Pig-a gene mutation and micronucleated reticulocyte induction in rats exposed to tumorigenic doses of the leukemogenic agents chlorambucil, thiotepa, melphalan, and 1,3-propane sultone.
Pig-a gene mutation and micronucleated reticulocyte induction in rats exposed to tumorigenic doses of the leukemogenic agents chlorambucil, thiotepa, melphalan, and 1,3-propane sultone.
复制标题
暴露于致瘤剂量的苯丁酸氮芥、塞替派、美法仑和 1,3-丙磺酸内酯的大鼠中的 Pig-a 基因突变和微核网织红细胞诱导。
DOI：
10.1002/em.21846
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发表时间：
2014
影响因子：
2.8
通讯作者：
Macgregor,JamesT
中科院分区：
文献类型：
--
作者：
Dertinger,StephenD;Phonethepswath,Souk;Avlasevich,SvetlanaL;Torous,DorotheaK;Mereness,Jared;Cottom,John;Bemis,JeffreyC;Macgregor,JamesT
To evaluate whether blood‐based genotoxicity endpoints can provide temporal and dose‐response data within the low‐dose carcinogenic range that could contribute to carcinogenic mode of action (MoA) assessments, we evaluated the sensitivity of flow cytometry‐based micronucleus andPig‐agene mutation assays at and below tumorigenic dose rate 50 (TD50) levels. The incidence of micronucleated reticulocytes (MN‐RET) was used to evaluate chromosomal damage, and the frequency of CD59‐negative reticulocytes (RETCD59−) and erythrocytes (RBCCD59−) served as phenotypic reporters of mutation at the X‐linkedPig‐agene. Several leukemogenic agents with a presumed genotoxic MoA were studied. Specifically, male Sprague Dawley rats were treated via oral gavage for 28 days with chlorambucil, thiotepa, melphalan, and 1,3‐propane sultone at doses corresponding to 0.33x, 1x, and 3x TD50, as well as at the maximum tolerated dose. Frequencies of MN‐RET were determined at Days 4 and 29, and RETCD59−and RBCCD59−data were collected pretreatment as well as Days 15/16, 29, and 56/57. Dose‐related increases were observed for each endpoint, and time to maximal effect was consistently: MN‐RET < RETCD59−< RBCCD59−. For each of the chemicals studied, the genotoxic events occurred long before tumors or preneoplastic lesions would be expected. Furthermore, in the case ofPig‐agene mutation, the responses were observed at or below the TD50 dose for three out of the four chemicals studied. These data illustrate the potential for quantitative blood‐based analyses to provide dose‐response and temporality information that relates genetic damage to cancer induction. Environ. Mol. Mutagen. 55:299–308, 2014. © 2014 Wiley Periodicals, Inc.
