p53 heterozygosity alters the mRNA expression of p53 target genes in the bone marrow in response to inhaled benzene

Abstract

C57BL/6 Trp53 heterozygous (N5) mice (p53+/- mice) show an increased sensitivity to tumorigenesis following exposure to genotoxic compounds and are being used as an alternate animal model for carcinogenicity testing. However, there is relatively little data regarding the effect of p53 heterozygosity on the genomic and cellular responses of target tissues in these mice to toxic insult, especially under chronic exposure conditions used in carcinogenicity bioassays. We hypothesized that heterozygosity at the p53 locus in p53+/- mice alters the expression of bone marrow p53-regulated genes involved in cell cycle control and apoptosis during chronic genotoxic stress. We used real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) to examine gene expression alterations in bone marrow cells from C57BL/6 p53+/+ and isogenic p53+/- mice chronically exposed for 15 weeks to genotoxic and carcinogenic levels (100 ppm) of inhaled benzene. Examination of mRNA levels of p53-regulated genes involved in cell cycle control (p21, gadd45, and cyclin G) or apoptosis (bax and bcl-2) showed that during chronic genotoxic stress, bone marrow cells from p53+/+ mice expressed significantly higher levels of a majority of these genes compared to p53+/- bone marrow cells. Our results indicate that p53 heterozygosity results in a haploinsufficient phenotype in p53+/- bone marrow cells as evident by significantly altered mRNA levels of key genes involved in the p53-regulated DNA damage response pathway.