Differential genotoxicity of acrylamide in the micronucleus and Pig-a gene mutation assays in F344 rats and B6C3F1 mice
Differential genotoxicity of acrylamide in the micronucleus and Pig-a gene mutation assays in F344 rats and B6C3F1 mice
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DOI：
10.1093/mutage/gew028
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发表时间：
2016-11-01
期刊：
影响因子：
2.7
通讯作者：
Recio, Leslie
中科院分区：
文献类型：
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作者：
Hobbs, Cheryl A.;Davis, Jeffrey;Recio, Leslie
丙烯酰胺用于许多工业过程，并存在于各种油炸和烘焙食品中。在啮齿动物致癌性试验中，丙烯酰胺暴露导致肿瘤形成的剂量低于已证明可诱导遗传毒性损伤的剂量。我们评估了丙烯酰胺诱导啮齿类动物DNA结构损伤和基因突变的潜力，分别使用高灵敏度的流式细胞仪分析微核和Pig-a突变频率。雄性F344大鼠和B6 C3 F1小鼠连续30天饮用含丙烯酰胺的饮用水，剂量跨越并超过癌症生物测定中检测的丙烯酰胺暴露范围-小鼠和大鼠的最高剂量分别为12.0和24.0 mg/kg/天。在研究开始和结束时给予阳性对照N-乙基-N-亚硝基脲，以满足两种DNA损伤表型的表达时间。暴露于检测浓度丙烯酰胺的雄性大鼠的微核和Pig-a试验结果分别为阴性和不确定。相比之下，丙烯酰胺诱导微核形成呈剂量依赖性增加，但在小鼠Pig-a试验中检测为阴性。假设小鼠中甘氨酰胺的血浆浓度高于大鼠，至少部分解释了反应的差异。基准剂量建模表明，与点突变相反，结构DNA损伤与丙烯酰胺诱导致癌性的遗传毒性作用模式最相关。此外，在<6.0 mg/kg/天剂量下未检测到遗传毒性，这与非遗传毒性机制导致啮齿动物中丙烯酰胺诱导的致癌性的观点一致。
Acrylamide is used in many industrial processes and is present in a variety of fried and baked foods. In rodent carcinogenicity assays, acrylamide exposure leads to tumour formation at doses lower than those demonstrated to induce genotoxic damage. We evaluated the potential of acrylamide to induce structural DNA damage and gene mutations in rodents using highly sensitive flow cytometric analysis of micronucleus and Pig-a mutant frequencies, respectively. Male F344 rats and B6C3F1 mice were administered acrylamide in drinking water for 30 days at doses spanning and exceeding the range of acrylamide exposure tested in cancer bioassays-top dose of 12.0 and 24.0mg/kg/day in mice and in rats, respectively. A positive control, N-ethyl-N-nitrosourea, was administered at the beginning and end of the study to meet the expression time for the two DNA damage phenotypes. The results of the micronucleus and Pig-a assays were negative and equivocal, respectively, for male rats exposed to acrylamide at the concentrations tested. In contrast, acrylamide induced a dose-dependent increase in micronucleus formation but tested negative in the Pig-a assay in mice. Higher plasma concentrations of glycidamide in mice than rats are hypothesized to explain, at least in part, the differences in the response. Benchmark dose modelling indicates that structural DNA damage as opposed to point mutations is most relevant to the genotoxic mode of action of acrylamide-induced carcinogenicity. Moreover, the lack of genotoxicity detected at < 6.0mg/kg/day is consistent with the notion that non-genotoxic mechanisms contribute to acrylamide-induced carcinogenicity in rodents.