1. DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk
- Author
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Shu Hua Ye, Mario Medvedovic, Gail S. Prins, Jing Chen, Wan Yee Tang, Ana Cheong, Yuk Yin Cheung, Shuk-Mei Ho, Xiang Zhang, and Yuet-Kin Leung
- Subjects
Male ,0301 basic medicine ,endocrine-disrupting chemicals (EDCs) ,Cancer Research ,Candidate gene ,Bisulfite sequencing ,Epigenesis, Genetic ,Rats, Sprague-Dawley ,stem cell pluripotency ,Estradiol ,Sprague Dawley rats ,The Cancer Genome Atlas (TCGA) ,Methylation ,Environmental exposure ,3. Good health ,DNA methylation ,Female ,Research Paper ,medicine.medical_specialty ,Pathway Analysis (IPA®) ,Air Pollutants, Occupational ,NimbleGen rat DNA methylation promoter array ,methylated-CpG island recovery assay (MIRA) ,Biology ,Andrology ,03 medical and health sciences ,Phenols ,SOX2 ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Epigenetics ,Benzhydryl Compounds ,early-life reprogramming ,Molecular Biology ,epigenetics ,Prostatic Neoplasms ,Ingenuity® ,Environmental Exposure ,DNA Methylation ,Survival Analysis ,Rats ,Developmental origin of health and disease (DOHaD) ,030104 developmental biology ,Differentially methylated regions ,Endocrinology ,Genetic Loci ,CpG Islands - 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.
- Published
- 2016