Neonatal Exposure to Estradiol/Bisphenol A Alters Promoter Methylation and Expression of Nsbp1 and Hpcal1 Genes and Transcriptional Programs of Dnmt3a/b and Mbd2/4 in the RatProstate Gland Throughout Life
Open accessAbstract
Evidence supporting an early origin of prostate cancer is growing. We demonstrated previously that brief exposure of neonatal rats to estradiol or bisphenol A elevated their risk of developing precancerous lesions in the prostate upon androgen-supported treatment with estradiol as adults. Epigenetic reprogramming may be a mechanism underlying this inductive event in early life, because we observed overexpression of phosphodiesterase 4D variant 4 (Pde4d4) through induction of hypomethylation of its promoter. This epigenetic mark was invisible in early life (postnatal d 10), becoming apparent only after sexual maturation. Here, we asked whether other estrogen-reprogrammable epigenetic marks have similar or different patterns in gene methylation changes throughout life. We found that hypomethylation of the promoter of nucleosome binding protein-1 (Nsbp1), unlike Pde4d4, is an early and permanent epigenetic mark of neonatal exposure to estradiol/bisphenol A that persists throughout life, unaffected by events during adulthood. In contrast, hippocalcin-like 1 (Hpcal1) is a highly plastic epigenetic mark whose hypermethylation depends on both type of early-life exposure and adult-life events. Four of the eight genes involved in DNA methylation/demethylation showed early and persistent overexpression that was not a function of DNA methylation at their promoters, including genes encoding de novo DNA methyltransferases (Dnmt3a/b) and methyl-CpG binding domain proteins (Mbd2/4) that have demethylating activities. Their lifelong aberrant expression implicates them in early-life reprogramming and prostate carcinogenesis during adulthood. We speculate that the distinctly different fate of early-life epigenetic marks during adulthood reflects the complex nature of lifelong editing of early-life epigenetic reprogramming.
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BPA is thought to be an endocrine disruptor that acts as an estrogen mimetic.
“BPA is thought to be an endocrine disruptor that acts as an estrogen mimetic [ 128–131 ], thus research has focused largely on its effects in reproductive tissues.”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [130]
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 [130]
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- Authors
- Tang, W.-Y., Morey, L. M., Cheung, Y. Y., Birch, L., Prins, G. S., & Ho, S.-M.
- Affiliations
- University of Cincinnati (US)
- Division of Environmental Genetics and Molecular Toxicology (W.-y.T., L.M.M., Y.Y.C., S.-m.H.), Cincinnati, Ohio 45267
- University of Illinois Chicago (US)
- Cincinnati VA Medical Center (US)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-01-01
- Volume
- 153
- Issue
- 1
- Pages
- 42-55
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3249669
- OpenAlex
- W2070584219
- Cited by
- 164
- References
- 62
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 13 · 2017: 20 · 2016: 19 · 2015: 22 · 2014: 12 · 2013: 9 · 2012: 11
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs (I01-BX000675)
- National Cancer Institute (T32CA117846, CA112532, R03CA136023, R01CA112532, CA136023)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 40890, R01DK040890)
- National Institute of Environmental Health Sciences (ES019480, ES-006096, ES-015584, K99ES016817, ES-018758, P30ES006096, ES016817, ES020988, U01ES019480, RC2ES018789, ES018789, U01ES020988, RC2ES018758, R01ES015584, R00ES016817)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- estradiol, bisphenol A, DNA methylation, promoter hypomethylation, promoter hypermethylation, epigenetic reprogramming, prostate cancer, prostate carcinogenesis, gene expression, rat prostate
- MeSH terms
- Decitabine, DNA Methyltransferase 3A, DNA Methyltransferase 3B, Bisphenol A Compounds, Animals, Animals, Newborn, Azacitidine, Base Sequence, Benzhydryl Compounds, Calcium-Binding Proteins, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Estradiol, Male, Nerve Tissue Proteins, Phenols, Promoter Regions, Genetic, Prostate, Gene Expression, Rats, Sprague-Dawley, DNA Primers, DNA Methylation, HMGN Proteins, RNA, Small Interfering, Rats
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