Hexavalent chromium is a well established human carcinogen and is a contaminant at numerous Superfund toxic waste dump sites. Carcinogenesis by hexavalent chromium is thought to involve the formation of Cr-DNA adducts. About 50% of the chromium is bound to DNA as ternary complexes of Cr (III) with either amino acids or glutathione. Additionally, hexavalent chromium has been shown to interact with DNA in a non-random fashion targeting itself to promoters and coding regions of highly inducible genes. Previous studies in humans have suggested that there is a large intra-individual variability in the uptake of chromate. Using he bacterial repair enzymes UvrABC and the technique of ligation-mediated PCR, we will study whether the UvrABC bacterial enzymes can detect and differentiate Cr-DNA complexes including Cr(III)-DNA binary, as well as (Cr(III)-DNA ternary complexes involving either cysteine, histidine, or glutathione within exon 7 of the p53 gene. We will also investigate the effect of cytosine methylation on the formation of adducts in human lymphocytes following exposure to hexavalent chromium within other DNA regions that we can analyze for hotspots of Cr-DNA adducts. Bacterial repair enzymes will cut at Cr adducts, and Southern blotting will measure the hybridization signal in the cut region compared to the uncut DNA using probes, such as the ornithine decarboxylase (ODC) promoter and the p53 coding regions. We will examine hexavalent chromium uptake in 60 human volunteers and identify those with the highest uptake capacity and highest intracellular levels of chromium and high chromate uptake will be utilized to map the Cr-DNA adducts at a single nucleotide level in p53 exon 5 and 7, as well as other DNA regions. These studies attempt to develop biomarkers of exposure and effect of carcinogenic hexavalent chromium. We consider important parameters of genetic diversity including epigenetic differences in DNA methylation and the interindividual diversity of chromatic uptake into cells. These studies should lead to new methodologies for assessing the impact of environmental exposure of hexavalent chromium to the human population and identify factors of susceptibility that enhance Cr toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES010344-03
Application #
6577817
Study Section
Special Emphasis Panel (ZES1)
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
$164,076
Indirect Cost
Name
New York University
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Brocato, Jason; Hernandez, Michelle; Laulicht, Freda et al. (2015) In Vivo Exposures to Particulate Matter Collected from Saudi Arabia or Nickel Chloride Display Similar Dysregulation of Metabolic Syndrome Genes. J Toxicol Environ Health A 78:1421-36
Brocato, Jason; Chen, Danqi; Liu, Jianli et al. (2015) A Potential New Mechanism of Arsenic Carcinogenesis: Depletion of Stem-Loop Binding Protein and Increase in Polyadenylated Canonical Histone H3.1 mRNA. Biol Trace Elem Res 166:72-81
Brocato, Jason; Costa, Max (2015) SATB1 and 2 in colorectal cancer. Carcinogenesis 36:186-91
Brocato, Jason; Wu, Fen; Chen, Yu et al. (2015) Association between sleeping hours and cardiometabolic risk factors for metabolic syndrome in a Saudi Arabian population. BMJ Open 5:e008590
Niu, Yingmei; DesMarais, Thomas L; Tong, Zhaohui et al. (2015) Oxidative stress alters global histone modification and DNA methylation. Free Radic Biol Med 82:22-8
Brocato, Jason; Chervona, Yana; Costa, Max (2014) Molecular responses to hypoxia-inducible factor 1? and beyond. Mol Pharmacol 85:651-7
Brocato, Jason; Fang, Lei; Chervona, Yana et al. (2014) Arsenic induces polyadenylation of canonical histone mRNA by down-regulating stem-loop-binding protein gene expression. J Biol Chem 289:31751-64
Brocato, Jason; Costa, Max (2013) Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis. Crit Rev Toxicol 43:493-514
Arita, Adriana; Muñoz, Alexandra; Chervona, Yana et al. (2013) Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects. Cancer Epidemiol Biomarkers Prev 22:261-9
Passantino, Lisa; Muñoz, Alexandra B; Costa, Max (2013) Sodium metavanadate exhibits carcinogenic tendencies in vitro in immortalized human bronchial epithelial cells. Metallomics 5:1357-67

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