Arsenicals are widespread environmental toxicants that are causally linked to a variety of human pathologies. Arsenic is a nonmutagenic human carcinogen to which long-term exposure has been correlated with increased incidence of cancers of the bladder, skin, lung, and liver. Arsenic is linked to inducing changes in DNA methylation and gene expression during malignant transformation, and therefore arsenic can act as an epimutagen – an exposure or treatment that can induce meta-stable epigenetic changes that produce alterations in genome structure and function, and that can be faithfully transmitted from one cell generation to the next.
Dr. Bernie Futscher is using emerging in vitro models of arsenical-induced malignant conversion of arsenic-sensitive human epithelial cells, an “in hand” and well-characterized human population of at risk individuals with known arsenical exposure, and advanced epigenomic and genomic technologies to gain a better understanding of the mechanisms of arsenical action. The long-term goal of this research project is to determine if environmental arsenic exposure is linked to disease-relevant epigenetic changes. This goal is predicated on the hypothesis that an important mechanism of arsenical toxicity is its ability to alter cellular phenotype through disruption of the normal epigenetic landscape.
These studies will identify and detail epigenetic targets of arsenicals, which in turn, will help identify potential biomarkers of exposure, therapeutic targets for treatment, as well as insights into the general rules of arsenical action that may ultimately aid in the understanding of the etiology of other arsenic-driven pathologies.
1. Develop Epigenetic Targets as Biomarkers of Arsenical Exposure.
2. Determine if Arsenicals Produce Common Perturbations to the Epigenomic Landscape in their Distinct Epithelial Targets.
3. Investigate the phenotypic consequences of epigenetic gene inactivation in arsenical-induced models of malignant transformation.