Disposition of Environmental Chemicals During Pregnancy

描述（由申请方提供）：在过去十年中，人们越来越关注子宫内暴露于外源性物质导致的内分泌和生殖系统破坏。预防这些反应的关键是确定调节产前处置内分泌干扰物（EDCs）的细胞机制。降低胎儿内分泌干扰物水平的一种潜在方法是将它们通过胎盘运输回母体循环。一个突出的转运蛋白，乳腺癌耐药蛋白（BCRP），已被证明参与胎盘转移的化学物质。该实验室的最新数据表明，模型EDC，植物雌激素染料木黄酮，是BCRP底物，并且各种EDC抑制BCRP转运。我们假设BCRP通过主动将EDCs转运回母体循环来维持胎儿室中EDCs的低浓度。这一点很重要，因为BCRP功能受损会增加胎儿内分泌干扰物的水平，并增强生殖发育的破坏。将使用体外和体内方法的组合来检验这一假设，这些方法评价BCRP转运EDC并确定影响人胎盘中BCRP表达和活性的调控机制。我们预期EDC将是BCRP的底物，BCRP转运蛋白功能降低将增加小鼠胎儿中EDC的水平。此外，与野生型相比，预期Bcrp缺失的后代在产前暴露于染料木黄酮后将具有更严重的生殖和乳腺发育异常。这些研究将填补胎盘运输和胎儿对环境毒物敏感性领域的重大知识空白。这项拟议的研究是非常必要的，因为我们的环境中存在多种来源的内分泌干扰物，并且在孕妇中已经记录了内分泌干扰物的暴露。对胎盘BCRP调节的详细了解将使我们能够预测哪些患者更容易发生EDCs不良反应。

DESCRIPTION (provided by applicant): Over the last decade, there has been increasing concern regarding disruption of endocrine and reproductive systems as a consequence of in utero exposure to xenobiotics. Key to preventing these responses is identification of cellular mechanisms that regulate prenatal disposition of endocrine disrupting chemicals (EDCs). One potential way to reduce levels of EDCs in the fetus is to transport them across the placenta back to the maternal circulation. One prominent transporter, breast cancer resistance protein (BCRP), has been shown to participate in the placental transfer of chemicals. Recent data from this laboratory demonstrate that the model EDC, the phytoestrogen genistein, is a BCRP substrate, and that various EDCs inhibit BCRP transport. We hypothesize that BCRP maintains low concentrations of EDCs in the fetal compartment by actively transporting them back to the maternal circulation. This is important because impaired BCRP function would increase fetal levels of EDCs and enhance disruption of reproductive development. This hypothesis will be tested using a combination of in vitro and in vivo approaches that evaluate BCRP transport of EDCs and identify the regulatory mechanisms that influence BCRP expression and activity in human placenta. We anticipate that EDCs will be BCRP substrates and that reduced Bcrp transporter function will increase EDC levels in mouse fetuses. Further, it is expected that Bcrp-null offspring will have more profound abnormalities in reproductive and mammary gland development following prenatal genistein exposure, compared to wild-types. These studies will fill significant knowledge gaps in the fields of placental transport and fetal susceptibility to environmental toxicants. The proposed research is critically needed because multiple sources of EDCs exist in our environment and exposure to EDCs has been documented in pregnant women. A detailed understanding of the regulation of placental BCRP will allow us to predict which patients are at greater risk for adverse effects of EDCs.