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Effects of exposure to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine on HTR-8/SVneo differential gene expression under hypoxic vs. normoxic conditions (O2 < 2%)

ABSTRACT: Effects of exposure to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine on HTR-8/SVneo differential gene expression under hypoxic vs. normoxic conditions (O2 < 2%)

PROVIDER: PRJNA1214252 | ENA |

REPOSITORIES: ENA

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Project description:Trichloroethylene is an industrial solvent and common environmental pollutant. Despite efforts to ban trichloroethylene, its availability and usage persist globally, constituting a hazard to human health. Recent studies reported associations between maternal trichloroethylene exposure and increased risk for low birth weight. Despite these associations, the toxicological mechanism underlying trichloroethylene adverse effects on pregnancy remains largely unknown. The trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) induces mitochondrial-mediated apoptosis in a trophoblast cell line. To gain further understanding of mitochondrial-mediated DCVC placental toxicity, this study investigated the effects of DCVC exposure on mitochondrial function using non-cytolethal concentrations in placental cells. Human trophoblasts, HTR-8/SVneo, were exposed in vitro to a maximum of 20 μM DCVC for up to 12 h. Cell-based oxygen consumption and extracellular acidification assays were used to evaluate key aspects of mitochondrial function. Following 6 h of exposure to 20 μM DCVC, elevated oxygen consumption, mitochondrial proton leak and sustained energy coupling deficiency were observed. Similarly, 12 h of exposure to 20 μM DCVC decreased mitochondrial-dependent basal, ATP-linked and maximum oxygen consumption rates. Using the fluorochrome TMRE, dissipation of mitochondrial membrane potential was detected after a 12-h exposure to 20 μM DCVC, and (±)-α-tocopherol, a known suppressor of lipid peroxidation, attenuated DCVC-stimulated mitochondrial membrane depolarization but failed to rescue oxygen consumption perturbations. Together, these results suggest that DCVC caused progressive mitochondrial dysfunction, resulting in lipid peroxidation-associated mitochondrial membrane depolarization. Our findings contribute to the biological plausibility of DCVC-induced placental impairment and provide new insights into the role of the mitochondria in DCVC-induced toxicity.

Project description:Trichloroethylene (TCE) is a widespread environmental contaminant following decades of use as an industrial solvent, improper disposal, and remediation challenges. Consequently, TCE exposure continues to constitute a risk to human health. Despite epidemiological evidence associating exposure with adverse birth outcomes, the effects of TCE and its metabolite S-(1, 2-dichlorovinyl)-L-cysteine (DCVC) on the placenta remain undetermined. Flexible and efficient macronutrient and energy metabolism pathway utilization is essential for placental cell physiological adaptability. Because DCVC is known to compromise cellular energy status and disrupt energy metabolism in renal proximal tubular cells, this study investigated the effects of DCVC on cellular energy status and energy metabolism pathways in placental cells. Human extravillous trophoblast cells, HTR-8/SVneo, were exposed to 5-20 μM DCVC for 6 or 12 h. After establishing concentration and exposure duration thresholds for DCVC-induced cytotoxicity, targeted metabolomics was used to evaluate overall energy status and metabolite concentrations from energy metabolism pathways. The data revealed glucose metabolism perturbations including a time-dependent accumulation of glucose-6-phosphate+frutose-6-phosphate (G6P+F6P) as well as independent shunting of glucose intermediates that diminished with time, with modest energy status decline but in the absence of significant changes in ATP concentrations. Furthermore, metabolic profiling suggested that DCVC stimulated compensatory utilization of glycerol, lipid, and amino acid metabolism to provide intermediate substrates entering downstream in the glycolytic pathway or the tricarboxylic acid cycle. Lastly, amino acid deprivation increased susceptibility to DCVC-induced cytotoxicity. Taken together, these results suggest that DCVC caused metabolic perturbations necessitating adaptations in macronutrient and energy metabolism pathway utilization to maintain adequate ATP levels.

Project description:Volatile organic chemicals Trichloroethylene (TCE) and perchloroethylene (PCE) are liquid solvents used for dry cleaning, industrial degreasing operations, and more. The multiple industrial uses of TCE and PCE have led to large volumes of TCE and PCE being released into the air, surface water, groundwater, and soil worldwide. Maternal exposure to TCE and/or PCE are associated with increased risk of restricted fetal growth (TCE), preterm birth (PCE), placental abruption (PCE) and stillbirth (PCE), suggesting that the placenta may be a key target of TCE and PCE due to its critical role in maintaining maternal and fetal health in pregnancy and mediating fetal growth. We previously showed that TCE and PCE metabolites activate stress response and cell death pathways in placental cell and tissue models. However, there are still key gaps in our knowledge on TCE and PCE metabolites impact the placenta, particularly across fetal sex. We aimed to identify transcriptomic responses to the TCE metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and PCE metabolite S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) using a placental explant model and to determine the extent to which fetal sex modifies DCVC and TCVC impacts on the transcriptome. We isolated both male- and female-associated villous placental tissue (n=8, four male and four female), followed by treatment with DCVC or TCVC at the following concentrations: 0 μM (control), 10 μM, and 20 μM. Following treatment, we isolated RNA from explants and generated whole transcriptome profiles using RNA sequencing. We conducted differential gene expression analysis to identify significant gene expression changes across treatment groups, stratified by fetal sex (adjusted p-value < 0.05 and |log2 fold change| > 1). We performed Gene Set Enrichment Analysis (GSEA) to evaluate differences in biological pathway enrichment across treatment groups. Finally, we performed placental cell type deconvolution using CIBERSORTx and used beta regression to compare proportions of cell types between VOC-metabolite exposed tissue and unexposed tissue in both fetal sexes. Significant gene expression changes for both fetal sexes were observed across all treatment groups compared to controls.

Dataset Information

Effects of exposure to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine on HTR-8/SVneo differential gene expression under hypoxic vs. normoxic conditions (O2 < 2%)

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