DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk

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ABSTRACT

Developmental exposure to endocrine-disrupting chemicals (EDCs), 17β-estradiol-3-benzoate (EB) and bisphenol A (BPA), increases susceptibility to prostate cancer (PCa) in rodent models. Here, we used the methylated-CpG island recovery assay (MIRA)-assisted genomic tiling and CpG island arrays to identify treatment-associated methylome changes in the postnatal day (PND)90 dorsal prostate tissues of Sprague-Dawley rats neonatally (PND1, 3, and 5) treated with 25 µg/pup or 2,500 µg EB/kg body weight (BW) or 0.1 µg BPA/pup or 10 µg BPA/kg BW. We identified 111 EB-associated and 86 BPA-associated genes, with 20 in common, that have significant differentially methylated regions. Pathway analysis revealed cancer as the top common disease pathway. Bisulfite sequencing validated the differential methylation patterns observed by array analysis in 15 identified candidate genes. The methylation status of 7 ( Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, Creb3l4) of these 15 genes exhibited an inverse correlation with gene expression in tissue samples. Cell-based assays, using 5-aza-cytidine-treated normal (NbE-1) and cancerous (AIT) rat prostate cells, added evidence of DNA methylation-mediated gene expression of 6 genes (exception: Paqr4). Functional connectivity of these genes was linked to embryonic stem cell pluripotency. Furthermore, clustering analyses using the dataset from The Cancer Genome Atlas revealed that expression of this set of 7 genes was associated with recurrence-free survival of PCa patients. In conclusion, our study reveals that gene-specific promoter methylation changes, resulting from early-life EDC exposure in the rat, may serve as predictive epigenetic biomarkers of PCa recurrence, and raises the possibility that such exposure may impact human disease.

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SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.

Soufiane Boumahdi, Gregory Driessens, Gaëlle Lapouge … (2014)

Cancer stem cells (CSCs) have been reported in various cancers, including in skin squamous-cell carcinoma (SCC). The molecular mechanisms regulating tumour initiation and stemness are still poorly characterized. Here we find that Sox2, a transcription factor expressed in various types of embryonic and adult stem cells, was the most upregulated transcription factor in the CSCs of squamous skin tumours in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human pre-neoplastic skin tumours, and continues to be expressed in a heterogeneous manner in invasive mouse and human SCCs. In contrast to other SCCs, in which SOX2 is frequently genetically amplified, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumour formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (SOX2-GFP knock-in mice), we showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumour-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumour regression, consistent with the critical role of SOX2-expressing cells in tumour maintenance. Conditional Sox2 deletion in pre-existing skin papilloma and SCC leads to tumour regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC functions. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumour epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumour cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumour stemness, survival, proliferation, adhesion, invasion and paraneoplastic syndrome. We demonstrate that SOX2, by marking and regulating the functions of skin tumour-initiating cells and CSCs, establishes a continuum between tumour initiation and progression in primary skin tumours.

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Urinary Concentrations of Bisphenol A and 4-Nonylphenol in a Human Reference Population

Antonia M Calafat, Zsuzsanna Kuklenyik, John A. Reidy … (2004)

Bisphenol A (BPA) is used to manufacture polycarbonate plastic and epoxy resins, which are used in baby bottles, as protective coatings on food containers, and for composites and sealants in dentistry. 4-Nonylphenol (NP) is used to make nonylphenol ethoxylates, nonionic surfactants applied as emulsifying, wetting, dispersing, or stabilizing agents in industrial, agricultural, and domestic consumer products. The potential for human exposure to BPA and NP is high because of their widespread use. We measured BPA and NP in archived urine samples from a reference population of 394 adults in the United States using isotope-dilution gas chromatography/mass spectrometry. The concentration ranges of BPA and NP were similar to those observed in other human populations. BPA was detected in 95% of the samples examined at concentrations ≥0.1 μg/L urine; the geometric mean and median concentrations were 1.33 μg/L (1.36 μg/g creatinine) and 1.28 μg/L (1.32 μg/g creatinine), respectively; the 95th percentile concentration was 5.18 μg/L (7.95 μg/g creatinine). NP was detected in 51% of the samples examined ≥0.1 μg/L. The median and 95th percentile concentrations were < 0.1 μg/L and 1.57 μg/L (1.39 μg/g creatinine), respectively. The frequent detection of BPA suggests widespread exposure to this compound in residents of the United States. The lower frequency of detection of NP than of BPA could be explained by a lower exposure of humans to NP, by different pharmacokinetic factors (i.e., absorption, distribution, metabolism, elimination), by the fact that 4-n-nonylphenol—the measured NP isomer—represents a small percentage of the NP used in commercial mixtures, or a combination of all of the above. Additional research is needed to determine the best urinary biomarker(s) to assess exposure to NP. Despite the sample population’s nonrepresentativeness of the U.S. population (although sample weights were used to improve the extent to which the results represent the U.S. population) and relatively small size, this study provides the first reference range of human internal dose levels of BPA and NP in a demographically diverse human population.

