Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes.

中文翻译：

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用于食品污染物乙酰胺风险评估的毒理学方法。


常见食品中可检测到乙酰胺（CAS 60-35-5）。由于在大鼠中诱导肝脏肿瘤，慢性啮齿动物生物测定将其归类为 2B 类可能的人类致癌物。我们对 Wistar 大鼠使用毒物基因组学方法，每天以 300 至 1500 mg/kg/天 (mkd) 的剂量灌胃，持续 7 或 28 天，以确定出发点 (POD) 并研究其作用模式 (MoA)。 Ki67 标记在剂量≥750 mkd 时增加至 3.3 倍，代表最敏感的顶端终点。治疗 28 天后，通过 RNA-Seq 进行差异基因表达分析，在雄性和雌性大鼠中分别鉴定出 1110 个和 1814 个差异表达基因。下调的基因与脂质代谢相关，而上调的基因包括细胞信号传导、免疫反应和细胞周期功能。 Ki67 标记指数的基准剂量 (BMD) 模型确定 BMD10 置信下限 (BMDL10) 为 190 mkd。转录 BMD 模型显示转录 POD 和顶端终点之间具有极好的一致性。总的来说，这些结果表明乙酰胺很可能通过促有丝分裂 MoA 发挥作用，尽管无法阐明具体的关键启动分子事件。建议为风险评估目的确定细胞增殖的 POD 值为 190 mkd。