7,12-Dimethylbenz[a]anthracene-induced bone marrow toxicity is p53-dependent.
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.
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Todd J
TJ
Department of Pathobiological Sciences, University of Wisconsin, Madison, 53706, USA.
O'Brien
Scott
S
Holston
Karrie
K
MacWilliams
Peter S
PS
Jefcoate
Colin R
CR
Czuprynski
Charles J
CJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity*; D002452:Cell Count; D002478:Cells, Cultured; D004396:Coloring Agents; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53 / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011419:Propidium; D013234:Stem Cells / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D002273:Carcinogens; D004396:Coloring Agents; D016159:Tumor Suppressor Protein p53; D011419:Propidium; D015127:9,10-Dimethyl-1,2-benzanthracene