title: Downregulation of peroxiredoxin-3 by hydrophobic bile acid induces mitochondrial dysfunction and cellular senescence in human trophoblasts.
abstract: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder characterised by raised bile acids in foetal-maternal circulation, which threatens perinatal health. During the progression of ICP, the effect of oxidative stress is underscored. Peroxiredoxin-3 (PRDX3) is a mitochondrial antioxidant enzyme that is crucial to balance intracellular oxidative stress. However, the role of PRDX3 in placental trophoblast cells under ICP is not fully understood. We demonstrated that the level of PRDX3 was downregulated in ICP placentas as well as bile acids-treated trophoblast cells and villous explant in vitro. Toxic levels of bile acids and PRDX3 knockdown induced oxidative stress and mitochondrial dysfunction in trophoblast cells. Moreover, silencing of PRDX3 in trophoblast cell line HTR8/SVneo induced growth arrest and cellular senescence via activation of p38-mitogen-activated protein kinase (MAPK) and induction of p21WAF1/CIPand p16INK4A. Additionally, enhanced cellular senescence, determined by senescence-associated beta-galactosidase staining, was obviously attenuated by p38-MAPK inhibitor SB203580. Our data determined that exposure to bile acid decreased PRDX3 level in human trophoblasts. PRDX3 protected trophoblast cells against mitochondrial dysfunction and cellular senescence induced by oxidative stress. Our results suggest that decreased PRDX3 by excessive bile acids in trophoblasts plays a critical role in the pathogenesis and progression of ICP.
authors.affiliation: Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Embryo-Fetal Original Adult Disease Shanghai Key laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wei-Bin
authors.initials: WB
authors.lastname: Wu
authors.affiliation: Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, the University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Menon
authors.affiliation: Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Xu
authors.affiliation: Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Embryo-Fetal Original Adult Disease Shanghai Key laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jiu-Ru
authors.initials: JR
authors.lastname: Zhao
authors.affiliation: Prenatal Diagnosis Center &Fetal Medicine Unit, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan-Lin
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Pathology and Bio-Bank, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Institute of Embryo-Fetal Original Adult Disease Shanghai Key laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Zhang
mesh_terms: D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D016922:Cellular Senescence / Q000187:drug effects*; D002780:Cholestasis, Intrahepatic / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D061105:Peroxiredoxin III / Q000096:biosynthesis*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism / Q000473:pathology; D014327:Trophoblasts / Q000201:enzymology* / Q000473:pathology
chemical_list: D001647:Bile Acids and Salts; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III