Initial Insights Regarding the Role of p53 in Maintaining Sperm DNA Integrity Following Treatment of Mice with Ethylnitrosourea or Cyclophosphamide

• Published in: Toxicologic pathology 2010-02, Vol.38 (2), p.244-257
• Main Authors: Sue Marty, M., Singh, Narendra P., Stebbins, Kenneth E., Ann Linscombe, V., Passage, Julie, Bhaskar Gollapudi, B.
• Format: Article
• Language: English
• Subjects: Alkylating Agents - toxicity; Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Chemical mutagenesis; Comet Assay; Cyclophosphamide; Cyclophosphamide - toxicity; Cytotoxicity; DNA - drug effects; DNA Damage; DNA Repair; Ethyl nitrosourea; Ethylnitrosourea - toxicity; Genotypes; Male; Medical sciences; Mice; Mice, Knockout; Models, Animal; Mutagens; p53 protein; Reproductive organs; Sperm; Spermatids; Spermatocytes; Spermatozoa - drug effects; Spermatozoa - metabolism; Testes; Testis - drug effects; Testis - pathology; Toxicology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Zygosity
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623309357947

If p53 is essential to eliminate damaged spermatogenic cells, then mutagen exposure in the absence of p53 would increase sperm containing damaged DNA. p53 knockout (−/−, NULL) and wild-type (+/+, WT) mice (five/group) were exposed to ethylnitrosourea (ENU) or cyclophosphamide (CP). In phase I, mice were exposed by gavage to 0 or 60 mg/kg/day ENU or CP for four days and examined on test day (TD) 4, and in phase II, mice were exposed to 0, 6, 20, or 60 mg/kg/day ENU or CP for four days and evaluated on TD 36 when exposed spermatocytes matured. In phase I, mutagens were not directly cytotoxic to mature sperm. In phase II, WT mice were more sensitive to decreases in reproductive organ weights, whereas both genotypes had decreased sperm counts. Testicular histology revealed similar CP responses, but genotype-specific ENU responses (WT mice had depletion of elongating spermatids; NULL mice had late-stage spermatocyte/early stage spermatid loss). Ethylnitrosourea increased DNA strand breaks in WT mice. Thus, mice responded similarly to CP, suggesting a primarily p53-independent response, whereas the ENU response differed by zygosity, suggesting a role for p53. As DNA damage increased at higher ENU doses, compensatory repair pathways may operate in NULL mice.