The interaction between NAT2 acetylator status and exposure to tobacco smoke on ovarian reserve and in vitro fertilization outcomes.

 描述（申请人提供）：美国妇女生育能力受损（>11%）和不孕症（>6%）的患病率相当高，目前的科学知识仍无法解释相当大比例（>15%）的不孕症。本研究的目的是进一步了解基因-环境相互作用在不孕症中的作用。吸烟对卵巢储备和体外受精程序的有害影响是显而易见的，但需要做更多的研究来了解终身暴露于吸烟和二手烟对不孕症的累积影响。暴露于烟草烟雾可能对携带特定慢乙酰化形式的NAT 2的患者更有害，NAT 2是一种在烟草烟雾中存在的芳香胺代谢中起重要作用的基因。在这项研究中，将评估单独吸烟、单独NAT 2及其联合作用对卵巢储备和体外受精（IVF）的影响。过去和现在的烟草烟雾暴露将通过问卷调查和测定可替宁来确定，可替宁是一种吸烟的生物标志物，将在尿液和卵泡液中进行测量。在目标1中，将评估终身暴露于主动吸烟和被动吸烟（二手烟）对卵巢储备和IVF成功的累积效应。将通过测量抗苗勒管激素水平和窦卵泡计数来确定卵巢储备。IVF的成功将取决于取卵计数、受精率和临床妊娠的建立。在目标2中，将对患者进行测试，以确定他们是否携带NAT 2基因的慢乙酰化形式，并确定这些个体是否会增加卵巢储备或降低IVF成功率。由于NAT 2可使芳香族和杂环胺解毒，并在整个生命周期中负责芳香胺和芳香肼药物作用的变异性，因此缓慢的NAT 2表型可能与卵巢储备和IVF结果的测量相关，而与暴露于烟草烟雾无关。在目标3中，将研究吸烟和NAT 2对卵巢储备和IVF成功的相互作用。据推测，烟草烟雾暴露对这些结果的影响将在缓慢乙酰化中加剧。这项工作的发现将有助于了解不孕症，特别是环境/行为风险因素和遗传易感性如何相互作用，以降低妇女的生育能力和缩短其生殖寿命。

 DESCRIPTION (provided by applicant): The prevalence of impaired fecundity (>11%) and infertility (>6%) among women in the United States is considerable, and a significant proportion (>15%) of infertility remains unexplained by current scientific knowledge. The aim of this research is to further the understanding of the role that gene-environment interactions play in infertility. The deleterious effects of smoking on ovarian reserve and on in vitro fertilization procedures are evident, but more research needs to be done to understand the cumulative effects of lifetime exposure to smoking and to secondhand smoke on infertility. Exposure to tobacco smoke may be more harmful in patients who carry a particular slow-acetylator form of NAT2, a gene which plays an important role in metabolism of aromatic amines present in tobacco smoke. In this study, the effects of smoking alone, NAT2 alone, and their combined effects on ovarian reserve and in vitro fertilization (IVF) will be estimated. Past and current exposure to tobacco smoke will be determined by questionnaires and by assaying cotinine, a biomarker of smoking that will be measured in urine and follicular fluid. In Aim 1, the cumulative effect of lifelong exposure to active and passive smoking (secondhand smoke) on ovarian reserve and IVF success will be estimated. Ovarian reserve will be determined by measuring anti-Müllerian hormone levels and antral follicle count. Success of IVF will be determined by oocyte retrieval count, fertilization rate, and establishment of a clinical pregnancy. In Aim 2, patients will be tested to determine whether they carry the slow-acetylator form of the NAT2 gene, and it will be determined whether these individuals experience increased ovarian reserve or lower IVF success. Because NAT2 detoxifies aromatic and heterocyclic amines and is responsible for variability in the effect of arylamine and arylhydrazine drugs throughout the lifespan, the slow NAT2 phenotype may be associated with measures of ovarian reserve and IVF outcomes regardless of exposure to tobacco smoke. In Aim 3, the interaction between smoking and NAT2 on ovarian reserve and IVF success will be investigated. It is hypothesized that the effects of tobacco smoke exposure on these outcomes will be exacerbated among slow acetylators. Findings from this work will contribute to the understanding of infertility, especiall how environmental/behavioral risk factors and genetic susceptibility may interact to reduce a woman's fertility and shorten her reproductive lifespan.