Evaluation of cytotoxicity, cell proliferation, and genotoxicity induced by p-cresidine in hetero- and nullizygous transgenic p53 mice.
The heterozygous p53 knockout mouse is being used as a short-term alternative model for carcinogenicity screening of chemicals. In most cases, these mice develop tumors within 6 months of exposure to genotoxic carcinogens. The bladder and liver carcinogen, p-cresidine, is recommended as a positive control chemical for these assays. To evaluate early effects of p53 deficiency on bladder and liver histopathology and genotoxicity induced by p-cresidine, we treated 4-week-old heterozygous and nullizygous p53 male mice with p-cresidine by gavage (100, 200, 400, and 800 mg/kg/day) 5 days/week for 7 weeks. Tissue sections were prepared for hematoxylin-eosin staining and immunohistochemistry for PCNA protein or 3'-OH DNA fragments to assess cell proliferation and apoptosis, respectively. Blood and bone marrow were examined for methemoglobin and micronuclei in polychromatic erythrocytes (MN-PCE), respectively. Individual cell necrosis of the bladder transitional epithelium was evident in both p53 heterozygous and nullizygous mice at all doses. In addition, diffuse hyperplasia of the bladder epithelium was observed at 400 and 800 mg/kg in both genotypes. In the liver, both genotypes exhibited similar increases in hepatocyte apoptosis (10-fold increase) and cell proliferation (20-fold increase) at 800 mg/kg/day. Methemoglobin levels were increased 6-fold in both genotypes at 800 mg/kg. Background MN-PCE rates were similar in both genotypes and there were no treatment-related increases. Also, no point mutations were observed in codon 12 of the c-Ha-ras gene from urinary bladder DNA from p-cresidine treated p53 mice. These results suggest that loss of p53 allele(s) in mice does not influence the early markers of carcinogenic activity induced by subchronic treatment with p-cresidine. Increased tumor susceptibility associated with a reduction in p53 dosage may be dependent on neoplastic progression rather than initiation and promotional events elicited by p-cresidine.
Delker
D A
DA
The Dow Chemical Company, Health and Environmental Research Laboratory, Midland, Michigan 48674, USA.
Yano
B L
BL
Gollapudi
B B
BB
D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000032:analysis / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects*; D017931:DNA Primers / Q000737:chemistry; D011905:Genes, ras / Q000187:drug effects; D006579:Heterozygote; D007124:Immunoenzyme Techniques; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D015162:Micronucleus Tests; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
D000814:Aniline Compounds; D002273:Carcinogens; D017931:DNA Primers; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C013453:cresidine; D004247:DNA