There is concern about human exposure to benzene arising from a variety of sources, including certain occupational settings, hazardous waste sites, automobiles and cigarette smoking. Exposure of humans to benzene is associated with the development of aplastic anemia and leukemia. While there is an appreciation of the bone marrow being a target organ of benzene-induced toxicity, the underlying mechanisms and determinants of toxicity are not fully understood. The hypothesis the investigators are investigating is that the susceptibility of bone marrow cell populations is determined in part by the activation of benzene-derived metabolites by CuZn superoxide dismutase and the relative protection provided by quinone reductase and glutathione. Moreover, they hypothesize that the induction of quinone reductase and glutathione by 1,2-dithiole-3-thione affords protections against benzene-induced hematoxicities both in vitro and in vivo. Accordingly the specific aims of this proposal are designed to: 1) investigate factors which regulate the biologically effective concentration and early biological effects of benzene-derived metabolites in relevant bone marrow cell populations and other cellular models; 2) assess if human peripheral blood cells can be used to screen for possible human susceptibility to benzene; and 3) conduct a mechanistically-based chemoprotection study for benzene-induced bone marrow toxicity in DBA/2 mice. These studies will utilize a spectrum of biochemical, cell and molecular biology approaches and analytical techniques, to address the hypotheses put forth in the specific aims. As a result of this project the investigators should better understand the mechanisms of benzene-induced toxicity so that this information can be applied to human risk assessment, biomarker and chemoprotection studies in susceptible individuals and exposed populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008078-02
Application #
2701328
Study Section
Special Emphasis Panel (ZRG4-ALTX-2 (01))
Project Start
1997-05-25
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Jia, Zhenquan; Zhu, Hong; Trush, Michael A et al. (2008) Generation of superoxide from reaction of 3H-1,2-dithiole-3-thione with thiols: implications for dithiolethione chemoprotection. Mol Cell Biochem 307:185-91
Zhu, Hong; Cao, Zhuoxiao; Zhang, Li et al. (2007) Glutathione and glutathione-linked enzymes in normal human aortic smooth muscle cells: chemical inducibility and protection against reactive oxygen and nitrogen species-induced injury. Mol Cell Biochem 301:47-59
Zhu, Hong; Zhang, Li; Trush, Michael A et al. (2007) Upregulation of endogenous glutathione system by 3H-1,2-dithiole-3-thione in pancreatic RINm5F beta-cells as a novel strategy for protecting against oxidative beta-cell injury. Free Radic Res 41:242-50
Cao, Zhuoxiao; Hardej, Diane; Trombetta, Louis D et al. (2003) Induction of cellular glutathione and glutathione S-transferase by 3H-1,2-dithiole-3-thione in rat aortic smooth muscle A10 cells: protection against acrolein-induced toxicity. Atherosclerosis 166:291-301
Win, William; Cao, Zhuoxiao; Peng, Xingxiang et al. (2002) Different effects of genistein and resveratrol on oxidative DNA damage in vitro. Mutat Res 513:113-20
Trush, M A; Zhu, H; Li, Y (2001) Assessing underlying mechanisms of quinoid-induced hematopoietic cell toxicity. Adv Exp Med Biol 500:509-12
Li, Y; Zhu, H; Trush, M A (1999) Detection of mitochondria-derived reactive oxygen species production by the chemilumigenic probes lucigenin and luminol. Biochim Biophys Acta 1428:1-12
He, H; Wang, X; Gorospe, M et al. (1999) Phorbol ester-induced mononuclear cell differentiation is blocked by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059. Cell Growth Differ 10:307-15
Li, Y; Stansbury, K H; Zhu, H et al. (1999) Biochemical characterization of lucigenin (Bis-N-methylacridinium) as a chemiluminescent probe for detecting intramitochondrial superoxide anion radical production. Biochem Biophys Res Commun 262:80-7
Li, Y; Trush, M A (1998) Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production. Biochem Biophys Res Commun 253:295-9

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