Maternal and Paternal Flame Retardant Exposure, Impact on Fertility and Pregnancy

描述(申请人提供)：男性和女性不孕不育和不良妊娠结局的原因尚不清楚，但很可能是在人口水平上明显的环境和生活方式因素的复杂相互作用。病因可能包括接触广泛的合成化学品，这些化学品已经变得无处不在，因此导致广泛的一般人群接触。疾病控制和预防中心发现，大多数美国人口，包括育龄男性和女性，都暴露在被称为多溴联苯醚(PBDE)的阻燃剂中。虽然多溴二苯醚是迄今为止最受关注的阻燃剂，但在美国和其他国家，它们的使用正在被逐步淘汰。尽管由于多溴二苯醚存在于现有的消费产品中并具有很高的持久性，因此在未来几十年内仍将继续成为公共卫生问题，但也迫切需要考虑越来越多地用作多溴二苯醚替代品的其他阻燃剂。尽管来自实验研究的证据表明，多溴二苯醚及其某些替代品是发育和生殖毒物，但关于多溴二苯醚潜在健康风险的人体研究有限，没有关于其替代品的人体研究。我们建议通过扩大招募来充分利用我们正在进行的前瞻性先孕队列研究(ES009718)，以充分支持对母亲和父亲暴露于FRS对妊娠结局的影响的探索，并探索对妊娠结果的联合影响(母父相互作用)。这项研究是创新的，因为我们可以获得孕前和围产期、母亲和父亲的暴露测量和夫妇水平的临床结果数据。我们建议使用体外受精(IVF)作为模型来研究阻燃剂对人类早期发育和妊娠的影响。体外受精为流行病学家提供了研究早期发育和临床前妊娠丢失的新的和独特的机会。这些早期终点在自然受孕的妇女中观察不到，但非常重要，因为它们代表了所有妇女中大多数怀孕失败的情况，并且被认为比后期怀孕终点对环境化学物质更敏感。在拟议的研究中，我们不仅将测量多溴二苯醚，还将应用新的和新的暴露于环境中的生物标记物来替代它们，包括Firemaster 550的成分和有机磷阻燃剂。具体目的是探索阻燃剂对母方和父方的影响，以及它们对临床妊娠结局的联合影响。令人感兴趣的临床结果包括卵母细胞受精、植入失败、妊娠丢失和活产。正如我们的初步数据显示，我们的队列广泛接触多溴二苯醚和替代阻燃剂，使用我们的研究团队开发的新分析方法进行测量。此外，在我们的初步数据中，我们报告了阻燃剂与生殖结果之间的关联，尽管耐人寻味的是小数据集，但需要通过拟议的应用扩展到完整的队列研究。

DESCRIPTION (provided by applicant): The causes of male and female infertility and adverse pregnancy outcomes are not well understood, but likely arise as a complex interplay of environmental and lifestyle factors evident at the population level. Etiologic factors may include exposure to a wide range of synthetic chemicals that have become ubiquitous and as such result in widespread general population exposure. The Centers for Disease Control and Prevention found that a majority of the U.S. population, including men and women of reproductive age, are exposed to the flame retardants known as polybrominated diphenyl ethers (PBDE). While PBDEs are the flame retardants that have received the most attention to date, their use is being phased out in the U.S. and other countries. Although PBDEs will continue to be a public health concern for decades to come due to their presence in existing consumer products and their high level of persistence, there is an urgent need to also consider other flame retardants that are increasingly being used as alternatives to PBDEs. Despite evidence from experimental studies that PBDEs and some of their alternatives are developmental and reproductive toxicants, there are limited human studies on the potential health risks of PBDEs and no human studies on their alternatives. We propose to leverage our ongoing prospective preconception cohort study (ES009718) by extending recruitment to sufficiently power the exploration of the effect of maternal and paternal exposure to FRs on pregnancy outcomes and to also explore the joint effects (maternal-paternal interactions) on pregnancy outcomes. The study is innovative because we have access to both pre- and peri-conception maternal and paternal measures of exposure and couple level clinical outcome data. We propose to use in vitro fertilization (IVF) as a model to study the impact of flame retardants on early human development and pregnancy. IVF provides epidemiologists with novel and unique opportunities to study early development and pre-clinical pregnancy loss. These early endpoints are not observable in women conceiving naturally, but are of high importance as they represent the majority of failures of pregnancy among all women and are considered more sensitive to environmental chemicals than later pregnancy endpoints. In the proposed study, we will measure not only PBDEs, but will apply new and novel biomarkers of exposure for their replacements, including components of Firemaster 550 and organophosphate flame retardants. The specific aims are to explore both the maternal and paternal effects of flame retardants, as well as their joint effects on clinical pregnancy outcomes. Clinical outcomes of interest include oocyte fertilization, implantation failure, pregnancy loss and live birth. As shown in our preliminary data, there is widespread exposure of our cohort to PBDEs and alternative flame retardants, measured using novel analytical methods developed by our research team. Furthermore, in our preliminary data, we report suggestive associations of flame retardants with reproductive outcomes that although intriguing were within small datasets and need to be expanded to the full cohort study through the proposed application.