ROLE OF ENVIRONMENTAL MUTAGENS IN POOR PREGNANCY OUTCOME

致突变和致癌环境污染物的作用 不良妊娠结局。 定义化学物质 将使用在不连续的发育期的体外暴露。 化学处理的囊胚期胚胎将被转移到 假孕代孕母亲和随后的植入后 将研究发展。 这个实验室以前的实验 确定了预先暴露会导致 胚泡功能（例如，着床率、吸收率 活产率）。 经过化学处理的后代 囊胚的粗死亡率较高（特别是在 围产期）比来自溶剂暴露的后代 胚泡。 暴露于化学物质的胚泡发育成胎儿 患有生长迟缓和严重畸形 先前数据 提示胚泡功能障碍是由于 囊胚毒性暴露导致的致命突变 发展阶段。 我们将用（+）syn BP来检验这个假设 7，8-二氢二醇9，10-环氧化物与（+）抗BP 7，8- 二氢二醇9，10-eposides。 前者具有细胞毒性， 致突变，而后者是细胞毒性和致突变的。 我们有 确定子宫内膜衬里细胞有能力 将（-）反式苯并（α）芘7，8-二氢二醇代谢为BP 7，8- 二氢二醇9，10-内酯，然后可以改变发展， 将胚泡植入胎儿体内 子宫内膜在数量上 能够生物活化异生素酶的重要来源 会导致胚泡功能障碍的化合物。 感应 这些酶可以通过类固醇调节。 我们将 确定有毒化学品的可诱导生物活化作用 在不良妊娠结局和建立类固醇的机制 调节这种酶活性的诱导。 最后我们将 试图干预亲电性毒性损害 在过度表达 我们生产的谷胱甘肽-S-转移酶（Ya）。

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.