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Transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue

ABSTRACT: Transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue

PROVIDER: PRJNA706597 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13856500_1.fastq.gz	Fastqsanger.gz
	SRR13856500_2.fastq.gz	Fastqsanger.gz
	SRR13856501_1.fastq.gz	Fastqsanger.gz
	SRR13856501_2.fastq.gz	Fastqsanger.gz
	SRR13856502_1.fastq.gz	Fastqsanger.gz

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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.

Project description:Numerous Superfund sites are contaminated with the volatile organic chemical trichloroethylene (TCE). In women, exposure to TCE in pregnancy is associated with reduced birth weight. Our previous study reported that TCE exposure in pregnant rats decreased fetal weight and elevated oxidative stress biomarkers in placentae, suggesting placental injury as a potential mechanism of TCE-induced adverse birth outcomes. In this study, we investigated if co-exposure with the antioxidant N-acetylcysteine (NAC) attenuates TCE exposure effects on RNA expression. Timed-pregnant Wistar rats were exposed orally to 480 mg TCE/kg/day on gestation days 6-16. Exposure of 200 mg NAC/kg/day alone or as a pre/co-exposure with TCE occurred on gestation days 5-16 to stimulate antioxidant genes prior to TCE exposure. Tissue was collected on gestation day 16. In male and female placentae, we evaluated TCE- and/or NAC-induced changes to gene expression and pathway enrichment analyses using false discovery rate (FDR) and fold-change criteria. In female placentae, exposure to TCE caused significant differential expression 129 genes while the TCE+NAC altered 125 genes, compared with controls (FDR< 0.05 + fold-change >1). In contrast, in male placentae TCE exposure differentially expressed 9 genes and TCE+NAC differentially expressed 35 genes, compared with controls (FDR< 0.05 + fold-change >1). NAC alone did not significantly alter gene expression in either sex. Differentially expressed genes observed with TCE exposure were enriched in mitochondrial biogenesis and oxidative phosphorylation pathways in females whereas immune system pathways and endoplasmic reticulum stress pathways were differentially expressed in both sexes (FDR<0.05). TCE treatment was differentially enriched for genes regulated by the transcription factors ATF6 (both sexes) and ATF4 (males only), indicating a cellular condition triggered by misfolded proteins during endoplasmic reticulum stress. This study demonstrates novel genes and pathways involved in TCE-induced placental injury and showed antioxidant co-treatment largely did not attenuate TCE exposure effects.

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Transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue

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