Manjanatha Mugimane G, Aidoo Anane, Shelton Sharon D, Bishop Michelle E, McDaniel Lea P, Lyn-Cook Lascelles E, Doerge Daniel R
Division of Genetic and Reproductive Toxicology, US FDA/National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
Environ Mol Mutagen. 2006 Jan;47(1):6-17. doi: 10.1002/em.20157.
The recent discovery of acrylamide (AA), a probable human carcinogen, in a variety of fried and baked starchy foods has drawn attention to its genotoxicity and carcinogenicity. Evidence suggests that glycidamide (GA), the epoxide metabolite of AA, is responsible for the genotoxic effects of AA. To investigate the in vivo genotoxicity of AA, groups of male and female Big Blue (BB) mice were administered 0, 100, or 500 mg/l of AA or equimolar doses of GA, in drinking water, for 3-4 weeks. Micronucleated reticulocytes (MN-RETs) were assessed in peripheral blood within 24 hr of the last treatment, and lymphocyte Hprt and liver cII mutagenesis assays were conducted 21 days following the last treatment. Further, the types of cII mutations induced by AA and GA in the liver were determined by sequence analysis. The frequency of MN-RETs was increased 1.7-3.3-fold in males treated with the high doses of AA and GA (P < or = 0.05; control frequency = 0.28%). Both doses of AA and GA produced increased lymphocyte Hprt mutant frequencies (MFs), with the high doses producing responses 16-25-fold higher than that of the respective control (P < or = 0.01; control MFs = 1.5 +/- 0.3 x 10(-6) and 2.2 +/- 0.5 x 10(-6) in females and males, respectively). Also, the high doses of AA and GA produced significant 2-2.5-fold increases in liver cII MFs (P < or = 0.05; control MFs = 26.5 +/- 3.1 x 10(-6) and 28.4 +/- 4.5 x 10(-6)). Molecular analysis of the mutants indicated that AA and GA produced similar mutation spectra and that these spectra were significantly different from that of control mutants (P < or = 0.001). The predominant types of mutations in the liver cII gene from AA- and GA-treated mice were G:C-->T:A transversions and -1/+1 frameshifts in a homopolymeric run of Gs. The results indicate that both AA and GA are genotoxic in mice. The MFs and types of mutations induced by AA and GA in the liver are consistent with AA exerting its genotoxicity in BB mice via metabolism to GA.
最近在各种油炸和烘焙淀粉类食品中发现了丙烯酰胺（AA），一种可能的人类致癌物，这引起了人们对其遗传毒性和致癌性的关注。有证据表明，AA的环氧化物代谢产物缩水甘油酰胺（GA）是导致AA遗传毒性作用的原因。为了研究AA的体内遗传毒性，将雄性和雌性大蓝（BB）小鼠分成几组，分别饮用含0、100或500 mg/l AA或等摩尔剂量GA的水，持续3 - 4周。在最后一次处理后24小时内评估外周血中的微核网织红细胞（MN - RETs），并在最后一次处理后21天进行淋巴细胞次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（Hprt）和肝脏cII基因突变检测。此外，通过序列分析确定AA和GA在肝脏中诱导的cII基因突变类型。高剂量AA和GA处理的雄性小鼠中MN - RETs频率增加了1.7 - 3.3倍（P≤0.05；对照频率 = 0.28%）。AA和GA的两种剂量均使淋巴细胞Hprt突变频率（MFs）增加，高剂量产生的反应比各自对照组高16 - 25倍（P≤0.01；雌性和雄性对照组MFs分别为1.5±0.3×10⁻⁶和2.2±0.5×10⁻⁶）。而且，高剂量的AA和GA使肝脏cII MFs显著增加了2 - 2.5倍（P≤0.05；对照MFs = 26.5±3.1×10⁻⁶和28.4±4.5×10⁻⁶）。对突变体的分子分析表明，AA和GA产生了相似的突变谱，并且这些谱与对照突变体的谱有显著差异（P≤0.001）。来自AA和GA处理小鼠的肝脏cII基因中的主要突变类型是G:C→T:A颠换以及在一段同聚G序列中的 - 1/+1移码突变。结果表明，AA和GA在小鼠中均具有遗传毒性。AA和GA在肝脏中诱导的MFs和突变类型与AA通过代谢为GA在BB小鼠中发挥其遗传毒性作用一致。