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In vitro molecular mechanisms of bisphenol A action.

Yelena B Wetherill, Benson T Akingbemi, Jun Kanno … (2007)

Bisphenol A (BPA, 2,2-bis (4-hydroxyphenyl) propane; CAS# 80-05-7) is a chemical used primarily in the manufacture of polycarbonate plastic, epoxy resins and as a non-polymer additive to other plastics. Recent evidence has demonstrated that human and wildlife populations are exposed to levels of BPA which cause adverse reproductive and developmental effects in a number of different wildlife species and laboratory animal models. However, there are major uncertainties surrounding the spectrum of BPA's mechanisms of action, the tissue-specific impacts of exposures, and the critical windows of susceptibility during which target tissues are sensitive to BPA exposures. As a foundation to address some of those uncertainties, this review was prepared by the "In vitro" expert sub-panel assembled during the "Bisphenol A: An Examination of the Relevance of Ecological, In vitro and Laboratory Animal Studies for Assessing Risks to Human Health" workshop held in Chapel Hill, NC, Nov 28-29, 2006. The specific charge of this expert panel was to review and assess the strength of the published literature pertaining to the mechanisms of BPA action. The resulting document is a detailed review of published studies that have focused on the mechanistic basis of BPA action in diverse experimental models and an assessment of the strength of the evidence regarding the published BPA research.

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Author and article information

Journal

Journal ID (nlm-ta): Epigenetics

Journal ID (iso-abbrev): Epigenetics

Journal ID (publisher-id): KEPI

Journal ID (publisher-id): kepi20

Title: Epigenetics

Publisher: Taylor & Francis

ISSN (Print): 1559-2294

ISSN (Electronic): 1559-2308

Publication date Collection: September 2016

Publication date (Electronic): 14 July 2016

Publication date PMC-release: 14 July 2016

Volume: 11

Issue: 9

Pages: 674-689

Affiliations

[a ]Department of Environmental Health, University of Cincinnati College of Medicine , Cincinnati, OH, USA

[b ]Center for Environmental Genetics, University of Cincinnati College of Medicine , Cincinnati, OH, USA

[c ]Department of Urology, College of Medicine, University of Illinois at Chicago , Chicago, IL, USA

[d ]Cincinnati Cancer Center , Cincinnati, OH, USA

[e ]University of Illinois Cancer Center , Chicago, IL, USA

[f ]Cincinnati Veteran Affairs Hospital Medical Center , Cincinnati, OH, USA

Author notes

Supplemental data for this article can be accessed on the publisher's website.

[*]

These authors contributed equally to this work.

[**]

Current address: Life Giving Foundation Education Center, Cheung Sha Wan, Kowloon, Hong Kong

[#]

Current address: Department of Environmental Health Sciences, John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

[##]

Current address: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

CONTACT Shuk-Mei Ho hosm@ 123456ucmail.uc.edu Room 128, Department of Environmental Health, Kettering, Complex, 160 Panzeca Way University of Cincinnati Medical Center Cincinnati, OH 45267-0056, USA.

Article

Publisher ID: 1208891

DOI: 10.1080/15592294.2016.1208891

PMC ID: 5048723

PubMed ID: 27415467

SO-VID: 0d538118-1823-4b42-bd41-8595f7a17f94

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

History

Date received : 25 April 2016

Date revision received : 25 June 2016

Date accepted : 27 June 2016

Page count

Figures: 6, Tables: 3, References: 100, Pages: 16

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DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk

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Most cited references 83

SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.

Urinary Concentrations of Bisphenol A and 4-Nonylphenol in a Human Reference Population

In vitro molecular mechanisms of bisphenol A action.

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Cited by 22

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