Disposition of Environmental Chemicals During Pregnancy

描述（由申请人提供）：在过去的十年中，越来越多的人关注由于子宫内暴露于异种抗生素而导致的内分泌和生殖系统的破坏。预防这些反应的关键是确定调节产前内分泌干扰化学物质（EDCs）处置的细胞机制。降低胎儿体内EDCs水平的一种潜在方法是将它们通过胎盘运送回母体循环系统。一个重要的转运蛋白，乳腺癌抵抗蛋白（BCRP），已被证明参与化学物质的胎盘转移。该实验室最近的数据表明，模型EDC（植物雌激素染料木素）是BCRP的底物，并且各种EDC抑制BCRP的转运。我们假设BCRP通过主动将EDCs运送回母体循环来维持胎儿室中低浓度的EDCs。这一点很重要，因为BCRP功能受损会增加胎儿的EDCs水平，并加剧对生殖发育的破坏。这一假设将通过体外和体内结合的方法进行验证，评估BCRP对EDCs的转运，并确定影响人类胎盘中BCRP表达和活性的调节机制。我们预计EDC将是BCRP底物，而BCRP转运蛋白功能的降低将增加小鼠胎儿中的EDC水平。此外，与野生型相比，bcrp缺失的后代在产前暴露于染料木黄酮后，在生殖和乳腺发育方面会有更严重的异常。这些研究将填补胎盘转运和胎儿对环境毒物易感性领域的重大知识空白。我们迫切需要这项研究，因为环境中存在多种来源的EDCs，孕妇暴露于EDCs中已有记录。对胎盘BCRP调控的详细了解将使我们能够预测哪些患者发生EDCs不良反应的风险更大。

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.