The role of mutagenic and carcinogenic environmental contaminants in adverse pregnancy outcome will be investigated. Define chemical exposures in vitro at discrete development periods will be used. Chemically-treated blastocyst stage embryos will be transferred to pseudopregnant surrogate mothers and subsequent post-implantation development will be studied. Previous experiments in this lab have established that preimplanatation exposure results in disruption of blastocyst function (e.g., implantation rate, resorption rate and live birth rate). Offspring developed from chemically treated blastocyst have a higher crude mortality rate (especially in the perinatal period) than offspring derived from solvent exposed blastocyst. Chemically exposed blastocysts develop into fetuses with growth retardation and gross dysmorphogenesis. Previous data suggest that blastocyst dysfunction is the result of subtle non- lethal mutations as a results of toxic exposure at the blastocyst stage of development. We will test the hypothesis with (+) syn BP 7,8-dihydrodiol 9,10-epoxides in comparison with (+) anti BP 7,8- dihydrodiol 9,10-eposides. The former are cytotoxic but not mutagenic while the latter are cytotoxic and mutagenic. We have established that endometrial lining cells have the capacity to metabolize (-)trans benzo(alpha)pyrene 7,8-dihydrodiol to BP 7,8- dihydrodiol 9,10-expoides which can than alter the development of the blastocyst into a fetus. The endometrium is a quantitatively important source of enzymes capable of bioactivation of xenobiotic compounds which can cause blastocyst dysfunction. The induction of these enzymes can be modulated by steroids. We will to establish the role of inducible bioactivation of toxic chemicals in poor pregnancy outcome and to establish the mechanism of steroid modulation of induction of such enzyme activity. Finally we will attempt to intervene in electrophilic toxic damage to the developing embryo in transgenic mice produced to overexpress the enzyme glutathione-S-transferase (Ya) which we have produced.
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