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Grant Details

Grant Number: 5R01CA127989-04 Interpret this number
Primary Investigator: Futscher, Bernard
Organization: University Of Arizona
Project Title: Epigenetic Remodeling By Environmental Arsenicals
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): Environmental exposure to arsenic and its metabolites is a significant health concern to US and world populations, playing a causative role in the etiology of human pathologies, including cancer. The long-term goal of the proposed study is designed to identify mechanisms of toxicity that are a result of environmental exposures to arsenicals. It is hypothesized that arsenical toxicity, in part, is mediated through its disruption of the normal epigenetic state of cells, and this hypothesis is based on reports in the extant literature as well as these preliminary studies. This premise will be tested using advanced epigenetic technologies to analyze models of arsenical exposure. These models range from in vitro models of arsenical-mediated malignant transformation of human uroepithelial cells to well-characterized, ethnically important human populations exposed to known levels of environmental arsenicals through drinking water. Through three specific aims the effects of arsenicals on epigenetic regulation from the level of the individual gene to the level of the entire genome will be tested. The aims are to: 1) Investigate the mechanisms and phenotypic consequences of epigenetic activation of Wnt5a gene that has been observed in an in vitro model of arsenical-induced malignant transformation. 2) Identify the decisive changes in the epigenomic landscape over the time course of arsenical induced malignant conversion of the immortalized human bladder cell UROtsa, and determine the stability of these changes after removal of this stressor. 3) Identify epigenetic targets of arsenic in human populations exposed to known levels of arsenic in their drinking water. While this research application focuses on the epigenetic perturbations induced by arsenicals with respect to human cancer, it is likely that if the hypothesis is backed by the studies, that of arsenical induced epigenetic changes as a mechanism of long-term toxicity, then the knowledge generated will likely extend to other metal-induced human pathologies, such as diabetes and cardiovascular disease.

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Publications

Monomethylarsonous acid produces irreversible events resulting in malignant transformation of a human bladder cell line following 12 weeks of low-level exposure.
Authors: Wnek S.M. , Jensen T.J. , Severson P.L. , Futscher B.W. , Gandolfi A.J. .
Source: Toxicological sciences : an official journal of the Society of Toxicology, 2010 Jul; 116(1), p. 44-57.
EPub date: 2010-04-07.
PMID: 20375083
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Arsenicals produce stable progressive changes in DNA methylation patterns that are linked to malignant transformation of immortalized urothelial cells.
Authors: Jensen T.J. , Novak P. , Wnek S.M. , Gandolfi A.J. , Futscher B.W. .
Source: Toxicology and applied pharmacology, 2009-12-01; 241(2), p. 221-9.
EPub date: 2009-08-28.
PMID: 19716837
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Epigenetic mediated transcriptional activation of WNT5A participates in arsenical-associated malignant transformation.
Authors: Jensen T.J. , Wozniak R.J. , Eblin K.E. , Wnek S.M. , Gandolfi A.J. , Futscher B.W. .
Source: Toxicology and applied pharmacology, 2009-02-15; 235(1), p. 39-46.
EPub date: 2008-11-06.
PMID: 19061910
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Reactive oxygen species regulate properties of transformation in UROtsa cells exposed to monomethylarsonous acid by modulating MAPK signaling.
Authors: Eblin K.E. , Jensen T.J. , Wnek S.M. , Buffington S.E. , Futscher B.W. , Gandolfi A.J. .
Source: Toxicology, 2009-01-08; 255(1-2), p. 107-14.
EPub date: 2008-10-22.
PMID: 19014992
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The role of reactive oxygen species in arsenite and monomethylarsonous acid-induced signal transduction in human bladder cells: acute studies.
Authors: Eblin K.E. , Hau A.M. , Jensen T.J. , Futscher B.W. , Gandolfi A.J. .
Source: Toxicology, 2008-08-19; 250(1), p. 47-54.
EPub date: 2008-06-05.
PMID: 18588940
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Epigenetic remodeling during arsenical-induced malignant transformation.
Authors: Jensen T.J. , Novak P. , Eblin K.E. , Gandolfi A.J. , Futscher B.W. .
Source: Carcinogenesis, 2008 Aug; 29(8), p. 1500-8.
EPub date: 2008-04-30.
PMID: 18448484
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