Abstract

In the present application, the investigators propose further studies with the overall objective of assessing the hypothesis that ring-opened metabolites play a role in benzene hematotoxicity.
The specific aims of the proposal first are to perform toxicity studies to further assess the hematologic toxicity of reactive ring-opened metabolites by synthesizing four additional compounds and comparing their effects with those of MUC and benzene. The four new compounds are the mixed aldehyde carboxylic acid derivative, (MUC-COOH); the as yet unidentified MUC-Y derivative; cis, cis-muconaldehyde; and, cis,trans-muconaldehyde. Secondly, metabolism studies will be performed for determine whether MUC is formed from benzene in bone marrow microsomes in vitro, and in comparison with liver microsomes; and to further investigate the metabolism of MUC in liver fractions, including the identification of """"""""MUC-Y"""""""". Finally, the investigators will conduct adduct studies to assess the formation of macromolecular adducts of MUC in vivo with the aim of both providing an assay of MUC formation and of providing information about the toxicity of MUC using benzene and MUC-treated animals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES002558-08A1
Application #
3249878
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1980-06-01
Project End
1994-02-28
Budget Start
1991-03-15
Budget End
1992-02-29
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854

  Publications

Weisel, Clifford P; Park, Seongsoo; Pyo, Heesoo et al. (2003) Use of stable isotopically labeled benzene to evaluate environmental exposures. J Expo Anal Environ Epidemiol 13:393-402
Oshiro, Y; Balwierz, P S; Witz, G (2001) Micronucleus formation in mouse bone marrow cells in vivo in response to trans, trans-muconaldehyde. Toxicol Lett 121:159-66
Amin, R P; Witz, G (2001) DNA-protein crosslink and DNA strand break formation in HL-60 cells treated with trans,trans-muconaldehyde, hydroquinone and their mixtures. Int J Toxicol 20:69-80
Daiker, D H; Shipp, B K; Schoenfeld, H A et al. (2000) Effect of CYP2E1 induction by ethanol on the immunotoxicity and genotoxicity of extended low-level benzene exposure. J Toxicol Environ Health A 59:181-96
Schoenfeld, H A; Witz, G (2000) Structure-activity relationships in the induction of DNA-protein cross-links by hematotoxic ring-opened benzene metabolites and related compounds in HL60 cells. Toxicol Lett 116:79-88
Schoenfeld, H A; Witz, G (1999) DNA-protein cross-link levels in bone marrow cells of mice treated with benzene or trans,trans-muconaldehyde. J Toxicol Environ Health A 56:379-95
Ho, T Y; Witz, G (1997) Increased gene expression in human promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a hematotoxic benzene metabolite. Carcinogenesis 18:739-44
Zhang, Z; Cooper, K; Goldstein, B D et al. (1997) Distribution studies in CD-1 mice administered [14C]muconaldehyde. Arch Toxicol 71:703-8
Medeiros, A M; Bird, M G; Witz, G (1997) Potential biomarkers of benzene exposure. J Toxicol Environ Health 51:519-39
Witz, G; Zhang, Z; Goldstein, B D (1996) Reactive ring-opened aldehyde metabolites in benzene hematotoxicity. Environ Health Perspect 104 Suppl 6:1195-9

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