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首页> 外文期刊>Archives of Toxicology >Transcriptional profiling of the response to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine revealed activation of the eIF2 alpha/ATF4 integrated stress response in two in vitro placental models
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Transcriptional profiling of the response to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-l-cysteine revealed activation of the eIF2 alpha/ATF4 integrated stress response in two in vitro placental models

机译：对三氯乙烯代谢物S-（1,2-二氯丙基）-1-半胱氨酸的反应的转录分析显示出两种体外胎盘模型中EIF2α/ ATF4综合应力响应的激活

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摘要

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 0.35 [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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