title: The role of PGC-1α and MRP1 in lead-induced mitochondrial toxicity in testicular Sertoli cells.
abstract: The lead-induced toxic effect on mitochondria in Sertoli cells is not well studied and the underlying mechanism is poorly understood. Here we reported the potential role of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and multidrug resistance protein 1 (MRP1) in lead acetate-induced mitochondrial toxicity in mouse testicular Sertoli cells TM4 line. We found that lead acetate treatment significantly reduced the expression level of PGC-1α, but increased the level of MRP1 in mitochondria of TM4 cells. To determine the role of PGC-1α and MRP1 in lead acetate-induced mitochondrial toxicity, we then generated PGC-1α stable overexpression and MRP1 stable knockdown TM4 cells, respectively. The lead acetate treatment caused TM4 cell mitochondrial ultrastructure damages, a decrease in ATP synthesis, an increase in ROS levels, and apoptotic cell death. In contrast, stably overexpressing PGC-1α significantly ameliorated the lead acetate treatment-caused mitochondrial toxicity and apoptosis. Moreover, it was also found that stably knocking down the level of MRP1 increased the TM4 cell mitochondrial lead-accumulation by 4-6 folds. Together, the findings from this study suggest that PGC-1α and MRP1 plays important roles in protecting TM4 cells against lead-induced mitochondrial toxicity, providing a better understanding of lead-induced mitochondrial toxicity.
authors.affiliation: Department of Toxicology, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Toxicology, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Preventive Medicine, College of Basic Medical Sciences, Hubei University of Chineses Medicine, Wuhan 430065, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Toxicology, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, PR China.
authors.forename: Chuang
authors.initials: C
authors.lastname: Du
authors.affiliation: Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Academy for Preventive Medicine, Wuhan 430079, PR China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Toxicology, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, PR China.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, PR China. Electronic address: wchunhong027@whu.edu.cn.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Michigan State University East Lansing, MI 48824, USA. Electronic address: yangcf@msu.edu.
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009942:Organometallic Compounds / Q000633:toxicity*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012708:Sertoli Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D000255:Adenosine Triphosphate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009942:Organometallic Compounds; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; C485290:Ppargc1a protein, mouse; C008261:lead acetate; C421109:multidrug resistance-associated protein 1
keywords: Lead acetate; MRP1; Mitochondrial toxicity; PGC-1α; Sertoli cell