Transcriptional profiling of the response to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine revealed activation of the eIF2α/ATF4 integrated stress response in two in vitro placental models

• Published in: Archives of toxicology 2021-05, Vol.95 (5), p.1595-1619
• Main Authors: Elkin, Elana R., Bakulski, Kelly M., Colacino, Justin A., Bridges, Dave, Kilburn, Brian A., Armant, D. Randall, Loch-Caruso, Rita
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 4; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cell Line; Cells, Cultured; Cellular stress response; Contaminants; Cysteine; Cytotoxicity; Enrichment; Environmental Health; Epidemiology; Eukaryotic Initiation Factor-2; Explants; Exposure; Female; Gene expression; Gene regulation; Genes; Genomes; Humans; Industrial pollution; Kidney Tubules, Proximal; Metabolites; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Phosphorylation; Placenta; Pregnancy; Protein biosynthesis; Protein folding; Protein synthesis; Proteins; Signal transduction; Solvents; Solvents - toxicity; Toxicity; Toxicogenomics and Omics Technologies; Transcription activation; Trichloroethene; Trichloroethylene; Trichloroethylene - toxicity; Trophoblasts
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-021-03011-5

Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Although TCE exposure is prevalent, epidemiological studies of TCE exposure associations with adverse birth outcomes are inconclusive. Prior studies show that the TCE metabolite S -(1,2-dichlorovinyl)- l -cysteine (DCVC) exhibits toxicity in a placental cell line. In the current study, genome-wide gene expression and gene set enrichment analyses were used to identify novel genes and pathway alterations in the HTR-8/SVneo human trophoblast cell line and human placental villous explants treated with DCVC at concentrations relevant to human exposures. In the cells, concentration- and time-dependent effects were observed, as evidenced by the magnitude of altered gene expression after treatment with 20 µM DCVC versus 10 µM, and 12-h versus 6-h of treatment. Comparing the two models for the transcriptional response to 12-h 20 µM DCVC treatment, no differentially expressed genes reached significance in villous explants, whereas 301 differentially expressed genes were detected in HTR-8/SVneo cells compared with non-treated controls (FDR  0.35 [FC > 1.3]). GSEA revealed five upregulated enriched pathways in common between explants and cells (FDR