Trichloroethylene metabolite S-(1,2-dichlorovinyl)- l -cysteine induces lipid peroxidation-associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first-trimester placental cell line

Abstract

Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)-l-cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast cell line, HTR-8/SVneo. We exposed the cells in vitro to 10-100μM DCVC for various time points up to 24h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p<0.05). DCVC also significantly stimulated caspase 3, 7, 8 and 9 activities after 12h (p<0.05), suggesting that DCVC stimulates the activation of both the intrinsic and extrinsic apoptotic signaling pathways simultaneously. Pre-treatment with the tBID inhibitor Bl-6C9 partially reduced DCVC-stimulated caspase 3 and 7 activity, signifying crosstalk between the two pathways. Additionally, DCVC treatment increased lipid peroxidation in a concentration-dependent manner. Co-treatment with the antioxidant peroxyl radical scavenger (±)-α-tocopherol attenuated caspase 3 and 7 activity, suggesting that lipid peroxidation mediates DCVC-induced apoptosis in extravillous trophoblasts. Our findings suggest that DCVC-induced apoptosis and lipid peroxidation in extravillous trophoblasts could contribute to poor placentation if similar effects occur in vivo in response to TCE exposure, indicating that further studies into this mechanism are warranted.

Preeclampsia and intrauterine growth restriction: Role of human umbilical cord mesenchymal stem cells-trophoblast cross-talk

“…Thus, previous in vitro data about the cross-talk of HTR-8/SVneo and healthy hUMSCs was related to the influence of migratory and invasive abilities of the former [29]. We have chosen HTR-8/SVneo cell line basing on the role of early pregnancy extravillous cytotrophoblasts on spiral artery remodeling [57] and its relation to the generation of oxidative stress [58,59]. Our study is the first to examine the cross-talk HTR-8/SVneo and hUMSCs from pathologic pregnancies with regard to cell viability under gestational endocrine stimuli.…”

Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis

“…The products of lipid peroxidation interacts with membrane receptors and transcription factors/repressors to induce signaling for apoptosis. It can stimulate the activation of both the intrinsic and extrinsic apoptotic signaling pathways [62, 63]. ROS may lead to cardiolipin peroxidation, a mitochondrion-specific inner membrane phospholipid, and subsequent products of lipid peroxidation formation activated intrinsic apoptosis [64].…”

Emerging Roles of 5-Lipoxygenase Phosphorylation in Inflammation and Cell Death

“…Available evidences show that lipid peroxidation evokes multiple patterns of cell death including apoptosis, pyroptosis, and ferroptosis [54]. For instance, lipid peroxidation induced by trichloroethylene stimulates caspase-3/7 and causes apoptosis in a human extravillous trophoblast cell line [61]. Meanwhile, the downregulation of ALOX5 via RNA interference or an ALOX5 inhibitor could decrease apoptosis induced by carcinogen benzidine in the human tracheobronchial epithelial cell [62].…”