Exposure to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine under hypoxic conditions (%O2 =2 %) alters differential gene expression and mitigates decreased invasion capacity, compared to normoxic conditions (%O2 ≥ 21 %) in HTR-8/SVn

Trichloroethylene (TCE) is a volatile organic compound used as an industrial solvent until the recent EPA phaseout. Despite regulatory restrictions, legacy TCE pollution persists in soil and groundwater and poses a risk to human health. This chemical exerts its toxic effects through its metabolites including the glutathione conjugation metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC). Although a known nephrotoxicant, limited research has explored its effects on placental development - despite a reported epidemiological association between maternal exposure and elevated risk of restricted fetal growth. The placenta plays a critical role in the first trimester, functioning under hypoxic conditions to support fetal growth. Extravillous trophoblasts (EVTs), essential for placental development, are sensitive to environmental stressors. In this study, effects of human-relevant DCVC concentrations on cytotoxicity, differential gene expression, and invasion capacity were evaluated and compared under normoxic and hypoxic conditions using the placental EVT cell line HTR-8/SVneo. Differential gene expression between normoxic and hypoxic controls was also evaluated to characterize the simulated hypoxic experimental conditions. DCVC exposure induced significant cytotoxicity at concentrations as low as 10 μM under both normoxic and hypoxic conditions. DCVC also caused differential gene expression under both conditions, with a more robust response under normoxia. Similar biological pathways were altered under both conditions, including those involved in oxidative balance, cell migration, and apoptotic signaling. Invasion capacity significantly decreased with 10 and 20 μM DCVC under normoxia but was partially rescued under hypoxia, indicating a possible protective effect. Overall, HTR-8/SVneo cell responses to DCVC were similar under both oxygen conditions, with some evidence of hypoxia offering mild protection. This study builds on previous literature and offers new evaluation of exposure under different simulated oxygen conditions mimicking those experienced during the first trimester of pregnancy.