Abstract
The role of deficiency of oxoguanine glycosylase 1 (Ogg1) Mmh homolog, a repair enzyme of the 8-hydroxy-2’-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J background carrying a mutant Mmh allele of the Mmh/Ogg1 gene (Ogg1−/−) and wild type (Ogg1+/+) mice were administered N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), N-bis (2-hydroxypropyl) nitrosamine (DHPN) and 1,2-dimethylhydrazine dihydrochloride (DMH) (DMBDD) to induce carcinogenesis in multiple organs, and observed up to 34 weeks. Significant increase of lung adenocarcinomas incidence was observed in DMBDD-treated Ogg1−/− male mice, but not in DMBDD-administered Ogg1+/+ animals. Furthermore, incidences of lung adenomas were significantly elevated in both Ogg1−/− males and females as compared with respective Ogg1−/− control and DMBDD-treated Ogg1+/+ groups. Incidence of total liver tumors (hepatocellular adenomas, hemangiomas and hemangiosarcomas) was significantly higher in the DMBDD-administered Ogg1−/− males and females. In addition, in DMBDD-treated male Ogg1−/− mice, incidences of colon adenomas and total colon tumors showed a trend and a significant increase, respectively, along with significant rise in incidence of simple hyperplasia of the urinary bladder, and a trend to increase for renal tubules hyperplasia in the kidney. Furthermore, incidence of squamous cell hyperplasia in the forestomach of DMBDD-treated Ogg1−/− male mice was significantly higher than that of Ogg1+/+ males. Incidence of small intestine adenomas in DMBDD Ogg1−/− groups showed a trend for increase, as compared to the wild type mice. The current results demonstrated increased susceptibility of Ogg1 mutant mice to the multiorgan carcinogenesis induced by DMBDD. The present bioassay could become a useful tool to examine the influence of various targets on mouse carcinogenesis.
Highlights
DNA damage and disruption of DNA repair are considered key factors in the susceptibility of mammals to endogenous and exogenous carcinogens, as well as processes of aging and cancer development [1]
The present study revealed that oxoguanine glycosylase 1 (Ogg1) mutant mice are more susceptible to the induction of tumors due to the treatment with DMBDD, than wild type C57Bl/6J mice
Mice, main causes of death besides malignant lymphoma/leukemia were lung adenocarcinoma and skin/subcutis fibrosarcoma, while Ogg1+/+ animals died from malignant lymphoma/leukemia and urinary bladder carcinoma
Summary
DNA damage and disruption of DNA repair are considered key factors in the susceptibility of mammals to endogenous and exogenous carcinogens, as well as processes of aging and cancer development [1]. 8-OHdG is used as an oxidative DNA damage marker which mispairs with adenine (A) residues, resulting in increase of spontaneous G:C to T:A transversion mutations [3]. Three DNA repair enzymes from various bacteria and Saccharomyces cerevisiae, namely, the MutM (Fpg), MutY and MutT DNA glycosylase homologs are known to prevent spontaneous mutagenesis induced by 8-OHdG [4]. The MutM homolog (MMH; the glycosylase/apurinic, apyrimidinic (AP) lyase), MutY and MutT homolog enzymes have been identified [5,6,7] In both mammalian and yeast cells, cloned human and mouse cDNAs encode distinct nuclear and mitochondrial forms of the DNA glycosylase, the product of the Ogg gene, which is generated by alternative RNA splicing [8,9,10]. Analysis of the mutation spectrum revealed that the frequency of G:C to T:A transversions increased five-fold in Ogg mutant mice compared with wild-type animals [8]
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