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- Title
Comparison of male versus female responses in the Pig-a mutation assay.
- Authors
Labash, Carson; Avlasevich, Svetlana L.; Carlson, Kristine; Torous, Dorothea K.; Berg, Ariel; Bemis, Jeffrey C.; MacGregor, James T.; Dertinger, Stephen D.
- Abstract
Validation of the Pig-a gene mutation assay has been based mainly on studies in male rodents. To determine if the mutagen-induced responses of the X-linked Pig-a gene differ in females compared to males, 7- or 14-week old male and female Sprague Dawley rats were exposed to N-ethyl-Nnitrosourea (ENU). In the study with the 7-week old rats, exposure was to 0, 1, 5 or 25 mg ENU/kg/ day for three consecutive days (study Days 1-3). Pig-a mutant phenotype reticulocyte (RETCD59-) and mutant phenotype erythrocyte (RBCCD59-) frequencies were determined on study Days - 4, 15, 29 and 46 using immunomagnetic separation in conjunction with flow cytometric analysis (In Vivo MutaFlow®). Additionally, blood samples collected on Day 4 were analysed for micronucleated reticulocyte (MNRET) frequency (In Vivo MicroFlow®). The percentage of reticulocytes (%RET) was markedly higher in the 7-week old males compared to females through Day 15 (2.39-fold higher on Day -4). At 25 mg/ kg/day, ENU reduced Day 4 RET frequencies in both sexes, and the two highest dose levels resulted in elevated MN-RET frequencies, with no sex or treatment x sex interaction. The two highest dose levels significantly elevated the frequencies of mean RETCD59- and RBCCD59- in both sexes from Day 15 onward. RETCD59- and RBCCD59- frequencies were somewhat lower for females compared to males at the highest dose level studied, and differences in RETCD59- resulted in a statistically significant interaction effect of treatment x sex. In the study with 14-week old rats, treatment was for 3 days with 0 or 25 mg ENU/kg/day. RET frequencies differed to a lesser degree between the sexes, and in this case there was no evidence of a treatment x sex interaction. These results suggest that the slightly higher response in younger males than in the younger females may be related to differences in erythropoiesis function at that age. In conclusion, while some quantitative differences were noted, there were no qualitative differences in how males and females responded to a prototypical mutagen, and support the contention that both sexes are equally acceptable for Pig-a gene mutation studies.
- Subjects
LABORATORY rodents; GENETIC mutation; PHYSIOLOGICAL effects of urea; SEX differences (Biology); PHOSPHATIDYLINOSITOLS; BIOLOGICAL assay
- Publication
Mutagenesis, 2015, Vol 30, Issue 3, p349
- ISSN
0267-8357
- Publication type
Article
- DOI
10.1093/mutage/geu055