Study of Metals and Assisted Reproductive Technologies(SMART)

目的：总体目标是表征卵泡液中有毒微量元素和抗氧化酶活性的变异性，并确定变异性的预测因素。第二个目标是试点家庭精浆(SP)采集，并评估有毒微量元素的时间变化。 意义：拟议项目的结果将使我们能够修改计划中的更大规模研究的方案和分析策略，旨在更明确地调查微量接触有毒元素对体外受精(IVF)结果和种族差异的影响。根据最近公布的NHANES数据，2011-2012年间，亚洲人的有毒微量元素平均水平高于其他美国种族/民族，包括As、Cd、Pb和Hg。此外，在美国，亚洲女性的试管受精结果一直比白人女性差。一个受到越来越多关注的可能解释是，与饮食和健康行为相关的环境生殖有毒物质的不同暴露，包括有毒的微量元素。确定潜在的可改变的毒物暴露是必要的，以设计干预措施，最大限度地增加通过试管受精活产的可能性，或识别有高失败风险的夫妇。然而，进行试管受精的医生经常收集多个卵母细胞，从而产生多个胚胎，这些胚胎根据临床因素进行移植，以最大限度地提高活产的可能性。因此，研究人员无法确保来自采样卵泡的卵母细胞被转移并导致怀孕和活产，因此无法直接联系在FF中测量的分析物浓度。来自我们小组和其他人的初步数据表明，卵泡间有毒微量元素在卵泡内的变异性，因此无法实施一个卵泡-一个妊娠/分娩的调查性研究设计可能会降低统计能力。在缺乏数量惊人的研究参与者的情况下，需要一种方法论的解决方案。 创新：拟议的项目具有创新性，因为它是唯一一项表征有毒微量金属在FF中的可变性的研究，并评估它们作为研究试管受精结果的暴露生物标记物的有效性。 方法：我们在美国的研究人群中近三分之一由亚洲女性组成，因此我们将评估在试管受精程序的正常临床背景下与有毒微量元素的差异。我们将从本中心招募50对体外受精夫妇，并在取卵过程中从4个单独的卵泡收集卵泡液。我们将：1)检测卵泡内砷、镉、铅、汞的水平和6种抗氧化酶活性，以确定卵泡之间、卵巢之间、女性之间和分析因素之间的变异性来源；2)考虑卵泡体积、体外受精治疗方案、不孕不育诊断、年龄、种族、体重指数、吸烟、鱼类消费和其他因素作为预测卵泡变异性的因素；以及3)试行家庭精液样本收集策略，以评估SP有毒微量元素的纵向变化。研究团队的广泛合作经验和专业知识提高了成功的可能性。

Aims: The overall goal is to characterize the variability of toxic trace elements and anti-oxidant enzyme activities in ovarian follicular fluid (FF) and to identify predictors of variability. A secondary goal is to pilot home seminal plasma (SP) collection and to assess temporal changes in toxic trace elements. Significance: The results of the proposed project will allow us to modify the protocol and analytic strategy for our planned larger study intended to more definitively investigate the impact of trace exposures to toxic elements on in vitro fertilization (IVF) outcomes and race disparities. According to recently released NHANES data, Asians had higher average levels of toxic trace elements than other U.S. race/ethnicities in 2011-2012, including As, Cd, Pb and Hg. In addition, Asian women consistently demonstrate poorer IVF outcomes than white women in the U.S. One probable explanation that has received increasing attention is differential exposure to environmental reproductive toxicants associated with diet and health behaviors, including toxic trace elements. Identification of potentially modifiable toxicant exposures is necessary to design interventions that maximize the likelihood for live birth by IVF or to identify couples with a high risk of failure. However, physicians conducting IVF often collect multiple oocytes, leading to multiple embryos, which are transferred based on clinical factors to maximize the likelihood for a live birth. Investigators are thus unable to ensure oocytes from sampled follicles are transferred and lead to pregnancy and live birth, and so cannot directly link concentrations of analytes measured in FF. Preliminary data from our group and others indicate between-follicles variability for toxic trace elements in FF, and so an inability to implement a one follicle-one pregnancy/delivery investigational study design may reduce statistical power. In the absence of a prohibitively large number of study participants a methodologic solution is required. Innovation: The proposed project is innovative because it is the only study to characterize the variability of toxic trace metals in FF, and to assess their utility as biomarkers of exposure for studying IVF outcomes. Approach: Nearly 1/3 of our U.S. based study population is comprised of Asian women and so we will assess the disparity in relation to toxic trace elements in the normal clinical context of IVF procedures. We will recruit 50 IVF couples from our center, and collect FF from four individual ovarian follicles during oocyte retrieval. We will: 1) measure levels of As, Cd, Pb, Hg and six anti-oxidant enzyme activities in FF to characterize sources of variability between follicles, between ovaries, between women and from analytic factors; 2) consider FF volume, IVF treatment protocol, infertility diagnosis, age, race, body mass index, cigarette smoking, fish consumption and other factors as predictors of FF variability; and 3) pilot a home semen specimen collection strategy to allow evaluation of longitudinal changes in SP toxic trace elements. The likelihood of success is enhanced by the extensive collaborative experience and expertise of the research team.