Effects of exposure to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and percholorethylene metoblite S-(1,1,2-trichlorovinyl)-L-cysteine (TCVC) on term placental villous explants differential gene expression

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.