Alternative Vertebrate and Invertebrate Model Organisms Show Similar Sensitivity as Rodents to a Diverse Set of Chemicals

Current regulations aimed at safeguarding human health and the environment from chemical risks require toxicity testing, while regulatory bodies worldwide are phasing out the use of protected animals. Here, we systematically produced toxicity data from five alternative nonmammalian model organisms and a human cell line to demonstrate similarities and differences among distantly related species in their responses to chemical exposure (concentration range 1.8 pM to 2.1 M). We show that Daphnia magna and Danio rerio embryos are affected by more chemicals than Xenopus laevis embryos, Drosophila melanogaster and Caenorhabditis elegans. Lethality/immotility data assembled 72 diverse chemicals into 11 clusters, revealing species-specific outcomes and showing differential enrichment of the clusters for certain chemical structures and modes of action. The ranked relative toxicities of chemicals across the model organisms were highly correlated (Spearman’s correlation, maximum rho = 0.86, p-value = 0; minimum rho = 0.57, p-value = 0.000312), and their average toxicity values closely matched published values for rodents (rat: rho = 0.88, p = 2.8e-06; mouse: rho = 0.88, p = 2.7e-06). Our findings suggest that chemical toxicity under standardized experimental conditions is broadly conserved across a phylogenetically diverse set of model organisms, providing a conservative estimate of mammalian toxicity.

当前旨在保护人类健康与环境免受化学风险危害的法规均要求开展毒性测试，而全球各国监管机构正逐步淘汰受保护动物的使用。本研究系统性获取了5种非哺乳类替代模式生物与1株人类细胞系的毒性数据，以阐明亲缘关系较远的物种在化学暴露（浓度范围1.8皮摩尔至2.1摩尔）下的响应异同。研究结果显示，大型溞（Daphnia magna）与斑马鱼（Danio rerio）胚胎受化学物质影响的种类数，多于非洲爪蟾（Xenopus laevis）胚胎、黑腹果蝇（Drosophila melanogaster）及秀丽隐杆线虫（Caenorhabditis elegans）。基于致死性/运动能力丧失数据，本研究将72种不同化学物质划分为11个聚类，揭示了物种特异性的响应结果，并发现部分聚类在特定化学结构与作用机制上存在富集差异。各模式生物对应的化学物质相对毒性排序具有高度相关性（斯皮尔曼相关性分析：最大相关系数rho=0.86，p值=0；最小相关系数rho=0.57，p值=0.000312）；同时，各模式生物的平均毒性值与已发表的啮齿类动物毒性数据高度吻合（大鼠：rho=0.88，p=2.8×10^-6；小鼠：rho=0.88，p=2.7×10^-6）。本研究结果表明，在标准化实验条件下，化学物质毒性在系统发育多样性各异的模式生物类群中整体具有保守性，可为哺乳动物毒性评估提供保守性估算依据。