Simulated solar light-induced p53 mutagenesis in SKH-1 mouse skin: a dose-response assessment.
Sunlight and ultraviolet-induced mutation of the p53 gene is a frequent, possibly obligate step in skin cancer development, making quantitative measurement of p53 mutation an ideal biomarker for sunlight-induced skin carcinogenesis. To understand how the appearance of p53 mutation relates to skin tumor development, SKH-1 hairless mice were exposed 5 d per week to one of four different doses of simulated solar light (SSL; 0, 6.85, 13.70, 20.55 mJ x CIE/cm(2)) previously characterized for their tumorigenic potential. Allele-specific competitive blocker-PCR (ACB-PCR) was used to measure levels of p53 codon 270 CGT to TGT mutation within DNA isolated from dorsal skin of exposed mice. For each dose, p53 mutant fraction (MF) was measured after 4, 16, and 28 wk of exposure. Significant dose- and time-dependent increases in p53 MF were identified. All p53 MF measurements were integrated by relating the observed p53 MF to the cumulative dose of SSL. The increase in the logarithm of p53 MF was described by the linear function: log(10) MF = alpha + 0.0016 x d, where alpha is the spontaneous log(10) MF after a particular time point and d is the dose of SSL in mJ x CIE/cm(2). The p53 MF induced in nontumor bearing skin by 28 wk of exposure at the high dose of SSL was significantly lower than that found in skin tumors induced by approximately 32 wk of exposure to the same dose of SSL. p53 MF showed a strong negative correlation with tumor latency, suggesting this quantitative biomarker has the potential to predict tumorigenicity.
Verkler
Tracie L
TL
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research (NCTR), USFDA, Jefferson, Arkansas 72079, USA.
Delongchamp
Robert R
RR
Miller
Barbara J
BJ
Webb
Peggy J
PJ
Howard
Paul C
PC
Parsons
Barbara L
BL
D000483:Alleles; D000818:Animals; D014408:Biomarkers, Tumor; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D016158:Genes, p53; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D009381:Neoplasms, Radiation-Induced; D016133:Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced*; D013472:Sunlight; D014466:Ultraviolet Rays
D014408:Biomarkers, Tumor