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).
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. Benzo(a)pyrene increased neoplasia in the thymus, spleen, stomach, and hematopoietic system after 28 weeks. We observed modest NAC-associated decreases in BP-induced pathology of the liver, papilloma formation and hyperplasia in the forestomach, and the occurrence of malignant lymphoma. Benzo(a)pyrene exposure reduced survival to approximately 40% in male mice, suggesting toxicity; however, survival in control groups was approximately 60%. Survival decreased to approximately 30% for females in all groups. We noted a clear, but nonsignificant, 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.
Martin
Keith R
KR
Nutrition and Cancer Laboratory, Pennsylvania State University, 126 Henderson Building South, University Park, Pennsylvania 16802. USA. krm12@psu.edu
Jokinen
Micheal P
MP
Honeycutt
Hayden P
HP
Quinn
Anita
A
Kari
Frank W
FW
Barrett
J Carl
JC
French
John E
JE
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents; D000975:Antioxidants / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D004032:Diet; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009369:Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D010212:Papilloma / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D019310:Pseudolymphoma / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D012727:Sex Characteristics; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D002273:Carcinogens; D001564:Benzo(a)pyrene; D000111:Acetylcysteine