Environmental exposures to toxic or carcinogenic compounds rarely result from the action of single toxicants. More often, the toxic agent is a complex mixture of chemical entities in numbers ranging from a few, such as in many occupational exposures, to several thousand, as in cigarette smoke. Frequently, these mixtures include a combination of carcinogenic metals and polycyclic aromatic hydrocarbons (PAH). Of these, hexavalent chromium, a carcinogenic metal often found as an environmental co-contaminant with PAHs, and benzo[a]pyrene (BaP), a prototypical PAH, are among the top 20 hazardous substances in the ATSDR/EPA priority list. The long-range goal of the research funded by this grant has been to develop an understanding of the mechanisms responsible for the adverse health effects of exposure to binary mixtures of BaP and chromium(VI). We have shown that high-dose acute chromium treatment interferes with the assembly of productive transcriptional complexes by cross-linking HDAC1.DNMT1 complexes to promoter chromatin and inhibiting phosphorylation, acetylation and methylation epigenetic marks established by BaP-induced gene transactivation in histones H3 and H4. These changes inhibit recruitment of RNA polymerase II to the Cyp1a1 promoter, block BaP-inducible gene expression and stimulate the formation of BPDE-DNA adducts. Similarly, sustained exposure to low doses of chromium leads to gradual changes in histone marks and signal transduction pathways that cumulatively affect gene expression and silencing. Specifically, environmentally relevant doses of chromium(VI) have opposite effects on the BaP-mediated induction of CYP1A1, CYP1B1 and CYP1A2 cytochrome P450 genes, repress tumor suppressor gene expression and induce expression of pro-apoptotic genes, leading us to the hypothesis that environmentally relevant binary mixtures of chromium(VI) and BaP have a synergistic effect on BaP toxicity and carcinogenicity. Based on our findings, the objectives for the next 5 years of this grant are, (1) to elucidate the epigenetic mechanisms by which low-dose, long-term exposure to chromium affects BaP-inducible gene expression;(2) to evaluate how chronic exposure to environmentally relevant chromium doses in drinking water affects BaP toxicity and carcinogenicity. Epigenetic modification of gene expression is a key element of the developmental and carcinogenic outcomes of exposure to chromium, alone or in combination with PAHs. Hypermethylation of the promoter of the tumor suppressor p16ink4a gene has been found in chromium-exposed workers who developed lung cancer, although p16ink4a promoter methylation accounts for only one third of cancer in this population, suggesting that there may be additional chromium targets and alternative mechanisms underlying cancer development. The knowledge derived from this research will have a major impact on the medical translation of these epidemiological findings and, by identifying molecular targets useful to reduce disease incidence, will significantly contribute to the development of therapeutic and preventative measures.

Public Health Relevance

Environmental exposure to hexavalent chromium in drinking water and cigarette smoking and occupational exposure in the workplace are often compounded with concomitant exposures to aromatic hydrocarbon procarcinogens, resulting in health problems including lung, stomach and intestinal tract tumors. The objective of this grant proposal is to evaluate how mixtures of hexavalent chromium and aromatic hydrocarbons cooperate to cause greater toxicity and carcinogenicity than the sum of the toxicities and carcinogenicities of the two compounds. The knowledge derived from this research will identify molecular targets to reduce disease incidence and will significantly contribute to the development of therapeutic and preventative measures with major impact on the treatment of the diseases caused by these agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010807-14
Application #
8599770
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Chadwick, Lisa
Project Start
2001-01-16
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
14
Fiscal Year
2014
Total Cost
$406,813
Indirect Cost
$141,293
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Kurita, Hisaka; Schnekenburger, Michael; Ovesen, Jerald L et al. (2014) The Ah receptor recruits IKK? to its target binding motifs to phosphorylate serine-10 in histone H3 required for transcriptional activation. Toxicol Sci 139:121-32
Ovesen, Jerald L; Fan, Yunxia; Zhang, Xiang et al. (2014) Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) analysis uncovers broad changes in chromatin structure resulting from hexavalent chromium exposure. PLoS One 9:e97849
Ovesen, Jerald L; Fan, Yunxia; Chen, Jing et al. (2014) Long-term exposure to low-concentrations of Cr(VI) induce DNA damage and disrupt the transcriptional response to benzo[a]pyrene. Toxicology 316:14-24
Ko, Chia-I; Wang, Qin; Fan, Yunxia et al. (2014) Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells. Stem Cell Res 12:296-308
Ovesen, Jerald L; Schnekenburger, Michael; Puga, Alvaro (2011) Aryl hydrocarbon receptor ligands of widely different toxic equivalency factors induce similar histone marks in target gene chromatin. Toxicol Sci 121:123-31
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Puga, Alvaro (2011) Perspectives on the potential involvement of the AH receptor-dioxin axis in cardiovascular disease. Toxicol Sci 120:256-61
Wang, Ying; Fan, Yunxia; Puga, Alvaro (2010) Dioxin exposure disrupts the differentiation of mouse embryonic stem cells into cardiomyocytes. Toxicol Sci 115:225-37
Fan, Yunxia; Boivin, Gregory P; Knudsen, Erik S et al. (2010) The aryl hydrocarbon receptor functions as a tumor suppressor of liver carcinogenesis. Cancer Res 70:212-20
Reichard, John F; Puga, Alvaro (2010) Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics 2:87-104

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