title: Reactive Oxygen Stimulation of Interleukin-6 Release in the Human Trophoblast Cell Line HTR-8/SVneo by the Trichlorethylene Metabolite S-(1,2-Dichloro)-l-Cysteine.
abstract: Trichloroethylene (TCE) is a common environmental pollutant associated with adverse reproductive outcomes in humans. TCE intoxication occurs primarily through its biotransformation to bioactive metabolites, including S-(1,2-dichlorovinyl)-l-cysteine (DCVC). TCE induces oxidative stress and inflammation in the liver and kidney. Although the placenta is capable of xenobiotic metabolism and oxidative stress and inflammation in placenta have been associated with adverse pregnancy outcomes, TCE toxicity in the placenta remains poorly understood. We determined the effects of DCVC by using the human extravillous trophoblast cell line HTR-8/SVneo. Exposure to 10 and 20 μM DCVC for 10 h increased reactive oxygen species (ROS) as measured by carboxydichlorofluorescein fluorescence. Moreover, 10 and 20 μM DCVC increased mRNA expression and release of interleukin-6 (IL-6) after 24-h exposure, and these responses were inhibited by the cysteine conjugate beta-lyase inhibitor aminooxyacetic acid and by treatments with antioxidants (alpha-tocopherol and deferoxamine), suggesting that DCVC-stimulated IL-6 release in HTR-8/SVneo cells is dependent on beta-lyase metabolic activation and increased generation of ROS. HTR-8/SVneo cells exhibited decreased mitochondrial membrane potential at 5, 10, and 20 μM DCVC at 5, 10, and 24 h, showing that DCVC induces mitochondrial dysfunction in HTR-8/Svneo cells. The present study demonstrates that DCVC stimulated ROS generation in the human placental cell line HTR-8/SVneo and provides new evidence of mechanistic linkage between DCVC-stimulated ROS and increase in proinflammatory cytokine IL-6. Because abnormal activation of cytokines can disrupt trophoblast functions necessary for placental development and successful pregnancy, follow-up investigations relating these findings to physiologic outcomes are warranted.
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Iman
authors.initials: I
authors.lastname: Hassan
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Anjana M
authors.initials: AM
authors.lastname: Kumar
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Hae-Ryung
authors.initials: HR
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lash
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan rlc@umich.edu.
authors.forename: Rita
authors.initials: R
authors.lastname: Loch-Caruso
mesh_terms: D002461:Cell Line, Transformed; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D014241:Trichloroethylene / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D017382:Reactive Oxygen Species; D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; D003545:Cysteine
keywords: DCVC; HTR-8/SVneo cells; S-(1,2-dichlorovinyl)-l-cysteine; cytokines; human placental cells; oxidative stress; reactive oxygen species; trichloroethylene; trophoblasts