Exposure to environmental arsenicals has been linked to a number of human pathologies, include bladder and lung cancer. We hypothesize that arsenical-mediated perturbation of the epigenetic landscape is an important factor that drives malignant progression. Three integrated specific aims are described in this proposal will address this hypothesis from a gene to genome wide analysis, and from in vitro to """"""""real world"""""""" settings.
Aim 1 is designed to develop epigenetic targets as biomarkers of arsenical exposure. Preliminary epigenome-wide scanning studies of urine sediments from individuals with known exposure levels in their drinking water have identified candidate epigenetic biomarkers are correlated with arsenical exposure level. The utility of these candidate biomarkers will be evaluated using high sensitivity, high resolution technologies in a new cohort population.
Aim 2 will determine if arsenicals produce common perturbations to the epigenomic landscape in their distinct epithelial targets. Experimental strategies of arsenical exposure that caused malignant transformation of urothelial cells will be expanded to lung epithelial model systems. Results from these experiments will help determine if there are seminal epigenetic changes that are common to epithelial malignant transformation in general, as well as the epigenetic changes that display tissue-origin specificity.
Aim 3 will provide a detailed investigation of the phenotypic consequences of epigenetic gene inactivation of an arsenical target gene, G0S2, which is closely linked to the malignant transformation of urothelial cells. If our hypothesis is correct, then results from these studies will provide new insights into the mechanisms of their chronic arsenical exposure, as well as serve as a platform for inquiries into other, non-cancer, arsenic-induced human pathologies, such as diabetes and cardiovascular disease.

Public Health Relevance

Environment - genome interactions are becoming more important in understanding pollutant associated diseases. Epigenetic studies will provide new insights into the mechanisms of arsenic-induced cancers, as well as serve as a platform for inquiries into other, non-cancer, arsenic-induced human pathologies, such as diabetes and cardiovascular disease. An important mechanism of arsenical toxicity is its ability to alter cellular phenotype through disruption of the normal epigenetic landscape.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Special Emphasis Panel (ZES1-LWJ-M)
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University of Arizona
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Youn, Jong-Sang; Csavina, Janae; Rine, Kyle P et al. (2016) Hygroscopic Properties and Respiratory System Deposition Behavior of Particulate Matter Emitted By Mining and Smelting Operations. Environ Sci Technol 50:11706-11713
Olivares, Christopher I; Sierra-Alvarez, Reyes; Abrell, Leif et al. (2016) Zebrafish embryo toxicity of anaerobic biotransformation products from the insensitive munitions compound 2,4-dinitroanisole. Environ Toxicol Chem 35:2774-2781
Rehman, Zahir Ur; Khan, Sardar; Qin, Kun et al. (2016) Quantification of inorganic arsenic exposure and cancer risk via consumption of vegetables in southern selected districts of Pakistan. Sci Total Environ 550:321-9
Zhong, Hua; Liu, Guansheng; Jiang, Yongbing et al. (2016) Effect of low-concentration rhamnolipid on transport of Pseudomonas aeruginosa ATCC 9027 in an ideal porous medium with hydrophilic or hydrophobic surfaces. Colloids Surf B Biointerfaces 139:244-8
Rodriguez-Freire, Lucia; Moore, Sarah E; Sierra-Alvarez, Reyes et al. (2016) Arsenic remediation by formation of arsenic sulfide minerals in a continuous anaerobic bioreactor. Biotechnol Bioeng 113:522-30
Beamer, Paloma I; Klimecki, Walter T; Loh, Miranda et al. (2016) Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int J Environ Res Public Health 13:
Honeker, Linnea K; Root, Robert A; Chorover, Jon et al. (2016) Resolving colocalization of bacteria and metal(loid)s on plant root surfaces by combining fluorescence in situ hybridization (FISH) with multiple-energy micro-focused X-ray fluorescence (ME μXRF). J Microbiol Methods 131:23-33
Ezeh, Peace C; Xu, Huan; Lauer, Fredine T et al. (2016) Monomethylarsonous acid (MMA+3) Inhibits IL-7 Signaling in Mouse Pre-B Cells. Toxicol Sci 149:289-99
Gil-Loaiza, Juliana; White, Scott A; Root, Robert A et al. (2016) Phytostabilization of mine tailings using compost-assisted direct planting: Translating greenhouse results to the field. Sci Total Environ 565:451-61
Olivares, Christopher I; Wang, Junqin; Luna, Carlos D Silva et al. (2016) Continuous treatment of the insensitive munitions compound N-methyl-p-nitro aniline (MNA) in an upflow anaerobic sludge blanket (UASB) bioreactor. Chemosphere 144:1116-22

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