PMID- 31421572 OWN - NLM STAT- MEDLINE DCOM- 20191206 LR - 20191217 IS - 1873-6424 (Electronic) IS - 0269-7491 (Linking) VI - 254 IP - Pt A DP - 2019 Nov TI - Activation of autophagy inhibits cadmium-triggered apoptosis in human placental trophoblasts and mouse placenta. PG - 112991 LID - S0269-7491(19)31328-4 [pii] LID - 10.1016/j.envpol.2019.112991 [doi] AB - Cadmium (Cd), a ubiquitous environmental pollutant, is known to impair placental development. However, the underlying mechanisms remain unclear. The present study used in vivo and in vitro models to investigate the effects of Cd on apoptosis and autophagy in placental trophoblasts and its mechanism. Pregnant mice were exposed to CdCl(2) (4.5 mg/kg) on gestational day (GD) 9. Human JEG-3 cells were exposed to CdCl(2) (0-40 muM) for different time points. Gestational Cd exposure obviously lowered the weight and diameter of mouse placentas. Number of TUNEL-positive cells was markedly elevated in Cd-administered mouse placentas and JEG-3 cells. Correspondingly, Cd significantly up-regulated cleaved caspase-3 protein level, a key indicator of apoptosis, in murine placentas and JEG-3 cells. Simultaneously, Cd also triggered autophagy, as determined by an elevation of LC3B-II and p62 protein, and accumulation of LC3-positive puncta, in placental trophoblasts. Chloroquine an autophagy inhibitor, obviously aggravated Cd-induced apoptosis in JEG-3 cells. By contrast, rapamycin, a specific autophagy inducer, significantly alleviated Cd-triggered apoptosis in JEG-3 cells. Mechanistically, autophagy inhibited Cd-induced apoptosis mainly via degrading caspase-9. Co-localizations of p62, a classical autophagic receptor, and caspase-9 were observed in Cd-stimulated human JEG-3 cells. Moreover, p62 siRNAs pretreatment markedly blocked the degradation of caspase 9 proteins via Cd-activated autophagy in JEG-3 cells. Collectively, our data suggest that activation of autophagy inhibits Cd-induced apoptosis via p62-mediated caspase-9 degradation in placental trophoblasts. These findings provide a new mechanistic insight into Cd-induced impairments of placental and fetal development. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Zhu, Hua-Long AU - Zhu HL AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Xu, Xiao-Feng AU - Xu XF AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, China. FAU - Shi, Xue-Ting AU - Shi XT AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Feng, Yu-Jie AU - Feng YJ AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Xiong, Yong-Wei AU - Xiong YW AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Nan, Yuan AU - Nan Y AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Zhang, Cheng AU - Zhang C AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Gao, Lan AU - Gao L AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Chen, Yuan-Hua AU - Chen YH AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Xu, De-Xiang AU - Xu DX AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. FAU - Wang, Hua AU - Wang H AD - Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. Electronic address: wanghuadev@126.com. LA - eng PT - Journal Article DEP - 20190805 PL - England TA - Environ Pollut JT - Environmental pollution (Barking, Essex : 1987) JID - 8804476 RN - 0 (Hazardous Substances) RN - 00BH33GNGH (Cadmium) RN - EC 3.4.22.- (CASP3 protein, human) RN - EC 3.4.22.- (CASP9 protein, human) RN - EC 3.4.22.- (Caspase 3) RN - EC 3.4.22.- (Caspase 9) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Autophagy/drug effects/*physiology MH - Cadmium/metabolism/*toxicity MH - Caspase 3 MH - Caspase 9 MH - Cell Line, Tumor MH - Female MH - Hazardous Substances/*toxicity MH - Humans MH - Mice MH - Placenta/metabolism/*physiology MH - Pregnancy MH - Toxicity Tests MH - Trophoblasts/drug effects/*physiology MH - Up-Regulation/drug effects OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Cadmium OT - Placenta OT - Trophoblasts EDAT- 2019/08/20 06:00 MHDA- 2019/12/18 06:00 CRDT- 2019/08/18 06:00 PHST- 2019/03/16 00:00 [received] PHST- 2019/07/31 00:00 [revised] PHST- 2019/07/31 00:00 [accepted] PHST- 2019/08/20 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2019/08/18 06:00 [entrez] AID - S0269-7491(19)31328-4 [pii] AID - 10.1016/j.envpol.2019.112991 [doi] PST - ppublish SO - Environ Pollut. 2019 Nov;254(Pt A):112991. doi: 10.1016/j.envpol.2019.112991. Epub 2019 Aug 5.