Prenatal Exposure to BPA Alters the Epigenome of the Rat Mammary Gland and Increases the Propensity to Neoplastic Development
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Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns. These events may contribute to the development of pre-neoplastic and neoplastic lesions that manifest during adulthood.
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Epigenetic alterations have been implicated in BPA-associated changes in pathology and function in several hormone-responsive tissues including the brain.
“Epigenetic alterations have been implicated in BPA-associated changes in pathology and function in several hormone-responsive tissues including the brain [ 49 , 130 , 138–141 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [141]
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- Authors
- Dhimolea, E., Wadia, P. R., Murray, T. J., Settles, M. L., Treitman, J. D., Sonnenschein, C., Shioda, T., & Soto, A. M.
- Affiliations
- Tufts University (US)
- University of Idaho (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Soto, Ana M.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-07-02
- Volume
- 9
- Issue
- 7
- Pages
- e99800
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4079328
- OpenAlex
- W2112620557
- Cited by
- 104
- References
- 58
- Citations by year
- 2026: 3 · 2025: 4 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 12 · 2017: 14 · 2016: 14 · 2015: 17 · 2014: 4
- FWCI
- 10.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- Centers for Disease Control and Prevention
- Tufts University School of Medicine
- National Institute of Environmental Health Sciences (RC2ES018822, ES08314, R21ES015182, R01ES008314, ES015182, ES018822)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- bisphenol A, prenatal exposure, mammary gland, DNA methylation, epigenome, xenoestrogens, breast cancer, ductal carcinoma in situ, histone H3 lysine 4 trimethylation, alpha-lactalbumin, estrogen receptor, epithelial-mesenchymal interactions, gene expression
- MeSH terms
- Bisphenol A Compounds, Animals, Antibodies, Benzhydryl Compounds, Female, Gene Expression Regulation, Histones, Lactalbumin, Mammary Glands, Animal, Phenols, Pregnancy, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, Rats, Wistar, DNA Methylation, Oligonucleotide Array Sequence Analysis, Transcription Initiation Site, Epigenesis, Genetic, 5-Methylcytosine, Rats, Tandem Mass Spectrometry, Carcinogenesis
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