Compensatory erythropoiesis has no impact on the outcome of the in vivo Pig-a mutation assay in rats following treatment with the haemolytic agent 2-butoxyethanol
Compensatory erythropoiesis has no impact on the outcome of the in vivo Pig-a mutation assay in rats following treatment with the haemolytic agent 2-butoxyethanol
复制标题
DOI：
10.1093/mutage/geu051
复制
发表时间：
2015-05-01
期刊：
影响因子：
2.7
通讯作者：
Dobo, Krista L.
中科院分区：
文献类型：
--
作者：
Kenyon, Michelle O.;Coffing, Stephanie L.;Dobo, Krista L.
Pig-a 测定作为评估化合物体内诱变潜力的有用工具，迅速引起了国际关注。尽管已经在大鼠造血细胞 Pig-a 测定中测试了大量化合物，包括诱变剂和非诱变剂，但对造血扰动如何影响测定性能的了解有限。特别值得关注的是，在不接触基因毒性剂的情况下，仅再生造血可能会导致 Pig-a 突变细胞频率升高。为了解决这个问题，Wistar-Han 大鼠通过口服强饲法给予非基因毒性溶血剂 2-丁氧基乙醇 (2-BE)。使用单次给药和 28 天治疗方案测试了 0 至 450mg/kg 的剂量水平。至少在治疗的前 24 小时内和最终给药后 8 天内评估血液学参数。对于两种治疗方案，在第 15 天和第 30 天评估 Pig-a 突变频率；对于 28 天方案，也在第 43 天和第 57 天评估 Pig-a 突变频率。即使在诱导显着血管内溶解和强代偿性红细胞生成的2-BE剂量下，平均Pig-a突变表型红细胞和网织红细胞频率也在历史载体对照分布内。因此，在这些研究中，2-BE 没有显示出体内致突变性的证据。数据表明，仅造血作用的扰动不会导致 Pig-a 测定中观察到突变频率增加。
The Pig-a assay has rapidly gained international interest as a useful tool for assessing the mutagenic potential of compounds in vivo. Although a large number of compounds, including both mutagens and non-mutagens, have been tested in the rat Pig-a assay in haematopoietic cells, there is limited understanding of how perturbations in haematopoiesis affect assay performance. Of particular concern is the possibility that regenerative haematopoiesis alone, without exposure to a genotoxic agent, could result in elevated Pig-a mutant cell frequencies. To address this concern, Wistar-Han rats were dosed by oral gavage with a non-genotoxic haemolytic agent, 2-butoxyethanol (2-BE). Dose levels ranging from 0 to 450mg/kg were tested using both single administration and 28-day treatment regimens. Haematology parameters were assessed at minimum within the first 24h of treatment and 8 days after the final administration. Pig-a mutant frequencies were assessed on Days 15 and similar to 30 for both treatment protocols and also on Days 43 and 57 for the 28-day protocol. Even at doses of 2-BE that induced marked intravascular lysis and strong compensatory erythropoiesis, the average Pig-a mutant phenotype red blood cell and reticulocyte frequencies were within the historical vehicle control distribution. 2-BE therefore showed no evidence of in vivo mutagenicity in these studies. The data suggest that perturbations in haematopoiesis alone do not lead to an observation of increased mutant frequency in the Pig-a assay.