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ToxSci Advance Access published online on July 14, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh226
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received May 17, 2004
Accepted July 9, 2004

Carcinogenicity

Tumor Profile of Novel p53 Heterozygous Tg.AC (v-Ha-ras) Bitransgenic Mice Treated with Benzo(a)pyrene and Fed Dietary N-Acetyl-L-Cysteine (NAC)

Keith R. Martin 1*, Micheal P. Jokinen 2, Hayden P. Honeycutt 3, Anita Quinn 3, Frank W. Kari 3, J. Carl Barrett 4, John E. French 3

1 Nutrition and Cancer Laboratory, Pennsylvania State University, University Park, PA 16802
2 Pathology Associates International, Durham, NC 27709
3 Laboratory of Environmental Carcinogenesis & Mutagenesis, NIEHS, RTP, NC 27709
4 Laboratory of Molecular Carcinogenesis, NIEHS, RTP, NC 27709

* To whom correspondence should be addressed. E-mail: krm12{at}psu.edu.


  Abstract

We designed a novel short-term bitransgenic model to better characterize the effects of benzo(a)pyrene (BP) exposure on multi-organ carcinogenesis and to evaluate the effects of a well-recognized antioxidant, N-acetyl-L-cysteine (NAC), on neoplasia. We selected the p53 heterozygous Tg.AC (v-Ha-ras) mouse model for our studies because these mice possess a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele. Both mutations occur frequently in human cancers. In a 2 x 2 experimental design, both female and male mice were fed basal diet alone or containing 3% NAC and administered by gavage corn oil vehicle alone or containing 20 mg BP/kg body weight given twice weekly for 10 weeks. Mice (n=15 for each grouping and sex) were subsequently observed an additional 18 weeks followed by tissue collection for evaluation of multi-organ pathology. BP increased neoplasia in the thymus, spleen, stomach, and hematopoietic system after 28 weeks. We observed modest NAC-associated decreases in BPinduced pathology of the liver, papilloma formation and hyperplasia in the forestomach, and the occurrence of malignant lymphoma. BP exposure reduced survival to ~40% in male mice suggesting toxicity however survival in control groups was ~60%. Survival decreased to ~30% for females in all groups. We noted a clear, but non-significant, 15% decline in body weights of male, but not female, mice fed NAC although food intake did not differ. Collectively, the data suggested carcinogen and antioxidant-associated effects on neoplasia that appeared sex-dependent. Thus, this novel short-term bitransgenic model may potentially be useful for testing dietary modulation of carcinogenesis.

Keywords: p53; Tg.AC; v-Ha-ras; antioxidant; NAC.
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