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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.
KEYWORDS:
- Developmental origin of health and disease (DOHaD)
- early-life reprogramming
- endocrine-disrupting chemicals (EDCs)
- epigenetics
- Ingenuity®
- Pathway Analysis (IPA®)
- methylated-CpG island recovery assay (MIRA)
- NimbleGen rat DNA methylation promoter array
- Sprague Dawley rats
- stem cell pluripotency
- The Cancer Genome Atlas (TCGA)
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
The results published here are in whole or in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. We thank The Genomics, Epigenomics, and Sequencing Core for the array service. We also thank Lynn Birch, Wen Yang Hu, Saikumar Karyala, Miral Patel, Hong Xiao and for their technical assistance and Jennifer Veevers for her excellent editing of the manuscript.
Funding
This study was supported in part by grants from the National Institutes of Environmental Health Sciences: R01CA015776 (SMH), R01ES015584 (GSP, SMH), RC2ES018758 (GSP, SMH, MM), RC2ES018789 (SMH, MM), U01ES019480 (SMH, MM), U01ES020988 (SMH, MM), CA172220 (GSP), and P30ES006096 (SMH, MM), the United States Department of Veterans Affairs I01BX000675 (SMH), and the Department of Defense Prostate Cancer Research Program W81XWH-06-1-0373 (WT) and W81XWH-15-1-0496 (AC).
