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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZES1-TN-J (R0))
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Heindel, Jerrold
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Rutgers University
Schools of Pharmacy
New Brunswick
United States
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Bright, Amanda S; Herrera-Garcia, Guadalupe; Moscovitz, Jamie E et al. (2016) Regulation of Drug Disposition Gene Expression in Pregnant Mice with Car Receptor Activation. Nucl Receptor Res 3:
Brunetti, Luigi; Kagan, Leonid; Forrester, Glenn et al. (2016) Cefoxitin Plasma and Subcutaneous Adipose Tissue Concentration in Patients Undergoing Sleeve Gastrectomy. Clin Ther 38:204-10
Lin, Yixin; Bircsak, Kristin M; Gorczyca, Ludwik et al. (2016) Regulation of the placental BCRP transporter by PPAR gamma. J Biochem Mol Toxicol :
Szilagyi, John T; Mishin, Vladimir; Heck, Diane E et al. (2016) Selective Targeting of Heme Protein in Cytochrome P450 and Nitric Oxide Synthase by Diphenyleneiodonium. Toxicol Sci 151:150-9
Moscovitz, Jamie E; Kong, Bo; Buckley, Kyle et al. (2016) Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064. Toxicol Appl Pharmacol 310:60-67
Udasin, Ronald G; Wen, Xia; Bircsak, Kristin M et al. (2016) Nrf2 Regulates the Sensitivity of Mouse Keratinocytes to Nitrogen Mustard via Multidrug Resistance-Associated Protein 1 (Mrp1). Toxicol Sci 149:202-12
Bircsak, Kristin M; Gupta, Vivek; Yuen, Poi Yu Sofia et al. (2016) Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter. J Pharmacol Exp Ther 357:103-13
Moscovitz, Jamie E; Nahar, Muna S; Shalat, Stuart L et al. (2016) Correlation between Conjugated Bisphenol A Concentrations and Efflux Transporter Expression in Human Fetal Livers. Drug Metab Dispos 44:1061-5
Xiao, Jingcheng; Wang, Qi; Bircsak, Kristin M et al. (2015) In Vitro Screening of Environmental Chemicals Identifies Zearalenone as a Novel Substrate of the Placental BCRP/ABCG2 Transporter. Toxicol Res (Camb) 4:695-706
Fiedler, Nancy; Rohitrattana, Juthasiri; Siriwong, Wattasit et al. (2015) Neurobehavioral effects of exposure to organophosphates and pyrethroid pesticides among Thai children. Neurotoxicology 48:90-9

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