Evaluation of nonthreshold leukemogenic response to methyl nitrosourea in p53-deficient C3H/He mice.
The classic controversy of whether genotoxic chemicals induce cancers with or without a certain low-dose limit, i.e., the threshold, is revisited because of a number of current publications available addressing the plausibility of "practical" thresholds even for genotoxic carcinogens, the mechanism of which may be hypothesized to be due, in part, to a repair system composed of ordinarily available various defense mechanisms under the steady-state DNA damage. The question of whether an absolute nonthreshold or a relative nonthreshold, i.e., a "practical" threshold specifically in the low-dose level, is present may not be answered even with the use of a prohibitively large number of wild-type mice. Could the excessive incidence of tumorigenesis in p53-deficient mice contribute to our understanding of the threshold vs nonthreshold issue in genotoxic carcinogenesis? This is considered because an exaggeration of tumorigenesis in p53-deficient mice is hypothesized to reduce or eliminate the range of threshold due to the p53-deficiency-mediated reduction of DNA repair and apoptosis. The present study of chemical leukemogenesis in p53-deficient mice by transplantation assay was designed to answer this question. Briefly, 218 C3H/He mice were lethally irradiated and repopulated with bone marrow cells from wild-type, heterozygous p53-deficient, and homozygous p53-deficient C3H/He mice. This was followed by treatment with a single and graded dose of methyl nitrosourea at 6.6, 14.8, 33.3, 50.0, and 75.0 mg/kg body wt, with the vehicle-treated control groups treated with zero dose for each genotype. Whereas mice repopulated with p53-deficient bone marrow cells showed a marked reduction of the threshold for leukemogenicity, mice repopulated with wild-type bone marrow cells did not exhibit leukemia at a dose of 33.3 mg/kg body wt and showed a curve with a high probability for the linear regression model with a positive dose intercept, predicting a threshold by the likelihood ratio test. Thus, the failure of wild-type mice to show an increase in incidence of leukemogenesis at low doses of genotoxic carcinogens may be due not to a statistical rarity, but to various p53-related pharmacophysiological functions, possibly including DNA repair and apoptosis that may account for a threshold.
Hirabayashi
Yoko
Y
Cellular and Molecular Toxicology Division, Center for Biological Safety and Research, National Institute of Health Sciences, Tokyo, Japan. yokohira@nihs.go.jp
Yoshida
Kazuko
K
Aizawa
Shin-ichi
S
Kodama
Yukio
Y
Kanno
Jun
J
Kurokawa
Yuji
Y
Yoshimura
Isao
I
Inoue
Tohru
T
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D016026:Bone Marrow Transplantation; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy; D007942:Leukemia, Experimental / Q000139:chemically induced / Q000401:mortality / Q000628:therapy; D008136:Longevity / Q000187:drug effects; D008297:Male; D008770:Methylnitrosourea / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D000477:Alkylating Agents; D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D008770:Methylnitrosourea