Lye Phetcharawan, Bloise Enrrico, Javam Mohsen, Gibb William, Lye Stephen J, Matthews Stephen G
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Laboratory of Translational Endocrinology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Am J Pathol. 2015 Jun;185(6):1666-75. doi: 10.1016/j.ajpath.2015.02.013. Epub 2015 May 8.
The ABC transporters P-glycoprotein (P-gp, official gene symbol ABCB1) and breast cancer resistance protein (BCRP, official gene symbol ABCG2) protect the conceptus from exposure to toxins and xenobiotics present in the maternal circulation. Viral or bacterial challenges alter expression of placental multidrug transporters in rodents. We hypothesized that exposure to lipopolysaccharide (LPS, bacterial antigen) and polyinosinic-polycytidylic acid (poly(I:C), viral antigen) would decrease P-gp and BCRP in the human placenta. Placental explants from first and third trimesters were challenged with 0.1 to 10 μg/mL LPS or 1 to 50 μg/mL poly(I:C) for 4 or 24 hours; mRNA levels, protein expression, and localization were assessed by quantitative real-time PCR, Western blot analysis, and immunohistochemistry, respectively. Toll-like receptor (TLR)-3 and TLR-4 mRNA expression increased from the first to third trimester (P < 0.01), and the receptors localized to cytotrophoblasts in the first trimester and to syncytiotrophoblasts in the third trimester. LPS exposure in first-trimester explants decreased (P < 0.001) ABCB1 and ABCG2 mRNA and protein levels. In contrast, poly(I:C) decreased (P < 0.05) ABCB1, TLR-3, and TLR-4 mRNA levels in the third trimester but not first trimester. LPS and poly(I:C) treatments increased (P < 0.01) IL-8 and chemokine ligand 2. Results suggest that bacterial infections likely alter exposure of the conceptus to toxins and drugs during early pregnancy, whereas viral infections may disrupt fetal protection in later stages of pregnancy.
ABC转运蛋白P-糖蛋白（P-gp，官方基因符号ABCB1）和乳腺癌耐药蛋白（BCRP，官方基因符号ABCG2）可保护胚胎免受母体循环中存在的毒素和外源性物质的影响。病毒或细菌刺激会改变啮齿动物胎盘多药转运蛋白的表达。我们假设，暴露于脂多糖（LPS，细菌抗原）和聚肌苷酸-聚胞苷酸（poly(I:C)，病毒抗原）会降低人胎盘中P-gp和BCRP的水平。将来自孕早期和孕晚期的胎盘外植体用0.1至10μg/mL LPS或1至50μg/mL poly(I:C)刺激4或24小时；分别通过定量实时PCR、蛋白质印迹分析和免疫组织化学评估mRNA水平、蛋白质表达和定位。Toll样受体（TLR）-3和TLR-4 mRNA表达从孕早期到孕晚期增加（P<0.01），这些受体在孕早期定位于细胞滋养层，在孕晚期定位于合体滋养层。孕早期外植体暴露于LPS会降低（P<0.001）ABCB1和ABCG2的mRNA和蛋白质水平。相比之下，poly(I:C)会降低（P<0.05）孕晚期而非孕早期的ABCB1、TLR-3和TLR-4 mRNA水平。LPS和poly(I:C)处理会增加（P<0.01）IL-8和趋化因子配体2。结果表明，细菌感染可能在妊娠早期改变胚胎对毒素和药物的暴露，而病毒感染可能在妊娠后期破坏对胎儿的保护。
