INFLUENCE OF BENZO(A)PYRENE ON OVARIAN FUNCTION

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 注：表和图与总体研究摘要文件一起上传。 背景 多环芳烃（PAH）家族包括100种不同的化合物，其中之一是苯并（a）芘（BaP）。这些化合物是由涉及高温热解过程的天然和合成来源形成的，然而，来自合成来源的多环芳烃在环境中的分布更多。人类接触的来源，尽管不是一个详尽的清单，但包括：家庭取暖和用煤或木头做饭、香烟烟雾、汽车尾气排放、受污染的食品、焦炭、石墨电极和碳阳极的制造业。 BaP及其代谢产物与E2的空间相似性赋予这些分子雌激素和抗雌激素活性。BaP的雌激素样作用的例证是其促进人乳腺终末导管细胞培养物的增殖以及改变E2代谢的能力。相反，苯并（a）芘和其他多环芳烃通过降低循环中的E2水平而表现出抗雌激素活性。循环中E2的减少可能是由于BaP诱导的E2合成和释放减少或通过肝细胞色素P-450酶促进E2代谢而发生的。E2减少的最终结果是E2受体合成和E2介导的生物学功能减少，特别是在卵巢中。 由于PAH在环境中的广泛存在以及人类接触的可能性很大，因此值得研究该化合物对哺乳动物卵巢功能的潜在不良影响。 具体目标 1)测定苯并（a）芘在雌性大鼠体内的生物利用度和毒代动力学。 2)确定苯并（a）芘处理对大鼠动情周期期间性腺类固醇和调节这些类固醇的垂体激素的血浆浓度的影响。 3)探讨苯并（a）芘（BaP）对卵巢外分泌功能及黄体维持的影响。 4)确定苯并（a）芘对受精和着床前发育的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NOTE: Tables and Figures were uploaded with the Overall Research Summary file. BACKGROUND The polycyclic aromatic hydrocarbon (PAH) family includes 100 different compounds one of them being benzo(a)pyrene (BaP). These compounds are formed from natural and synthetic sources that involve high-temperature pyrolytic processes, however, PAHs originating from synthetic sources are quantitatively more distributed in the environment. Sources of human exposures, albeit not an exhaustive list, include: home heating and cooking with coal or wood, cigarette smoke, automobile exhaust emissions, contaminated foods, manufacturing industries for coke, graphite-electrode and carbon-anode. The steric resemblance of BaP and their metabolites to E2 confers estrogenic and antiestrogenic activity to these molecules. Estrogenic effect of BaP is exemplified in its ability to promote the proliferation as well as the alteration of E2 metabolism of human mammary terminal duct cell cultures. On the contrary, BaP and other PAHs exhibit their antiestrogenic activity by decreasing circulating levels of E2. The reduction in circulating E2 could occur either by BaP-induced decreases in the synthesis and release of E2 or via the enhancement of E2 metabolism by liver cytochrome P-450 enzyme. The ultimate result of the reduction in E2 is the reduction of E2 receptor synthesis and E2 mediated biological function particularly in the ovaries. Because of the widespread availability of PAH in the environment and the considerable probability of human exposure, the potential adverse effects of this compound the functioning of the mammalian ovary merit investigation. SPECIFIC AIMS 1) To determine the bioavailability and toxicokinetics of benzo(a)pyrene in female rats. 2) To determine the effect of BaP treatment on plasma concentrations of gonadal steroids and the pituitary hormones that regulate these steroids during the rat estrous cycle. 3) To determine the effect of BaP on ovarian exocrine function and luteal maintenance. 4) To determine the effect of BaP on fertilization and pre-implantation development.