Integration of Pig‐a , micronucleus, chromosome aberration, and comet assay endpoints in a 28‐day rodent toxicity study with 4‐nitroquinoline‐1‐oxide

作者：Leon F. Stankowski, Daniel J. Roberts, Hepei Chen, Timothy E. Lawlor, Marie McKeon, Hemalatha Murli, Ajit Kumar Thakur, Yong Xu · 发表于：Environmental and Molecular Mutagenesis · 年份：2011 · DOI：10.1002/em.20692 · 被引用次数：42 · 研究领域：Carcinogens and Genotoxicity Assessment、Animal testing and alternatives、Animal Genetics and Reproduction

As part of the Stage III Pig-a multilaboratory validation trial, we examined the induction of CD59-negative reticulocytes and total red blood cells (RET(CD59-) and RBC(CD59-) , respectively) in male Sprague Dawley(®) rats treated with 4-nitroquinoline-1-oxide (4NQO), for 28 consecutive days by oral gavage, at doses of 1.25, 2.50, 3.75, 5.00, and 7.50 mg kg(-1) day(-1) (the high dose group was sacrificed on Day 15 due to excessive morbidity/mortality). Animals also were evaluated for: micronucleated reticulocytes (mnRET) by flow cytometry; DNA damage in peripheral blood, liver, and stomach using the Comet assay; and chromosome aberrations (CAb) in peripheral blood lymphocytes (PBL). All endpoints were analyzed at two or more timepoints where possible. Mortality, body and organ weights, food consumption, and clinical pathology also were evaluated, and demonstrated that the maximum tolerated dose was achieved at 5.00 mg kg(-1) day(-1) . The largest increases observed for the genetic toxicology endpoints (fold-increase compared to control, where significant; all at 5.00 mg kg(-1) day(-1) on Day 29) were: RET(CD59-) (21X), RBC(CD59-) (9.0X), and mnRET (2.0X). In contrast, no significant increases were observed for the CAb or Comet response, in any tissue analyzed, at any timepoint. Because 4NQO is a well known mutagen, clastogen, and carcinogen, the lack of response for these latter endpoints was unexpected. These results emphasize the extreme care that must betaken in dose and en...