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

描述(由申请人提供)：我们的提案测试了以下假设：多溴二苯醚(PBDEs)及其代谢产物(OH-PBDEs)在人胎肝和胎盘中的积累与在母体血清中的积累不同，并且胎儿暴露于PBDEs会影响胎儿的代谢能力。在美国，几乎所有的孕妇都会接触到至少一种，而且往往是多种多溴二苯醚，这是一类自20世纪70年代以来被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，子宫内暴露会对胎儿发育产生不利影响。人类暴露和流行病学研究在很大程度上是通过测量替代生物样本中的化学物质，如分娩时收集的母亲血液和脐带血，来确定子宫暴露的特征。这些样本不一定代表怀孕早期胎儿暴露，特别是对肝脏和胎盘等目标器官的暴露。我们建议测量自愿中期妊娠终止妊娠妇女的母体和胎儿生物标本中多溴二苯醚和羟基多溴二苯醚的水平。由于关于化学诱导的人类胎儿代谢能力变化的数据对于了解宫内毒性的机制至关重要，但目前缺乏，因此我们还将生成原始的人类数据，即胎儿暴露于多溴二苯醚是否会改变中期人类胎儿肝脏和胎盘中细胞色素P450(CYP)酶的基因表达。在这项研究结束时，我们将产生关于中期妊娠期间人类胎儿暴露于多溴二苯醚和羟基多溴二苯醚的独特信息，包括母亲和胎儿暴露之间的经验关系，当只有孕妇水平可用时，这些关系可用于估计胎儿暴露。此外，这将是有史以来第一次在VIO数据中了解多溴二苯醚暴露与人类胎儿细胞色素P450活性之间的关系。总体而言，这些信息将有助于弥合实验毒理学和人体观察研究之间的差距，并将提高我们对多溴二苯醚以及其他结构相似的环境化学品的种群风险的理解，这些化学物质与外源生物传感核受体相互作用。

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.