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.

Environmental contaminants and preeclampsia: a systematic literature review

“…Although few data are available on the effects of water contaminants and placental function, limited evidence from in vitro investigations suggests potential consequences. Results from one study by Hassan et al (2016) reported that a bioactive intermediate of TCE increased pro-inflammatory cytokines, leading to disruptions in trophoblast functions necessary for placental development. However, concentrations used in the study by Hassan et al (2016) were a magnitude higher than the US EPA’s maximum contaminant level standard for drinking water for TCE.…”

“…Results from one study by Hassan et al (2016) reported that a bioactive intermediate of TCE increased pro-inflammatory cytokines, leading to disruptions in trophoblast functions necessary for placental development. However, concentrations used in the study by Hassan et al (2016) were a magnitude higher than the US EPA’s maximum contaminant level standard for drinking water for TCE. Chen et al (2004) examined bromodichloromethane, a trihalomethane, and found that exposure disrupted syncytiotrophoblast formation.…”

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.…”

Oxidative Stress in Preeclampsia and Placental Diseases

“…Together with serum deprivation, it triggers an increase in necrotic cell death, which was able to be rescued by relaxin, an insulin superfamily hormone expressed by the maternal reproductive system. It has also been shown that trichloroethylene (TCE) or flame retardants such as Polybrominated diphenyl ethers (PBDE, such as BDE-47) do indeed modify the response to oxidative stress in this model [ 30 , 31 ]. The TCE metabolite DCVC (S-(1,2-dichlorovinyl)-l-cysteine) induces inflammation by releasing IL-6 following the generation of ROS, as a result of its disrupted mitochondrial function.…”