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ToxSci Advance Access published online on May 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg115
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received December 17, 2002; accepted April 10, 2003
© 2003 Society of Toxicology

Immunotoxicology

7,12-Dimethylbenz[a]anthracene Induced Bone Marrow Toxicity Is p53 Dependent

Todd J. Page 1, Scott O'Brien 1, Karrie Holston 1, Pete S. MacWilliams 1, Colin R. Jefcoate 2, Charles J. Czuprynski 3*

1 Dept. of Pathobiological Sciences, University of Wisconsin, 2015 Linden Dr, Madison, WI 53706
2 Dept. of Pharmacology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706; Dept. of Molecular and Environmental Toxicology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706
3 Dept. of Pathobiological Sciences, University of Wisconsin, 2015 Linden Dr, Madison, WI 53706; Dept. of Molecular and Environmental Toxicology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706

* To whom correspondence should be addressed. E-mail: czuprync{at}svm.vetmed.wisc.edu.


  Abstract

Polycyclic aromatic hydrocarbons (PAHs) are known immunotoxins and carcinogens. Our laboratory, and others, have demonstrated that metabolism of these compounds by CYP1B1 is required for carcinogenicity and immunotoxicity to occur. Previously our laboratory reported significantly decreased bone marrow cellularity in mice following 7,12-dimethlybenz[a]anthracene (DMBA) administration. In addition, we have observed that DMBA causes apoptosis via activation of both caspase-8 and -9 in preB cells cocultured with bone marrow stromal cells in vitro. In this study we investigated the importance of the p53 protein in the bone marrow response to DMBA. Through the use of p53 gene knockout mice we demonstrated that the effect of DMBA on bone marrow cellularity is p53 dependent. In addition, apoptosis of primary cultures of progenitor B cells cultured with bone marrow stromal cells and DMBA, is also p53 dependent. The results of this study provide evidence for the importance of p53 in the signaling pathways by which PAHs cause immunotoxicity.

Key Words: PAH, DMBA, apoptosis, B Cell, Bone Marrow, p53 .


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