DNA damage and repair in somatic and germ cells in vivo.
Alkylation-induced germ cell mutagenesis in the mouse versus Drosophila is compared based on data from forward mutation assays (specific-locus tests in the mouse and in Drosophila and multiple-locus assays in the latter species) but not including assays for structural chromosome aberrations. To facilitate comparisons between mouse and Drosophila, forward mutation test results have been grouped into three categories. Representatives of the first category are MMS (methyl methanesulfonate) and EO (ethylene oxide), alkylating agents with a high s value which predominantly react with ring nitrogens in DNA. ENU (N-ethyl-N-nitrosourea), MNU (N-methyl-N-nitrosourea), PRC (procarbazine), DEN (N-nitrosodiethylamine), and DMN (N-nitrosodimethylamine) belong to the second category. These agents have in common a considerable ability for modification at oxygens in DNA. Cross-linking agents (melphalan, chlorambucil, hexamethylphosphoramide) form the third category. The most unexpected, but encouraging outcome of this study is the identification of common features for three vastly different experimental indicators of genotoxicity: hereditary damage in Drosophila males, genetic damage in male mice, and tumors (TD50 estimates) in rodents. Based on the above three category classification scheme the following tentative conclusions are drawn. Monofunctional agents belonging to category 1, typified by MMS and EO, display genotoxic effects in male germ cell stages that have passed meiotic division. This phenomenon seems to be the consequence of a repair deficiency during spermiogenesis for a period of 3-4 days in Drosophila and 14 days in the mouse. We suggest that the reason for the high resistance of premeiotic stages, and the generally high TD50 estimates observed for this class in rodents, is the efficient error-free repair of N-alkylation damage. If we accept this hypothesis, then the increased carcinogenic potential in rodents, seen when comparing category 2 (ENU-type mutagens) to category 1 (MMS-type mutagens), along with the ability of category 2 genotoxins to induce genetic damage in premeiotic stages, must presumably be due to their enhanced ability for alkylations at oxygens in DNA; it is this property that actually distinguishes the two groups from each other. In contrast to category 1, examination of class 2 genotoxins (ENU and DEN) in premeiotic cells of Drosophila gave no indication for a significant role of germinal selection, and also removal by DNA repair was less dramatic compared to MMS. Thus category 2 mutagens are expected to display activity in a wide range of both post- and premeiotic germ cell stages. A number of these agents have been demonstrated to be among the most potent carcinogens in rodents.(ABSTRACT TRUNCATED AT 400 WORDS)
Vogel
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Medical Genetics Centre South-West Netherlands-MGC, Department of Radiation Genetics and Chemical Mutagenesis, Leiden University.
Natarajan
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D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects; D005260:Female; D018095:Germ-Line Mutation; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011995:Recombination, Genetic / Q000187:drug effects; D013045:Species Specificity; D013091:Spermatogenesis / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D002273:Carcinogens; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D009153:Mutagens