In vivo Approaches to Study Mechanism of Action of Genotoxic Carcinogens

Abstract

Genotoxic carcinogens are chemicals or factors which not only induce neoplastic lesions in animal bioassays but also test positive in genotoxicity assays in vitro or in vivo. However, it is actually di‹cult to discriminate genotoxic and non-genotoxic carcinogens because both assays are basically independent each other, which raises a simple query as to how much the detected genotoxic potential can consequently contribute to carcinogenicity. To clarify this critical issue, we have studied the mechanisms of action of carcinogens in transgenic rats or mice carrying reporter genes, which are expected as powerful tools for the simultaneous evaluation of both genotoxicity and carcinogenicity at the same organ level. A number of studies of genotoxic carcinogens using these transgenic rodents have revealed good correlations between genotoxicity and carcinogenicity in terms of mechanism of action. On the other hand, a known non-genotoxic carcinogen dicyclanil increased in vivo genotoxicity as well as oxidative DNA damage in female mice, consistently with the sex speciˆci-ty of its carcinogenicity, albeit without clear evidence of direct DNA reactivity. In contrast, a genotoxic chlorinated water by-product MX failed to exert in vivo genotoxicity and carcinogenicity in mice. We also conˆrmed that such reporter gene-carrying rodents are not susceptible or resistant to carcinogenicity as compared with intact counterparts. These results thus indicate that understanding of the detailed mechanism of carcinogenic action could be crucial for more precise risk assessment, and bioassay systems using transgenic rodents carrying reporter genes would be extremely useful for that purpose.

Mutagenic Bypass of 8-Oxo-7,8-dihydroguanine (8-Hydroxyguanine) by DNA Polymerase κ in Human Cells

“…DNA damage and damaged 2′-deoxyribonucleotides generated by endogenous and exogenous (environmental) factors are important sources of mutations. 2,3 Reactive oxygen species (ROS) are pivotal mutagens, and the oxidized bases in DNA and in the nucleotide pool cause mutagenesis, carcinogenesis, neurodegeneration, and aging. 4,5 8-Oxo-7,8-dihydroguanine (G O , also known as 8-hydroxyguanine) is one of the major oxidized bases produced by ROS, and more than 100 G O residues are generated per cell per day.…”

“…Many factors are known to disturb correct 2′-deoxyribonucleotide incorporation during DNA replication. DNA damage and damaged 2′-deoxyribonucleotides generated by endogenous and exogenous (environmental) factors are important sources of mutations. , Reactive oxygen species (ROS) are pivotal mutagens, and the oxidized bases in DNA and in the nucleotide pool cause mutagenesis, carcinogenesis, neurodegeneration, and aging. , …”

Carcinogenicity Assessment for Risk Factors in Food:

“…To clarify the threshold issue, various chemicals, having both carcinogenic and non-carcinogenic properties, were investigated using gpt delta rodents about in vivo genotoxicity in the target tissues where tumors are induced 19,23,59-76) because these rodent models would be powerful tools for the evaluation of both genotoxicity and carcinogenicity at the same organ level 59,60) . Some genotoxic carcinogens showed significantly increased genotoxicity in the liver of gpt delta rats, the target organ for carcinogenicity 75) .…”

Unexpectedly Weak Impacts of Decreased p53 and Retinoblastoma Protein Levels on Mutagenesis by 8-Oxo-7,8-dihydroguanine (8-Hydroxyguanine)

“…DNA is continuously damaged by endogenous and exogenous (environmental) factors, and the damaged bases cause mutations (1). Several tumor suppressor proteins play key roles in preventing the deleterious eŠects of damaged DNA (2).…”