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

项目摘要/摘要 在美国，大约12%的夫妇寻求不孕不育治疗，对一些人来说，这与 与治疗相关的副作用，与治疗相关的压力源，以及重大的经济负担。虽然是男性- 据估计，30%-50%的夫妇不孕不育是由因素不孕、危险因素、发病机制和 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 环境温度极端是与全身炎症和氧化有关的普遍暴露 应激，精子发生过程特别容易受到这种压力的影响。研究发现，暴露于 到高水平的空气污染可能会对精液质量产生不利影响；然而，在 精子发生的发育敏感窗口对精液质量的影响以及对精子表观遗传因素的影响 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 结果几乎没有得到评估。这项研究将利用叶酸和锌补充剂的数据 试验(FAZST)估计环境因素对男性生育能力的影响，增加了对 个人暴露在环境空气污染和温度下。增加了来自以下国家的稀少文学作品 低至中等水平的空气污染，这项研究将评估暴露在空气污染和高和低水平 发育敏感的精子发生窗口(有丝分裂、减数分裂、 精子发生和精子受精)与精液质量，利用来自更多 1900多名参与者(目标1)。精子的表观遗传学改变越来越被认为是一种潜在的 影响男性生育的机制，暴露于几种氧化应激诱导和内分泌- 破坏与精子中差异DNA甲基化有关的环境因素。这项研究将进行一部小说 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，这一点 研究将利用关于不孕症治疗周期(体外受精和宫内受精)结果的信息 受精周期)和治疗相关精液样本的时间，以评估男性伴侣的影响 生精过程中暴露于空气污染和环境温度对妊娠概率的影响 不孕不育治疗，说明胚胎形成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以前在环境方面的培训和研究经验 通过提供表观遗传学、空气质量和生殖流行病学方面的专家指导和有针对性的培训 暴露评估和因果推断。她的主要导师理查德·皮尔斯纳博士(表观遗传学)，以及 她的指导团队成员蒂莫西·坎蒂博士(空气质量模特)和劳拉·巴尔泽博士(因果 推理)，并为候选人提供所需的指导，以建立富有成效的独立研究 程序。除了有针对性的培训外，这个K01奖项还将为环境空气的影响增加新的证据 污染和温度对男性生殖健康和不孕不育治疗结果的影响。

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.