ROLE OF ENVIRONMENTAL MUTAGENS IN POOR PREGNANCY OUTCOME

致突变和致癌环境污染物的作用 将对不良妊娠结局进行调查。定义化学物质 将使用在不同发育时期的体外暴露。 经过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 将对发展进行研究。这个实验室之前的实验已经 已确定植入前暴露会导致破坏 胚泡功能(如着床率、吸收率 和活出生率)。从化学处理中培育出的后代 胚泡有较高的粗死亡率(特别是在 围产期)，而不是接触溶剂产生的后代 胚泡。暴露在化学物质中的胚泡发育成胎儿 患有生长迟缓和肉眼畸形。以前的数据 提示胚泡功能障碍是微妙的非 胚泡毒性暴露导致的致死性突变 发展阶段。我们将使用(+)syn BP来检验该假设 7，8-二氢二醇9，10-环氧化物与(+)抗BP 7，8-环氧化物的比较 二氢二醇9，10-环氧乙烷。前者具有细胞毒性，但不 后者具有细胞毒性和致突变性。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-环氧丙烷 胚泡发育成胎儿。子宫内膜是一种定量的 外源生物生物活性酶的重要来源 可能导致胚泡功能障碍的化合物。归纳法 这些酶中的一种可以受到类固醇的调节。我们会 确定有毒化学物质的可诱导生物激活的作用 不良妊娠结局及类固醇作用机制的研究 对这种酶活性的诱导的调节。最后我们会 试图干预亲电性毒性损害 转基因小鼠发育中的胚胎过表达 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.