Dataset Information

Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome.

ABSTRACT:

Background

Environmental 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.

Results

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 ?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.

Conclusions

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.

SUBMITTER: Kim JH

PROVIDER: S-EPMC3902427 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome.

Kim Jung H JH Sartor Maureen A MA Rozek Laura S LS Faulk Christopher C Anderson Olivia S OS Jones Tamara R TR Nahar Muna S MS Dolinoy Dana C DC

BMC genomics 20140117

<h4>Background</h4>Environmental 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 th ...[more]

PMID: 24433282

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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).

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 µg 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.

Project description:Genomic imprinting, a phenomenon by which genes are expressed in a monoallelic, parent-of-origin-dependent fashion, is critical for normal brain development. Expression of imprinted genes is regulated via epigenetic mechanisms, including DNA methylation (5-methylcytosine, 5mC), and disruptions in imprinting can lead to disease. Early-life exposure to the endocrine disrupting chemical bisphenol A (BPA) is associated with abnormalities in brain development and behavior, as well as with disruptions in epigenetic patterning, including 5mC and DNA hydroxymethylation (5-hydroxymethylcytosine, 5hmC). Using an established mouse model of perinatal environmental exposure, the objective of this study was to examine the effects of perinatal BPA exposure on epigenetic regulation of imprinted gene expression in adult mice. Two weeks prior to mating, dams were assigned to control chow or chow containing an environmentally relevant dose (50 µg/kg) of BPA. Exposure continued until offspring were weaned at post-natal day 21, and animals were followed until 10 months of age. Expression of three imprinted genes-Pde10a, Ppp1r9a, and Kcnq1, as well as three genes encoding proteins critical for regulation of 5mC and 5hmC-Dnmt1, Tet1, and Tet2, were evaluated in the right cortex and midbrain using qRT-PCR. Perinatal BPA exposure was associated with a significant increase in adult Kcnq1 (p = 0.04) and Dnmt1 (p = 0.02) expression in the right cortex, as well as increased expression of Tet2 in the midbrain (p = 0.03). Expression of Tet2 and Kcnq1 were positively correlated in the midbrain. Analysis of 5mC and 5hmC at the Kcnq1 locus was conducted in parallel samples using standard and oxidative bisulfite conversion followed by pyrosequencing. This analysis revealed enrichment of both 5mC and 5hmC at this locus in both brain regions. No significant changes in 5mC and 5hmC at Kcnq1 were observed with perinatal BPA exposure. Together, these data suggest that perinatal BPA exposure results in altered expression of Kcnq1, Dnmt1, and Tet2 in the adult mouse brain. Further studies with larger sample sizes are necessary to understand the mechanistic basis for these changes, as well as to determine the implications they have for brain development and function.

Dataset Information

Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome.

Background

Results

Conclusions

Publications

Perinatal bisphenol A exposure promotes dose-dependent alterations of the mouse methylome.

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