Our current understanding of how endocrine-disrupting chemicals (EDCs), such as the hormone mimics ('xenoestrogens') modify and maintain chromatin states, gene expression patterns and alter genomic nuclear receptor binding and chromatin structural patterns is nascent. Chromatin accessibility plays a major role in shaping the binding landscape of nuclear hormone receptors and all transcription factors. DNaseI hypersensitivity mapping provides a powerful approach for global, generic, and precise delineation of regulatory DNA. In this proposal, we aim to apply these powerful approaches to map alterations in the regulatory DNA landscape associated with EDCs, and to define the impact of EDC exposure on transcriptional control networks. Focusing on xenoestrogens, we aim to characterize systematically the impact of exposure on the regulatory DNA landscape using model cell lines as well as specialized primary cell and primary human tissue culture systems. We will also address major outstanding questions concerning transient exposures to EDCs giving rise to lasting phenotypic effects, and analyze transcriptional regulatory networks perturbed by EDCs.
Environmental toxins are synthetic or naturally occurring chemicals that are known to cause human disease. However, a mechanistic understanding of epigenetic modulation by these compounds remains elusive. The aims of this proposal will identify regulatory elements in the genome that are response to EDCs and will provide insight into processes whereby transient or low-dose exposure to EDCs have long-lasting effects into adulthood. Our studies will help understand how toxins impact regulatory processes.