Biological Safety Research Center, National Institute of Health Sciences, Kawasaki-shi, Kanagawa, Japan.
Toxicology Division, The Institute of Environmental Toxicology, Joso-shi, Ibaraki, Japan.
Environ Mol Mutagen. 2020 Jan;61(1):193-199. doi: 10.1002/em.22315. Epub 2019 Jul 25.
Genotoxic carcinogens are regulated under the policy that there is no threshold or safe dose. It has been pointed out, however, that self-defense mechanisms, such as detoxification, DNA repair, and error-free translesion synthesis, may protect chromosome DNA from genotoxic insults, thereby constituting practical threshold. In this study, we examined dose responses of chromosome aberrations induced by three oxidative genotoxins, that is, hydrogen peroxide (H O ), menadione and paraquat, with or without DNA polymerase kappa (Polκ) activities and mismatch repair capacities in human cells. Polκ is involved in translesion synthesis across DNA damage and mismatch repair is responsible for correction of base-base mismatch in DNA. Polκ activity of the cells was inactivated either by point mutations in the catalytically essential amino acids (catalytically dead or CD) or by deletion of the POLK gene (knockout or KO). In the absence of mismatch repair, frequencies of chromosome aberrations induced by H O and menadione were not significantly different among CD, KO, and the wild type (WT) cells. In the presence of mismatch repair, however, cytotoxicity and clastogenicity were enhanced and Polκ modulated the sensitivity of the cells. No-observed-genotoxic-effect-levels (NOGELs) for H O and menadione were CD = KO < WT cells. In contrast, the sensitivities of the cells to paraquat were not significantly affected by the status of mismatch repair or Polκ activity. The results suggest that mismatch repair and Polκ coordinately modulate NOGELs for the clastogenicity of H O and menadione and also that DNA lesion(s) responsible for paraquat-induced chromosome aberrations are different from those induced by H O and menadione. Environ. Mol. Mutagen. 61:193-199, 2020. © 2019 Wiley Periodicals, Inc.
遗传毒性致癌物受政策监管，政策规定不存在阈值或安全剂量。然而，已经指出，解毒、DNA 修复和无差错跨损伤合成等自我防御机制可能会保护染色体 DNA 免受遗传毒性损伤，从而构成实际的阈值。在这项研究中，我们研究了三种氧化遗传毒物（即过氧化氢（H2O2）、甲萘醌和百草枯）诱导的染色体畸变的剂量反应，这些毒物要么具有 DNA 聚合酶 κ（Polκ）活性和错配修复能力，要么没有这些活性和能力，在人类细胞中。Polκ 参与跨 DNA 损伤的易位合成，错配修复负责纠正 DNA 中的碱基对错配。通过催化必需氨基酸的点突变（催化失活或 CD）或 POLK 基因缺失（敲除或 KO）使细胞中的 Polκ 活性失活。在不存在错配修复的情况下，H2O2 和甲萘醌诱导的染色体畸变频率在 CD、KO 和野生型（WT）细胞之间没有显著差异。然而，在存在错配修复的情况下，细胞的细胞毒性和致突变性增强，Polκ 调节了细胞的敏感性。H2O2 和甲萘醌的无观察到遗传毒性效应水平（NOGELs）为 CD = KO < WT 细胞。相比之下，细胞对百草枯的敏感性不受错配修复或 Polκ 活性的状态的显著影响。结果表明，错配修复和 Polκ 协同调节 H2O2 和甲萘醌的致突变性的 NOGELs，并且百草枯诱导的染色体畸变的 DNA 损伤与 H2O2 和甲萘醌诱导的损伤不同。环境分子突变。61：193-199，2020. © 2019 Wiley Periodicals， Inc.
