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Acute PFOA exposure promotes epigenomic alterations in mouse kidney tissues.

ABSTRACT: Perfluorooctanoic acid (PFOA), a manufactured perfluorochemical is a common surfactant and environmental pollutant found in various consumer products and water sources. Epidemiological studies have demonstrated its association with kidney dysfunction. However, the mechanisms that trigger kidney dysfunction following PFOA exposure is a gap in the field. The work presented explores the potential epigenetic indicators of kidney disease due to exposure to PFOA. In this study, 30 days old CD-1 mice were exposed to 1, 5, 10, or 20 mg/kg/day of PFOA for 10 days. Following acute oral exposure, epigenetic alterations and expression levels of various markers of fibroblast activation were evaluated in kidney tissues. We noted that PFOA-exposed mice exhibited differential methylation yielding 879 differentially methylated regions compared to vehicle. The mRNA expression revealed significant increase in Dnmt1 with decreased Rasal1 expression at higher levels of PFOA exposure suggestive of Rasal1 hypermethylation (an early indicator of fibroblast activation in kidney). Like Dnmt1, we also observed significant increase in Hdac1, 3 and 4. These are class I & II HDACs which are known to be critically altered in some renal diseases. Further, the mRNA expression levels of TGF-? and ?-SMA significantly increased compared to vehicle. The KEGG and Go enrichment pathway analysis of reduced representation bisulfite data also revealed pathways implicated in renal fibrosis. Our study shows clear evidence of epigenetic alterations (DNA methylation and HDAC expression changes) in tissues from mouse kidney following PFOA exposure. Our results also suggest that epigenetic alterations in kidney promote the expression of early markers of fibroblast activation.

SUBMITTER: Rashid F

PROVIDER: S-EPMC6953769 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Acute PFOA exposure promotes epigenomic alterations in mouse kidney tissues.

Rashid Faizan F Ramakrishnan Anujaianthi A Fields Christopher C Irudayaraj Joseph J

Toxicology reports 20200102

Perfluorooctanoic acid (PFOA), a manufactured perfluorochemical is a common surfactant and environmental pollutant found in various consumer products and water sources. Epidemiological studies have demonstrated its association with kidney dysfunction. However, the mechanisms that trigger kidney dysfunction following PFOA exposure is a gap in the field. The work presented explores the potential epigenetic indicators of kidney disease due to exposure to PFOA. In this study, 30 days old CD-1 mice w ...[more]

PMID: 31938689

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Project description:BackgroundEnvironmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet.ResultsUsing a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 ?g BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response.ConclusionsIn this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways were identified and validated. The comprehensive methylome map presented here provides candidate loci underlying the role of early BPA exposure and later in life health and disease status.

Project description:Environmental factors during perinatal development influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring perinatally exposed to multiple doses of BPA through the maternal diet. Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 M-BM-5g BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N=4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response. In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways were identified and validated. The comprehensive methylome map presented here provides candidate loci underlying the role of early BPA exposure and later in life health and disease status. For this study, liver DNA from a subset of a/a wild-type animals was analyzed for full methylome characteristics: 1) standard diet (Ctr, n = 4 offspring; 2 male and 2 female); 2) 50 M-BM-5g BPA/kg diet (UG, n = 4 offspring; 2 male and 2 female); 3) 50 mg BPA/kg diet (MG, n = 4 offspring; 1 male and 3 female).

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Acute PFOA exposure promotes epigenomic alterations in mouse kidney tissues.

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Acute PFOA exposure promotes epigenomic alterations in mouse kidney tissues.

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