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

描述（由申请人提供）：男性和女性不孕症和不良妊娠结局的原因尚不清楚，但可能是由于环境和生活方式因素在人群水平上的复杂相互作用而引起的。致病因素可能包括暴露于广泛的合成化学品，这些化学品已变得无处不在，因此导致广泛的一般人群暴露。疾病控制和预防中心发现，大多数美国人口，包括育龄男女，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，它们的使用正在逐步淘汰。尽管由于多溴二苯醚存在于现有的消费品中，而且具有很高的持久性，因此在未来几十年内，多溴二苯醚仍将是一个公共健康问题，但仍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。尽管实验研究证明多溴二苯醚及其某些替代品对发育和生殖有毒，但对多溴二苯醚潜在健康风险的人体研究有限，而且没有对其替代品进行人体研究。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孕前队列研究（ES 009718），以充分探索母亲和父亲暴露于FR对妊娠结局的影响，并探索对妊娠结局的联合影响（母亲-父亲相互作用）。这项研究是创新的，因为我们可以获得怀孕前和围怀孕期的母亲和父亲的暴露措施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怀孕的影响。IVF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颖而独特的机会。这些早期终点在自然受孕的妇女中是不可观察的，但非常重要，因为它们代表了所有妇女中大多数妊娠失败的情况，并且被认为对环境化学物质比晚期妊娠终点更敏感。在拟议的研究中，我们不仅将测量多溴二苯醚，而且将应用新的和新颖的生物标志物来替代它们，包括Firemaster 550和有机磷酸盐阻燃剂的成分。具体目标是探索阻燃剂对母体和父亲的影响，以及它们对临床妊娠结局的联合影响。关注的临床结局包括卵母细胞受精、植入失败、妊娠丢失和活产。正如我们的初步数据所示，我们的研究小组使用新的分析方法测量，我们的队列广泛暴露于多溴联苯醚和替代阻燃剂。此外，在我们的初步数据中，我们报告了阻燃剂与生殖结果的暗示性关联，尽管这些关联在小数据集内很有趣，但需要通过拟议的应用扩展到整个队列研究。

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.