Abstract 1382: Developmental exposure to BPA increases the prostate cancer susceptibility via reprogramming of androgen-responsive genes via increased H3K4me3 methylation

Abstract

Abstract Background: Early life exposure to endocrine disrupting compounds (EDCs) during critical developmental periods increases susceptibility to cancer and other diseases in adulthood. Because EDC exposures cause life-long changes in gene expression of target tissues, identification of gene targets for developmental reprogramming holds promise for both understanding the etiology of environmental causes of cancer and development of biomarkers of EDC exposure. Aim: Our goal was to identify targets for developmental reprogramming in the prostate using a rat model for development of hormone-dependent early prostate (PIN) lesions induced by the EDC bisphenol A (BPA). Methods: Rats were exposed neonatally to vehicle or BPA and assessed at 12 months for development of hormone-dependent prostate lesions. Epigenetic status and gene expression were profiled in the at-risk (d70) adult prostate using CHIP- and RNA-seq, with qRT-PCR and ChIP used to confirm changes in gene expression and histone methylation (respectively). Results: As expected, BPA exposure significantly increased PIN lesions and the dysplasia score in 12 mo rats. CHIP-seq in adult rats (day 70) prior to lesion development showed a significant increase in histone H3, lysine 4 trimethylation (H3K4me3) levels in prostate cancer-associated KEGG pathway genes of rats exposed to BPA neonatally. Changes reflective of both increased basal, as well as hormone-induced, KEGG pathway gene expression were observed in BPA exposed animals at increased risk for development of PIN lesions. Conclusion: Neonatal BPA exposure reprograms the developing prostate to alter gene expression in adulthood and increase incidence and severity of prostatic dysplasia. Several KEGG-pathway prostate cancer pathway genes were identified as targets for epigenetic reprogramming, providing new tools for future studies to understand gene-environment interactions as determinants of prostate cancer risk. Citation Format: Quan Wang, Rebecca Lee Yean Wong, Donna F. Kusewitt, Maarten C. Bosland, Jing Chen, Mario Medvedovic, Gail S. Prins, Kurunthachalam Kannan, Shuk-Mei Ho, Cheryl Lyn Walker. Developmental exposure to BPA increases the prostate cancer susceptibility via reprogramming of androgen-responsive genes via increased H3K4me3 methylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1382. doi:10.1158/1538-7445.AM2014-1382