Human Maternal/Fetal Exposures to PBDEs and their Metabolites During Development

描述（由申请方提供）：我们的提案检验了以下假设：多溴联苯醚（PBDEs）及其代谢物（OH- PBDEs）在人类胎儿肝脏和胎盘中的累积与在母体血清中的累积不同，胎儿接触PBDEs会影响胎儿的代谢能力。事实上，美国所有孕妇都接触到至少一种，通常是多种多溴二苯醚，这是一类自20世纪70年代以来广泛用作消费品阻燃剂的持久性有机化学品。多溴二苯醚是一个重要的公共卫生问题，因为体外和体内研究表明，子宫内接触多溴二苯醚会对胎儿发育产生不利影响。人类接触和流行病学研究主要通过测量代用生物样本（如分娩时采集的母体血液和脐带血）中的化学品来确定子宫内接触的特征。这些样本不一定代表妊娠早期的胎儿暴露，特别是对肝脏和胎盘等相关靶器官的暴露。我们建议测量自愿终止妊娠的妇女的母体和胎儿生物样本中多溴二苯醚和羟基多溴二苯醚的水平。由于有关化学品引起的人类胎儿代谢能力变化的数据对于了解子宫内毒性机制至关重要，但目前缺乏，我们还将生成关于胎儿暴露于多溴二苯醚是否会改变中期妊娠人类胎儿肝脏和胎盘中细胞色素P450（P450）酶基因表达的原始人类数据。在本研究结束时，我们将产生独特的信息，人类胎儿暴露于多溴联苯醚和羟基多溴联苯醚在第二个三个月，包括经验之间的关系，母亲和胎儿的暴露，可用于估计胎儿暴露时，只有母亲的水平。此外，这将是有史以来第一个关于多溴联苯醚接触与人类胎儿肺活动之间关系的体内数据。总的来说，这些信息将有助于弥合实验毒理学和人类观察研究之间的差距，并将提高我们对多溴联苯醚以及其他结构相似的环境化学品与异生物素敏感核受体相互作用的人群风险的理解。

DESCRIPTION (provided by applicant): Our proposal tests the hypotheses that polybrominated diphenyl ethers (PBDEs) and their metabolites (OH- PBDEs) accumulate differently in the human fetal liver and placenta than in maternal serum, and that fetal exposure to PBDEs affects fetal metabolic capacity. Virtually all pregnant women in the United States are exposed to at least one and often multiple PBDEs, a class of persistent organic chemicals widely used as flame retardants in consumer products since the 1970s. PBDEs are an important public health concern, as in vitro and in vivo studies show that in utero exposure can adversely impact fetal development. Human exposure and epidemiologic studies have largely characterized in utero exposure by measuring chemicals in proxy biological specimens, such as maternal blood and umbilical cord blood collected at delivery. These samples are not necessarily representative of fetal exposures earlier in pregnancy, particularly to target organs of concern such as the liver and placenta. We propose to measure levels of PBDEs and OH-PBDEs in human maternal and fetal biological specimens from women undergoing voluntary, second trimester pregnancy terminations. Because data on chemical-induced changes in human fetal metabolic capacity are critical to understanding mechanisms of in utero toxicity but are currently lacking, we will also generate original human data on whether fetal exposures to PBDEs alter gene expression of cytochrome P450 (CYP) enzymes in the second-trimester human fetal liver and placenta. At the end of this study, we will produce unique information about human fetal exposure to PBDEs and OH-PBDEs during the second trimester, including empirical relationships between maternal and fetal exposures which can be used to estimate fetal exposures when only maternal levels are available. Further, this will be the first ever in vio data on the relationship between PBDE exposure and human fetal CYP activity. Collectively, this information will help bridge the gap between experimental toxicology and human observation studies and will improve our understanding of population risks to PBDEs as well as other structurally similar environmental chemicals that interact with xenobiotic-sensing nuclear receptors.