The broad, long term objective is to provide a better understanding of mechanisms whereby foreign organic chemicals produce persistent birth defects in humans. It is expected that such an understanding will lead to a minimization of human birth defects, an enormous problem in modern society. Specifically, the research is designed to elucidate the mechanistic roles of individual embryonic P450 cytochromes (whose genes are expressed during organogenesis in human embryonic tissues) as determinants of the capacity of certain chemicals to produce dysmorphogenesis/embryotoxicity. Focus is on organogenesis because this is the period of gestation during which the conceptus reputedly is most sensitive to chemical insult. The research will focus on P450 isoforms expressed in three specific human embryonic tissues - brain, adrenal gland and liver. Focus on the former two is because of high importance as target sites for embryotoxic effects and on the liver because of background information and relatively high levels of certain isoforms. Expression and regulation of expression of CYP1B1 in these tissues will be given high priority because P4501B1 mRNA has been detected in each of the three tissues of interest, because 1B1 seems likely to play an important role in developmental processes, and because 1B1 can be profoundly regulated by both environmental chemicals (e.g., TCDD) and endogenous chemicals (e.g., cAMP). Next priority will be given to isoforms now also found to be expressed in human embryonic tissues. These are P450s 2E1, 3A7 and 1A1. 2E1 has been detected in human embryonic cephalic tissues, 3A7 is present in relatively high quantities in human embryonic liver, and 1A1 has been found in human embryonic liver and brain. Evidence for still other P450 isoforms in these tissues has been found and efforts will be made to identify and determine their roles as determinants of chemically induced embryotoxicity. The tools of modern molecular biology and biochemistry will be used to characterize these isoforms, particularly in terms of mechanisms of their regulation in embryonic tissues. A rodent whole embryo culture system will be utilized for examination of the mechanistic roles that individual P450 isoforms can play in the embryotoxic effects of specific chemicals. Results obtained should provide health professionals and regulatory agencies a more rational basis for advising women with respect to their exposures to drugs and environmental chemicals during pregnancy.
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