Disposition of Environmental Chemicals During Pregnancy

点击翻译按钮获取中文摘要

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.