Modulation of PAH ovarian toxicity by biotransformation enzyme polymorphisms

描述（由申请人提供）：12%的美国女性患有不孕症或生育能力受损。卵巢功能障碍，包括卵巢早衰是不孕不育的主要原因。很可能暴露于环境毒物中导致卵巢功能受损的病例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，已知会损害卵巢功能并导致啮齿动物卵巢功能衰竭，并且可能是女性卵巢毒物。烟草烟雾、食物和空气污染都是接触多环芳烃的来源。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性可能起着重要作用。本提案中概述的工作将证明一项更大规模研究的可行性，以验证参与代谢多环芳烃的1期和2期生物转化酶的遗传变异调节女性多环芳烃卵巢毒性的假设。具体目的1：为分析多环芳烃暴露与生物转化酶多态性和可育性（妊娠时间）之间的关系，测试前瞻性测量妊娠时间和多环芳烃暴露的可行性，以及使用全基因组基因分型方法确定多环芳烃生物转化酶多态性的可行性。具体目的2：为了研究多环芳烃代谢酶多态性与多环芳烃暴露和月经周期异常之间的关系，测试使用微电子量尺监测仪测量多个月经周期内每日尿生殖激素浓度的可行性。特异性目的3：试点测试血清抗- m - |勒氏激素、促卵泡激素和抑制素B浓度作为卵巢储备的标志物，以研究多环芳烃暴露与卵巢储备减少之间的关系。公共卫生相关性：本研究的主要和长期目标是了解毒物如何导致卵巢功能障碍，以便我们能够预防它。这些研究将有助于我们理解为什么有些女性对卵巢毒物比其他女性更敏感。在这样做的过程中，他们也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.