Avlasevich Svetlana L, Labash Carson, Torous Dorothea K, Bemis Jeffrey C, MacGregor James T, Dertinger Stephen D
Litron Laboratories, Rochester, New York.
Toxicology Consulting Services, Bonita Springs, Florida.
Environ Mol Mutagen. 2018 Jan;59(1):30-37. doi: 10.1002/em.22122. Epub 2017 Aug 19.
The Pig-a assay is being used in regulatory studies to evaluate the potential of agents to induce somatic cell gene mutations and an OECD test guideline is under development. A working group involved with establishing the guideline recently noted that representative aneugenic agents had not been evaluated, and to help fill this data gap Pig-a mutant phenotype and micronucleated reticulocyte frequencies were measured in an integrated study design to assess the mutagenic and cytogenetic damage responses to vinblastine sulfate exposure. Male Sprague Dawley rats were treated for twenty-eight consecutive days with vinblastine dose levels from 0.0156 to 0.125 mg/kg/day. Micronucleated reticulocyte frequencies in peripheral blood were determined at Days 4 and 29, and mutant cell frequencies were determined at Days -4, 15, 29, and 46. Vinblastine affected reticulocyte frequencies, with reductions noted during the treatment phase and increases observed following cessation of treatment. Micronucleated reticulocyte frequencies were significantly elevated at Day 4 in the high dose group. Although a statistically significant increase in mutant reticulocyte frequencies were found for one dose group at a single time point (Day 46), it was not deemed biologically relevant because there was no analogous finding in mutant RBCs, it occurred at the lowest dose tested, and only 1 rat exceeded an upper bound tolerance interval established with historical negative control rats. Therefore, whereas micronucleus induction reflects vinblastine's well-established aneugenic effect on hematopoietic cells, the lack of a Pig-a response indicates that this tubulin-binding agent does not cause appreciable mutagenicity in this same cell type. Environ. Mol. Mutagen. 59:30-37, 2018. © 2017 Wiley Periodicals, Inc.
Pig-a试验正被用于监管研究，以评估药剂诱导体细胞基因突变的可能性，且一项经合组织测试指南正在制定中。一个参与制定该指南的工作组最近指出，尚未对具有代表性的非整倍体诱变剂进行评估，为填补这一数据空白，在一项综合研究设计中测量了Pig-a突变体表型和微核网织红细胞频率，以评估对硫酸长春碱暴露的诱变和细胞遗传学损伤反应。雄性Sprague Dawley大鼠连续28天接受剂量水平为0.0156至0.125 mg/kg/天的长春碱治疗。在第4天和第29天测定外周血中的微核网织红细胞频率，在第-4天、第15天、第29天和第46天测定突变细胞频率。长春碱影响网织红细胞频率，在治疗阶段出现降低，在停止治疗后观察到增加。高剂量组在第4天微核网织红细胞频率显著升高。尽管在一个剂量组的单个时间点（第46天）发现突变网织红细胞频率有统计学显著增加，但这在生物学上不被认为具有相关性，因为在突变红细胞中没有类似发现，它发生在测试的最低剂量，并且只有1只大鼠超过了用历史阴性对照大鼠建立的上限耐受区间。因此，虽然微核诱导反映了长春碱对造血细胞已确立的非整倍体诱变作用，但缺乏Pig-a反应表明这种微管结合剂在同一细胞类型中不会引起明显的诱变作用。《环境与分子诱变》59:30 - 37，2018年。©2017威利期刊公司
