Exposure to Ambient Air Pollution and Temperature During Spermatogenesis: Impact on Men's Reproductive Health and Infertility Treatment Outcomes

项目总结/摘要 在美国，大约12%的夫妇寻求不孕症治疗，这对一些人来说与不孕症有关。 治疗相关的副作用，治疗相关的压力源，以及重大的经济负担。尽管男性- 因素不孕症导致估计30-50%的夫妇不孕症病例，风险因素，机制， 对男性因素不育症的潜在干预措施研究严重不足。环境空气污染和 极端环境温度是与全身炎症和氧化性炎症相关的普遍暴露， 压力，精子发生过程可能是唯一易受影响的。研究发现， 高水平的空气污染可能会对精液质量产生不利影响;然而， 精子发生对精液质量的发育敏感窗口，对精子表观遗传因子的影响 包括DNA甲基化，以及男性伴侣暴露对不孕症治疗的累积影响 成果很少得到评价。本研究将利用叶酸和锌补充剂的数据， 试验（FAZST），以估计周围环境因素对男性生育力的影响， 个人暴露于环境空气污染和温度。除了来自那些 低至中度的空气污染水平，这项研究将评估暴露于空气污染和高，低 在精子发生（有丝分裂，减数分裂， 精子发生和精子形成）与精液质量，利用来自更多 超过1，900人（目标1）。精子的表观遗传改变越来越被认为是一种潜在的 影响男性生育力的机制，暴露于几种氧化应激诱导和内分泌- 破坏与精子中DNA甲基化差异相关的环境因素。这项研究将进行一个新的 评估环境空气污染暴露对精子DNA甲基化的影响（目标2）。最后 研究将利用不孕症治疗周期（体外受精和宫内节育）的结果信息， 授精周期）和处理相关精液样本的时间，以评估男性伴侣的影响 精子发生过程中暴露于空气污染和环境温度对怀孕概率的影响 不孕症治疗，考虑胚胎发生和植入期间的暴露窗口（目标3）。这 职业发展奖将延长候选人的环境培训和研究经验， 通过在表观遗传学、空气质量和生殖流行病学方面提供专家指导和有针对性的培训， 暴露评估和因果推断。她的主要导师Richard Pilsner博士（表观遗传学），沿着 她的指导团队成员Timothy Canty博士（空气质量建模）和Laura Balzer博士（因果关系 推理），为候选人提供必要的指导，以建立一个富有成效的独立研究 程序.除了有针对性的培训外，K 01奖还将为环境空气的影响提供新的证据 污染和温度对男性生殖健康和不孕症治疗结果的影响。

PROJECT SUMMARY/ABSTRACT Approximately 12% of couples in the United States seek infertility treatment, which for some is associated with treatment-related side-effects, treatment-related stressors, and a significant financial burden. Although male- factor infertility contributes to an estimated 30-50% of cases of couple infertility, risk factors, mechanisms, and potential interventions for male-factor infertility have been critically understudied. Ambient air pollution and ambient temperature extremes are ubiquitous exposures associated with systemic inflammation and oxidative stress, to which the process of spermatogenesis may be uniquely susceptible. Research has found exposure to high levels of air pollution may adversely impact semen quality; however, the effect of exposure during developmentally-sensitive windows of spermatogenesis on semen quality, impacts on sperm epigenetic factors including DNA methylation, and the cumulative impact of male partner exposure on infertility treatment outcomes have been little evaluated. This study will utilize data from the Folic Acid and Zinc Supplementation Trial (FAZST) to estimate impacts of ambient environmental factors on male fertility, adding estimates of individual exposure to ambient air pollution and temperature. Adding to sparse literature from countries with low-to-moderate levels of air pollution, this study will evaluate exposure to air pollution and high and low ambient temperatures during developmentally susceptible windows of spermatogenesis (mitosis, meiosis, spermiogenesis, and spermiation) with semen quality, leveraging four repeated semen samples from more than 1,900 participants (Aim 1). Epigenetic alterations in sperm are increasingly recognized as a potential mechanism impacting male fertility, with exposure to several oxidative stress-inducing and endocrine- disrupting environmental factors linked to differential DNA methylation in sperm. This study will conduct a novel assessment of the impact of ambient air pollution exposure on sperm DNA methylation (Aim 2). Finally, this study will utilize information on outcomes of infertility treatment cycles (in vitro fertilization and intrauterine insemination cycles) and timing of treatment-related semen samples to evaluate the impact of male partner exposure to air pollution and ambient temperature during spermatogenesis on probability of pregnancy during infertility treatment, accounting for exposure windows during embryogenesis and implantation (Aim 3). This career development award will extend the candidate’s prior training and research experience in environmental and reproductive epidemiology by providing expert mentoring and targeted training in epigenetics, air quality exposure assessment, and causal inference. Her primary mentor Dr. Richard Pilsner (epigenetics), along with members of her mentoring team Dr. Timothy Canty (air quality modeling) and Dr. Laura Balzer (causal inference), with provide the needed mentoring for the candidate to establish a productive independent research program. In addition to targeted training, this K01 award will add novel evidence for the impact of ambient air pollution and temperature on men’s reproductive health and outcomes of infertility treatment.