Germ cell mutagenicity of topoisomerase I inhibitor topotecan detected in the male mouse-dominant lethal study

• Published in: Food and chemical toxicology 2013-12, Vol.62, p.470-474
• Main Authors: Attia, S.M., Ahmad, S.F., Abd-Ellah, M.F., Hamada, F.M., Bakheet, S.A.
• Format: Article
• Language: English
• Subjects: acetylcysteine; Acetylcysteine - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - toxicity; Biological and medical sciences; Camptothecins; Chemical mutagenesis; Chemotherapy; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; DNA; DNA oxidative stress; DNA topoisomerase; Dominant lethality; Dose-Response Relationship, Drug; exposure duration; Female; free radical scavengers; Free Radical Scavengers - pharmacology; Genomic alterations; Male; males; Medical sciences; Mice; mutagenicity; Mutagenicity Tests; Mutagens - toxicity; mutation; N-acetylcysteine; oxidative stress; Pharmacology. Drug treatments; Pregnancy; reactive oxygen species; Reactive Oxygen Species - metabolism; spermatozoa; Spermatozoa - drug effects; Topoisomerase I; Topoisomerase I Inhibitors - toxicity; Topotecan - toxicity; Toxicology; virgin females
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2013.09.009

•Topotecan is a germ cell mutagen.•Its effect is more pronounced during the post-meiotic stages.•Its effects were directly correlated with free radicals accumulation.•N-acetylcysteine protected mice from topotecan-induce dominant lethality.•N-acetylcysteine had no antagonizing effect on topotecan-induce Topo-I inhibition. To investigate the ability of topotecan, a topoisomerase I-targeting anticancer drug, to induce dominant lethal mutations in male mouse germ cells, males were treated with single doses of 3, 6 and 12mg/kg topotecan. Each male was mated at 4-day intervals to virgin females for a total of nine 4-day mating intervals. The two highest doses of topotecan are shown to be mutagenic in post-meiotic cells. The greatest effect occurred in those cells which were in the early-spermatid stage at the time of exposure. Mice treated with 12mg/kg topotecan showed an additional peak of dominant lethal induction in mature sperm during the first 4-day matings after treatment. The mutagenic effects were directly correlated with free radicals accumulation as an obvious increase in the generation reactive oxygen species and 8-hydroxydeoxyguanosine was noted in animals treated with 6 and 12mg/kg topotecan. Treatment of male mice with N-acetylcysteine, a free radical scavenger, significantly protected mice from topotecan-induce dominant lethality. Moreover, N-acetylcysteine had no antagonizing effect on topotecan-induce topoisomerase-I inhibition. Our study provides evidence that topotecan is a germ cell mutagen and its effect is more pronounced during the post-meiotic stages through a mechanism that may involves increases in DNA oxidative stress.