Modulation of PAH ovarian toxicity by biotransformation enzyme polymorphisms

描述(由申请者提供)：12%的美国女性患有不孕不育或生育能力受损。卵巢功能障碍，包括卵巢早衰，是不孕不育的主要原因。暴露在环境毒物中的卵巢功能受损病例可能比目前所认识到的要多得多。多环芳烃(PAHs)是一种普遍存在的环境污染物，可损害啮齿动物的卵巢功能，导致卵巢功能衰竭，可能是女性的卵巢毒物。烟草烟雾、食品和空气污染是接触多环芳烃的来源之一。对多环芳烃卵巢毒性易感性个体间差异的机制基础尚不清楚，但代谢多环芳烃的酶的多态可能起到重要作用。这项建议中概述的工作将证明进行一项更大规模研究的可行性，以检验参与代谢多环芳烃的第一相和第二相生物转化酶的遗传变异调节多环芳烃对女性的卵巢毒性的假设。具体目的1：探讨前瞻性测量受孕时间和多环芳烃暴露的可行性，以及应用全基因组基因分型方法测定多环芳烃生物转化酶基因多态性的可行性，以分析多环芳烃暴露与生物转化酶基因多态和生殖力(妊娠时间)之间的关系。具体目的2：检测多个月经周期的每日尿生殖激素浓度，研究多环芳烃代谢酶基因多态性与多环芳烃暴露及月经周期异常的关系。具体目的3：初步检测血清抗M|llerian激素、卵泡刺激素和抑制素B浓度作为卵巢储备的标志物，以研究PAH暴露与卵巢储备减少的关系。公共卫生相关性：这项研究的主要和长期目标是了解毒物是如何导致卵巢功能障碍的，以便我们能够预防它。这些研究将提供一些见解，帮助我们理解为什么一些女性比其他女性对卵巢毒物更敏感。通过这样做，他们还将为可能的干预措施奠定基础，以防止卵巢功能障碍。

DESCRIPTION (provided by applicant): Infertility or impaired fecundity affects 12% of American women. Ovarian dysfunction, including premature ovarian failure is a major cause of infertility. It is likely that exposure to environmental toxicants is responsible for many more cases of impaired ovarian function than is currently appreciated. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, which are known to impair ovarian function and cause ovarian failure in rodents and are probable ovarian toxicants in women. Tobacco smoke, foods, and air pollution are among the sources of exposure to PAHs. The mechanistic basis for interindividual variation in susceptibility to PAH ovarian toxicity is not understood, but polymorphisms in enzymes that metabolize PAHs likely play an important role. The work outlined in this proposal will demonstrate the feasibility of a larger study to test the hypothesis that genetic variations in Phase 1 and Phase 2 biotransformation enzymes involved in metabolizing PAHs modulate the ovarian toxicity of PAHs in women. Specific Aim 1: To test the feasibility of prospectively measuring time to pregnancy and PAH exposure and of using genomewide genotyping methods to determine PAH biotransformation enzyme polymorphisms for a study analyzing the associations between PAH exposure and biotransformation enzyme polymorphisms and fecundability (time to pregnancy). Specific Aim 2: To test the feasibility of using microelectronic dipstick monitors to measure daily urinary reproductive hormone concentrations over multiple menstrual cycles for study of the associations between PAH metabolizing enzyme polymorphisms and PAH exposure and menstrual cycle abnormalities. Specific Aim 3: To pilot test serum anti-M|llerian hormone, follicle stimulating hormone, and inhibin B concentrations as markers of ovarian reserve for study of the associations between PAH exposure and diminished ovarian reserve. PUBLIC HEALTH RELEVANCE: The primary and long-term goal of this research is to understand how toxicants cause ovarian dysfunction so that we can prevent it. These studies will provide insights that will help us to understand why some women are more sensitive to ovarian toxicants than other women. In so doing, they will also lay the groundwork for possible interventions to protect against ovarian dysfunction.