Comparison of integrated genotoxicity endpoints in rats after acute and subchronic oral doses of 4-nitroquinoline-1-oxide.
Comparison of integrated genotoxicity endpoints in rats after acute and subchronic oral doses of 4-nitroquinoline-1-oxide.
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DOI：
10.1002/em.21981
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发表时间：
2016-01
影响因子：
2.8
通讯作者：
Stankowski LF Jr
中科院分区：
文献类型：
--
作者：
Roberts DJ;McKeon M;Xu Y;Stankowski LF Jr
在Pig-a基因突变试验的实验室间验证试验期间，我们评估了4-硝基喹啉-1-氧化物在多个组织中终点的遗传毒性：Pig-a突变红细胞（RBC）和网织红细胞（RET）的诱导;微核RET（MN RET）;以及通过碱性彗星试验（%尾强度[TI]）在血液和肝脏中的DNA损伤。在先前的亚慢性毒性研究（每日28次给药）中，仅观察到猪a突变型RBC/RET出现具有生物学意义的增加，同时观察到MN RET频率略有增加，其他致染色体断裂终点均为阴性。使用相同的累积剂量（0、35、70、105和140 mg/kg）进行随访急性研究，以推注方式给药，或分3次相等的每日剂量给药，在末次给药后1个月内采集样本。两种急性给药方案均产生了相似的结果，即无论1次或3次每日给药，终点均为阳性或阴性，但连续3次每日给药方案在TI（肝脏和血液中）和Pig-a突变频率方面产生了更有效的应答。在这些急性研究中，相同累积剂量的4 NQO在致染色体断裂终点中诱导了阳性应答，而使用亚慢性研究设计时，致染色体断裂终点为阴性或不确定。此外，使用环磷酰胺和甲磺酸乙酯联合给药的阳性对照组评估试验有效性，并可能确定用于综合遗传毒性研究的未来阳性对照处理。
During interlaboratory validation trials for the Pig-a gene mutation assay we assessed the genotoxicity of 4-nitroquinoline-1-oxide across endpoints in multiple tissues: induction of Pig-a mutant red blood cells (RBCs) and reticulocytes (RETs); micronucleated RETs (MN RETs); and DNA damage in blood and liver via the alkaline Comet assay (%tail intensity [TI]). In a previous subchronic toxicity study with 28 daily doses, biologically meaningful increases were observed only for Pig-a mutant RBCs/RETs while marginal increases in the frequency of MN RET were observed, and other clastogenic endpoints were negative. Follow up acute studies were performed using the same cumulative doses (0, 35, 70, 105, and 140 mg/kg) administered in a bolus, or split over 3 equal daily doses, with samples collected up to 1 month after the last dose. Both of the acute dosing regimens produced similar results, in that endpoints were either positive or negative, regardless of 1 or 3 daily doses, but the 3 consecutive daily dose regimen yielded more potent responses in TI (in liver and blood) and Pig-a mutant frequencies. In these acute studies the same cumulative doses of 4NQO induced positive responses in clastogenic endpoints that were negative or inconclusive using a subchronic study design. Additionally, a positive control group using combination doses of cyclophosphamide and ethyl methanesulfonate was employed to assess assay validity and potentially identify a future positive control treatment for integrated genetic toxicity studies.
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影响因子：
2.8
作者：
Johnson GE;Soeteman-Hernández LG;Gollapudi BB;Bodger OG;Dearfield KL;Heflich RH;Hixon JG;Lovell DP;MacGregor JT;Pottenger LH;Thompson CM;Abraham L;Thybaud V;Tanir JY;Zeiger E;van Benthem J;White PA
通讯作者：
White PA
DOI：
10.1083/jcb.200611141
发表时间：
2007-04-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cumming G;Fidler F;Vaux DL
通讯作者：
Vaux DL
DOI：
10.1016/j.mrgentox.2007.07.010
发表时间：
2007-12-01
影响因子：
1.9
作者：
Kissling, Grace E.;Dertinger, Stephen D.;MacGregord, James T.
通讯作者：
MacGregord, James T.
DOI：
10.1016/j.mrgentox.2011.06.005
发表时间：
2011-10-09
影响因子：
1.9
作者：
Dobo, Krista L.;Fiedler, Ronald D.;Schuler, Maik
通讯作者：
Schuler, Maik
影响因子：
2.8
作者：
Cao, Xuefei;Mittelstaedt, Roberta A.;Heflich, Robert H.
通讯作者：
Heflich, Robert H.