Putative Early Life Epigenetic Biomarkers of Hepatocellular Carcinoma in Mice Perinatally Exposed to Bisphenol A.

Abstract

Bisphenol A (BPA) is a high production-volume chemical with hormone-like properties that has been implicated as a potential carcinogen. Early life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between cancer development and exposure to BPA alone. The overall goal of this dissertation was to test the central hypothesis that early life BPA exposure dysregulates the DNA methylome and thereby modifies risk for adult liver tumors. Chapter 2 describes a monotonic increase in hepatic tumors with increasing dose of perinatal BPA. Chapter 2 further characterizes the observed liver tumor phenotype in a murine model and notes a lack of sexual dimorphism in incidence, as well as a lack of regenerative response to injury, suggesting a solely proliferative response to BPA. Chapter 3 provides proof of principle for a novel method for identification of epigenetic biomarkers of exposure and outcome across the life-course and across species. Chapter 4 demonstrates that epigenome-wide discovery experiments in animal models are effective tools for identification and understanding of paralagous epimutations in cell signaling pathways salient to human disease. Taken together, these findings are indicators of the relevance of the hepatic tumor phenotype seen in BPA-exposed mice to human health. This work combines a state-of-the-art epigenomic discovery approach with high resolution, quantitative epigenetic techniques to identify dose-dependent alterations in the fetal and adult epigenomes that correlate with HCC status. As such, this research represents a critical link between early life environment and a specific phenotypic outcome in later life, necessary to the determination of human health risk assessment and human disease prevention, diagnosis, and treatment