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ToxSci Advance Access originally published online on May 2, 2003
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Toxicological Sciences 74, 85-92 (2003)
Copyright © 2003 by the Society of Toxicology

IMMUNOTOXICOLOGY

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

Todd J. Page*, Scott O’Brien*, Karrie Holston*, Peter S. MacWilliams*, Colin R. Jefcoate{dagger},{ddagger} and Charles J. Czuprynski*,{ddagger},1

* Department of Pathobiological Sciences, {dagger} Department of Pharmacology, and {ddagger} Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53706

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 pre-B cells co-cultured 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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