Joint Graduate Program in Toxicology (D.K.) and Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.K., L.M.A.), Rutgers University, Piscataway, New Jersey; Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (E.B., L.M.A.); Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (E.B.); and Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, New Jersey (L.M.A.).
Joint Graduate Program in Toxicology (D.K.) and Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (D.K., L.M.A.), Rutgers University, Piscataway, New Jersey; Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (E.B., L.M.A.); Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (E.B.); and Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, New Jersey (L.M.A.)
Drug Metab Dispos. 2022 Oct;50(10):1364-1375. doi: 10.1124/dmd.121.000449. Epub 2022 Jan 6.
The placenta is essential for regulating the exchange of solutes between the maternal and fetal circulations. As a result, the placenta offers support and protection to the developing fetus by delivering crucial nutrients and removing waste and xenobiotics. ATP-binding cassette transporters, including multidrug resistance protein 1, multidrug resistance-associated proteins, and breast cancer resistance protein, remove chemicals through active efflux and are considered the primary transporters within the placental barrier. Altered transporter expression at the barrier could result in fetal exposure to chemicals and/or accumulation of xenobiotics within trophoblasts. Emerging data demonstrate that expression of these transporters is changed in women with pregnancy complications, suggesting potentially compromised integrity of placental barrier function. The purpose of this review is to summarize the regulation of placental efflux transporters during medical complications of pregnancy, including 1) placental inflammation/infection and chorioamnionitis, 2) hypertensive disorders of pregnancy, 3) metabolic disorders including gestational diabetes and obesity, and 4) fetal growth restriction/altered fetal size for gestational age. For each disorder, we review the basic pathophysiology and consider impacts on the expression and function of placental efflux transporters. Mechanisms of transporter dysregulation and implications for fetal drug and toxicant exposure are discussed. Understanding how transporters are up- or downregulated during pathology is important in assessing possible exposures of the fetus to potentially harmful chemicals in the environment as well as the disposition of novel therapeutics intended to treat placental and fetal diseases. SIGNIFICANCE STATEMENT: Diseases of pregnancy are associated with reduced expression of placental barrier transporters that may impact fetal pharmacotherapy and exposure to dietary and environmental toxicants.
胎盘对于调节母体和胎儿循环之间的溶质交换至关重要。因此，胎盘通过输送关键营养物质、清除废物和外源性物质，为发育中的胎儿提供支持和保护。ATP 结合盒转运蛋白，包括多药耐药蛋白 1、多药耐药相关蛋白和乳腺癌耐药蛋白，通过主动外排清除化学物质，被认为是胎盘屏障中的主要转运蛋白。屏障中转运蛋白的表达改变可能导致胎儿接触化学物质和/或外源性物质在滋养细胞中积累。新出现的数据表明，这些转运蛋白在患有妊娠并发症的女性中的表达发生改变，这表明胎盘屏障功能的完整性可能受损。本综述的目的是总结胎盘外排转运蛋白在妊娠并发症期间的调节，包括 1）胎盘炎症/感染和绒毛膜羊膜炎，2）妊娠高血压疾病，3）代谢紊乱，包括妊娠期糖尿病和肥胖，以及 4）胎儿生长受限/胎儿大小与胎龄不成比例。对于每种疾病，我们回顾基本的病理生理学，并考虑其对胎盘外排转运蛋白表达和功能的影响。讨论了转运蛋白失调的机制及其对胎儿药物和毒物暴露的影响。了解转运蛋白在病理状态下是如何上调或下调的，对于评估胎儿可能接触环境中潜在有害化学物质以及新型治疗药物用于治疗胎盘和胎儿疾病的处置情况非常重要。意义陈述：妊娠疾病与胎盘屏障转运蛋白的表达减少有关，这可能会影响胎儿的药物治疗和接触饮食和环境毒物。
