Larval fathead minnow exposed to organophosphate pesticides

New approach methods (NAMs) can reduce the need for chronic, animal studies. We applied benchmark concentration (BMC) response modeling to transcriptomic changes in whole fathead minnow larvae after 1-day exposure to several concentrations of three organophosphate pesticides (OPPs): fenthion, methidathion, and parathion. The fathead minnow larvae transcriptional points of departure were 0.007, 0.115, and 0.046 mg/L, respectively. transcriptional points of departure reflected the relative potencies from traditional, chronic studies with fenthion identified as the most potent. Moreover, the fathead minnow larvae transcriptional points of departure were within 18-fold of the chronic apical points of departure for fish species. Short-term exposure to OPPs significantly impacted acetylcholinesterase mRNA abundance (FDR p-value <0.05, |fold-change|>2) and canonical pathways (IPA, z-score>|2|) associated with organism death and neurological/immune dysfunctions, indicating the conservation of key events related to OPP toxicity. Together, these results build confidence in using short-term, molecular-based assays for the characterization of chemical toxicity and risk, thereby reducing reliance on chronic, animal studies.

新方法学（New Approach Methods，NAMs）可有效减少长期动物实验的使用需求。本研究将基准浓度（Benchmark Concentration，BMC）响应建模方法，应用于黑头呆鱼幼鱼暴露于三种有机磷农药（Organophosphate Pesticides，OPPs：倍硫磷、杀扑磷与对硫磷）的多个浓度梯度1天后的全身体转录组变化。三种农药对应的黑头呆鱼幼鱼转录组毒性起始点分别为0.007、0.115与0.046 mg/L。该转录组毒性起始点可反映传统长期实验中的相对毒性效力，其中倍硫磷被鉴定为毒性最强的化合物。此外，黑头呆鱼幼鱼的转录组毒性起始点与鱼类慢性顶端毒性起始点的差异范围在18倍以内。短期暴露于有机磷农药可显著影响乙酰胆碱酯酶mRNA的表达丰度（错误发现率（False Discovery Rate，FDR）p值<0.05，|倍数变化（Fold Change，FC）|>2），以及与机体死亡、神经/免疫功能紊乱相关的经典通路（Ingenuity Pathway Analysis，IPA，Z评分>|2|），这表明有机磷农药毒性相关的关键事件具有保守性。综上，本研究结果为使用短期分子水平检测方法表征化学物毒性与风险提供了可信度支撑，从而降低了对长期动物实验的依赖。