Disposition of Environmental Chemicals During Pregnancy

描述(由申请人提供)：在过去的十年里，人们越来越关注子宫内暴露于外源物质对内分泌和生殖系统的干扰。预防这些反应的关键是确定调节内分泌干扰物(EDCs)产前处置的细胞机制。降低胎儿内内皮细胞水平的一种潜在方法是将它们通过胎盘输送回母体循环。一种重要的转运蛋白，乳腺癌耐药蛋白(BCRP)，已被证明参与胎盘化学物质的转移。本实验室的最新数据表明，模型EDC，即植物雌激素染料木素，是BCRP的底物，并且各种EDCs抑制BCRP的转运。我们推测，BCRP通过积极地将其转运回母体循环来维持胎儿体内内皮细胞的低浓度。这一点很重要，因为BCRP功能受损会增加胎儿内皮细胞的水平，并加剧生殖发育的中断。这一假设将使用体外和体内相结合的方法进行验证，这些方法评估BCRP对内皮细胞的运输，并确定影响BCRP在人类胎盘中表达和活性的调节机制。我们预计EDC将成为BCRP的底物，BCRP转运蛋白功能的降低将增加小鼠胚胎中EDC的水平。此外，与野生型相比，出生前暴露于金雀异黄素后，BCRP缺失的后代在生殖和乳腺发育方面将出现更严重的异常。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。这项拟议的研究是非常必要的，因为在我们的环境中存在多种来源的内分泌干扰物，并且已经记录了孕妇接触内分泌干扰素的情况。对胎盘BCRP调节的详细了解将使我们能够预测哪些患者面临更大的EDCs不良反应风险。 与公共健康相关：胎盘将有毒化学物质从胎儿体内排出的机制还知之甚少。这些研究将确定胎盘转运蛋白BCRP是否在子宫内减少暴露在内分泌干扰物中，并保护胎儿免受发育异常的影响。

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. PUBLIC HEALTH RELEVANCE: The mechanism by which the placenta removes toxic chemicals away from the fetus is poorly understood. These studies will determine whether the placental transporter BCRP reduces in utero exposure to endocrine disrupting chemicals and protects the fetus from developmental abnormalities.