Abstract

As the carcinogenic risk of herbs containing aristolochic acids (AAs) is a global health issue, quantitative evaluation of toxicity is needed for the regulatory decision-making and risk assessment of AAs. In this study, we selected AA I (AAI), the most abundant and representative compound in AAs, to treat transgenic gpt delta mice at six gradient doses ranging from 0.125 to 4 mg/kg/day for 28 days. AAI-DNA adduct frequencies and gpt gene mutation frequencies (MFs) in the kidney, as well as Pig-a gene MFs and micronucleated reticulocytes (MN-RETs) frequencies in peripheral blood, were monitored. The dose–response (DR) relationship data for these in vivo genotoxicity endpoints were quantitatively evaluated using an advanced benchmark dose (BMD) approach with different critical effect sizes (CESs; i.e., BMD₅, BMD₁₀, BMD₅₀ and BMD₁₀₀). The results showed that the AAI-DNA adduct frequencies, gpt MFs and the MN-RETs presented good DR relationship to the administrated doses, and the corresponding BMDL₁₀₀ (the lower 90% confidence interval of the BMD₁₀₀) values were 0.017, 0.509 and 3.9 mg/kg/day, respectively. No positive responses were observed in the Pig-a MFs due to bone marrow suppression caused by AAI. Overall, we quantitatively evaluated the genotoxicity of AAI at low doses for multiple endpoints for the first time. Comparisons of BMD₁₀₀ values across different endpoints provide a basis for the risk assessment and regulatory decision-making of AAs and are also valuable for understanding the genotoxicity mechanism of AAs.

中文翻译：

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暴露于马兜铃酸 I 的 gpt delta 小鼠中多个基因毒性终点的基准剂量分析

摘要

由于含有马兜铃酸 (AAs) 的草药的致癌风险是一个全球性的健康问题，因此需要对 AA 的监管决策和风险评估进行毒性定量评估。在本研究中，我们选择了 AA 中含量最丰富、最具代表性的化合物 AAI (AAI)，以0.125 至 4 mg/kg/天的六种梯度剂量治疗转基因gpt delta 小鼠，持续 28 天。监测肾脏中的AAI-DNA 加合物频率和gpt基因突变频率 (MF)，以及外周血中的Pig-a基因 MF 和微核网织红细胞 (MN-RET) 频率。这些体内的剂量反应 (DR) 关系数据使用具有不同临界效应大小（CES；即 BMD ₅、BMD ₁₀、BMD ₅₀和 BMD ₁₀₀）的高级基准剂量（BMD）方法对基因毒性终点进行定量评估。结果表明，AAI-DNA 加合物频率、gpt MF 和 MN-RET 与给药剂量呈现良好的 DR 关系，相应的 BMDL ₁₀₀（BMD ₁₀₀的下 90% 置信区间）值为 0.017、0.509 和分别为 3.9 毫克/公斤/天。在Pig-a中未观察到阳性反应由于 AAI 引起的骨髓抑制而导致的 MF。总体而言，我们首次定量评估了低剂量 AAI 的多个终点的遗传毒性。不同终点的 BMD ₁₀₀值的比较为AA 的风险评估和监管决策提供了基础，对于了解 AA 的遗传毒性机制也很有价值。