期刊
ARCHIVES OF TOXICOLOGY
卷 95, 期 5, 页码 1595-1619出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-021-03011-5
关键词
Trichloroethylene; S-(1; 2-dichlorovinyl)-l-cysteine (DCVC); Placenta; Integrated stress response; ATF4
类别
资金
- National Institute of Environmental Health Sciences, National Institutes of Health [P42 ES017198, P30 ES017885, P30 ES020957, R01 ES025574, R01 ES025531, T32 ES007062, R01 ES028802]
- National Institute of Diabetes and Digestive Kidney Diseases [R01 DK107535, T32 DK071212]
- National Institute of Aging [R01 AG055406, P30 AG053760]
- Wayne State University's Office of the Vice President for Research
This study examines the impact of TCE metabolite DCVC on human trophoblast cells, revealing concentration- and time-dependent effects on gene expression. The findings identify a specific stress signaling pathway involved in DCVC-induced cytotoxicity.
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 mu M DCVC versus 10 mu M, and 12-h versus 6-h of treatment. Comparing the two models for the transcriptional response to 12-h 20 mu M 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 < 0.05 + LogFC > 0.35 [FC > 1.3]). GSEA revealed five upregulated enriched pathways in common between explants and cells (FDR < 0.05). Moreover, all 12-h DCVC treatment groups from both models contained upregulated pathways enriched for genes regulated by the ATF4 transcription factor. The overrepresentation of ATF4 regulation of differentially expressed genes indicated activation of the integrated stress response (ISR), a condition triggered by multiple stress stimuli, including the unfolded protein response. DCVC-induced ISR activation was confirmed by elevated eIF2 alpha phosphorylation, ATF4 protein concentrations, and decreased global protein synthesis in HTR-8/SVneo cells. This study identifies a mechanism of DCVC-induced cytotoxicity by revealing the involvement of a specific stress signaling pathway.
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