Integration of the rat liver micronucleus assay into a 28-day treatment protocol: testing the genotoxicity of four small-molecule nitrosamines with different carcinogenic potencies and tumor target specificities.
Xiaoqing Guo, Ji-Eun Seo, Hannah Xu, Jian Yan, Pritpal Malhi, Aisar H Atrakchi, Timothy Mcgovern, Karen L Davis Bruno, Robert H Heflich, Tao Chen
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引用次数: 0
Abstract
Several potent carcinogenic nitrosamines, including N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), induce micronuclei in the micronucleated hepatocyte (MNHEP) assay but not in the micronucleated reticulocyte (MNRET) assay. However, the MNHEP assay is not as frequently used as the MNRET assay for evaluating in vivo genotoxicity. The present study evaluated MN formation in the liver of Big Blue transgenic rats exposed to four small-molecule nitrosamines, NDMA, N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisoporpylamine (NEIPA), and N-nitrosomethylphenylamine (NMPA), using a repeat-dose protocol typically used for in vivo mutagenicity studies. NDMA is a potent liver carcinogen, while NDIPA and NEIPA are relatively weak liver carcinogens, and NMPA primarily produces esophageal tumors. Seven-week-old rats were treated with the nitrosamines for 28 consecutive days; liver was harvested three days after the last dose and used for conducting the flow-cytometry-based MNHEP assay. All four nitrosamines induced dose-dependent increases in %MNHEP and the magnitude of the responses correlated with their carcinogenicity in rat liver. These results indicate that the flow-cytometry-based MNHEP assay can be successfully integrated into 28-day repeat-dose studies, and that the MNHEP assay may be useful for evaluating the genotoxicity of nitrosamines that have different carcinogenic potencies and different tumor target specificities.
几种强致癌性亚硝胺,包括n -亚硝基二乙胺(NDEA)和n -亚硝基二甲胺(NDMA),在微核肝细胞(MNHEP)试验中诱导微核,但在微核网状细胞(MNRET)试验中没有。然而,在评估体内遗传毒性方面,MNHEP试验并不像MNRET试验那样经常使用。本研究评估了“蓝色巨人”转基因大鼠暴露于四种小分子亚硝胺,NDMA, n -亚硝基二异丙胺(NDIPA), n -亚硝基乙基异丙胺(NEIPA)和n -亚硝基苯胺(NMPA)的肝脏中MN的形成,使用了通常用于体内诱变研究的重复剂量方案。NDMA为强效致癌物,NDIPA和NEIPA为较弱致癌物,NMPA主要产生食道肿瘤。7周龄大鼠连续28天服用亚硝胺;最后一次给药后3天采集肝脏,用于进行基于流式细胞术的MNHEP测定。所有四种亚硝胺均诱导MNHEP呈剂量依赖性增加,其强度与其在大鼠肝脏中的致癌性相关。这些结果表明,基于流式细胞术的MNHEP测定可以成功地整合到28天的重复剂量研究中,并且MNHEP测定可能有助于评估具有不同致癌能力和不同肿瘤靶点特异性的亚硝胺的遗传毒性。
期刊介绍:
The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology.
The primary focus of Toxicological Sciences is on original research articles. The journal also provides expert insight via contemporary and systematic reviews, as well as forum articles and editorial content that addresses important topics in the field.
The scope of Toxicological Sciences is focused on a broad spectrum of impactful toxicological research that will advance the multidisciplinary field of toxicology ranging from basic research to model development and application, and decision making. Submissions will include diverse technologies and approaches including, but not limited to: bioinformatics and computational biology, biochemistry, exposure science, histopathology, mass spectrometry, molecular biology, population-based sciences, tissue and cell-based systems, and whole-animal studies. Integrative approaches that combine realistic exposure scenarios with impactful analyses that move the field forward are encouraged.