemicals to quantities of reactive intermediates sufficient to elicit readily observalbe gross malformations, an integral aspect of the outlined investigation is the study of specific embryonic bioactivating enzyme systems. Preliminary studies suggest that at least two embryonic P-45's (P-450c and P-450p) can effect highly significant bioactivating activity. It is the intention of this proposal to focus on these two hemoproteins in terms of their bioactivating potential in embryonic tissues. In order to avoid the influence of potentially confounding maternal factors, the whole embryo culture system has been chosen for study. The two hemoproteins will be analyzed with a combination of substrate probe analyses, inhibitor probe analyses and immunoquantitation. Investigations of the models of regulation of these embryonic hemoproteins will be initiated. The feasibiity of the approaches has been demonstrated in preliminary experiments. Comparisons of rodent embryos with prenatal tissues from humans and subhuman primates will also be made. Results obtained from the research should provide health professionals a more rational basis for providing advice to pregnant women with respect to their exposure to foreign organic chemicals.
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