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Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development.

ABSTRACT: The hypothesis of fetal origins of adult disease posits that early developmental exposures involve epigenetic modifications, such as DNA methylation, that influence adult disease susceptibility. In utero or neonatal exposure to bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic, is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function. This study shows that maternal exposure to this endocrine-active compound shifted the coat color distribution of viable yellow agouti (Avy) mouse offspring toward yellow by decreasing CpG (cytosine-guanine dinucleotide) methylation in an intracisternal A particle retrotransposon upstream of the Agouti gene. CpG methylation also was decreased at another metastable locus, the CDK5 activator-binding protein (CabpIAP). DNA methylation at the Avy locus was similar in tissues from the three germ layers, providing evidence that epigenetic patterning during early stem cell development is sensitive to BPA exposure. Moreover, maternal dietary supplementation, with either methyl donors like folic acid or the phytoestrogen genistein, negated the DNA hypomethylating effect of BPA. Thus, we present compelling evidence that early developmental exposure to BPA can change offspring phenotype by stably altering the epigenome, an effect that can be counteracted by maternal dietary supplements.

SUBMITTER: Dolinoy DC

PROVIDER: S-EPMC1941790 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development.

Dolinoy Dana C DC Huang Dale D Jirtle Randy L RL

Proceedings of the National Academy of Sciences of the United States of America 20070801 32

The hypothesis of fetal origins of adult disease posits that early developmental exposures involve epigenetic modifications, such as DNA methylation, that influence adult disease susceptibility. In utero or neonatal exposure to bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic, is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function. This study shows that maternal exposure to this endocrine ...[more]

PMID: 17670942

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Project description:This study was conducted to explore whether exposure to bisphenol A (BPA) during pregnancy could change intestinal digestion and absorption function in offspring using pigs as a model, and whether methyl donor (MET) could counteract the BPA-induced impacts. Fifty Landrace × Yorkshire sows were divided into four dietary groups throughout gestation: control diet (CON); control diet supplemented with BPA (50 mg/kg); control diet supplemented with MET (3 g/kg betaine, 400 mg/kg choline, 150 ?g/kg vitamin B12, and 15 mg/kg folic acid); and control diet with BPA and MET supplementation (BPA + MET). Intestine samples were collected from pigs' offspring at birth and weaning. Maternal BPA exposure during pregnancy significantly reduced the ratio of jejunum villus height to crypt depth, decreased the jejunum sucrase activity, down-regulated the mRNA expression of jejunum peptide transporter 1 (Pept1) and DNA methyl transferase 3a (DNMT3a), and decreased the DNA methylation level of jejunum Pept1 in offspring (p < 0.05). Maternal MET supplementation significantly raised the ratio of villus height to crypt depth in jejunum and ileum, improved the jejunum lactase activity, up-regulated the mRNA expression of jejunum Pept1, lactase (LCT), DNMT1, DNMT3a, and methylenetetrahydrofolate reductase (MTHFR), and increased the DNA methylation level of jejunum Pept1 in offspring (p < 0.05). However, the ratio of jejunum villus height to crypt depth was higher in BPA + MET treatment compared with CON and BPA treatment (p < 0.05). Meanwhile, there was no difference in the jejunum sucrase activity, the mRNA expression of jejunum Pept1 and DNMT3a, and the DNA methylation level of jejunum Pept1 between CON and BPA + MET treatment. These results indicated that maternal exposure to BPA during gestation might suppress offspring's intestinal digestion and absorption function, whereas supplementation of MET could counteract these damages, which might be associated with DNA methylation.

Project description:We measured the gene expression profile of fetal liver to identify differentially expressed genes (DEG), biological processes (BP), and pathways underlying hepatic function and development in response to vitamin and mineral supplementation (VTM or NoVTM – at least 71 days pre-breeding to day 83 of gestation) and rate of weight gain (low [LG] or moderate [MG] – from breeding to day 83). The treatments were arranged as follows: (1) no vitamin and mineral supplementation and low gain (NoVTM_LG, n = 8); (2) vitamin and mineral supplementation and low gain (VTM_LG, n = 8); (3) no vitamin and mineral supplementation and moderate gain (NoVTM_MG, n = 8), and (4) vitamin and mineral supplementation and moderate gain (VTM_MG, n = 7). Crossbred Angus beef heifers (n = 35) were randomly assigned to 1 of 4 treatments in a 2 × 2 factorial design. Fetal liver was collected on day 83 ± 0.27 of gestation snap-frozen, and stored at −80 °C. After RNA quality control, read mapping was performed with STAR aligner to the bovine ARS-UCD1.2 reference genome. Strand-specific RNA libraries were prepared using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina (New England BioLabs®, Ipswich, MA, USA). Total RNA was extracted and libraries were sequenced on the Illumina® NovaSeq 6000 platform. After RNA quality control, read mapping was performed with STAR aligner to the bovine ARS-UCD1.2 reference genome. After quality control, differential gene expression analysis was carried out using edgeR. Differentially expressed genes (DEGs) were identified after multiple testing correction of the p-values based on the Benjamini-Hochberg methodology (FDR < 0.1). Our results show that vitamin and mineral supplementation and the rate of weight gain led to differential expression of hepatic genes in all treatments. We identified 591 unique differentially expressed genes across all six VTM-gain contrasts (FDR < 0.1). Over-represented pathways were related to energy metabolism, including PPAR and PI3K-Akt signaling pathways, as well as lipid metabolism, mineral transport, and amino acid transport. Our findings suggest that periconceptual maternal nutrition affects fetal hepatic function through altered expression of energy and lipid-related genes.

Project description:We measured the gene expression profiles of maternal (caruncular; CAR) and fetal (cotyledonary; COT) portions of the placenta to identify differentially expressed genes (DEG), biological processes (BP), and pathways underlying placental development and function in response to early maternal nutrition. To this end, we used the RNA-Seq-based differential expression analysis of bovine placental tissues. The factors examined included vitamin and mineral supplementation (VTM or NoVTM) and rate of gain (low gain – LG or moderate gain – MG). The treatments were arranged as follows: (1) no vitamin and mineral supplementation and low gain (NoVTM_LG, n = 9); (2) vitamin and mineral supplementation and low gain (VTM_LG, n = 9); (3) no vitamin and mineral supplementation and moderate gain (NoVTM_MG, n = 9), and (4) vitamin and mineral supplementation and moderate gain (VTM_MG, n = 8). On day 83 ± 0.27 of gestation the uteroplacental tissues were collected through ovariohysterectomy and the largest placentome closest to the fetus was collected. Then, maternal (CAR) and fetal (COT) portions were manually dissected, snap-frozen, and stored at −80 °C. After RNA quality control, read mapping was performed with STAR aligner to the bovine ARS-UCD1.2 reference genome. Genes with expression values lower than 1 count per million in 50% of the samples were filtered out. After filtering, the genes of CAR and COT tissues were analyzed using the DESeq2 v.1.22.1 software to identify DEGs. The DESEq2 model was used to measure the treatment effect while controlling for batch effect differences that included the surrogated variables (sva) and the heifer’s birthplace (farm of origin). Genes were identified as differentially expressed for each one of the contrasts when the adjusted p-value (padj) cutoff < 0.1 and classified as up- or down-regulated based on the sign of the log2 fold change. We identified 267 unique DEGs throughout all tissues and group contrasts. The over-represented functions are essential to fetal growth and development, and included fatty acid metabolism, hormone synthesis, nutrient transport, energy metabolism, and biosynthesis of amino acids.

Dataset Information

Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development.

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Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development.

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