Gao Xiugong, Li Rong, Campasino Kayla, Yourick Miranda R, Zhao Yang, Sprando Robert L, Yourick Jeffrey J
Division of Toxicology, Office of Chemistry and Toxicology (OCT), Office of Laboratory Operations and Applied Science (OLOAS), Human Foods Program (HFP), U.S. Food and Drug Administration (FDA), Laurel, MD 20708, United States.
Curr Res Toxicol. 2025 May 15;8:100238. doi: 10.1016/j.crtox.2025.100238. eCollection 2025.
Interindividual differences in response to chemicals have been typically addressed through the use of a 10-fold default "uncertainty" factor. It was only recently that models emerged to quantitatively assess interindividual variability in the human population for specific chemicals. In the current study, we attempted to establish an model for assessing population variability in hepatotoxicity testing using a panel of hepatocytes derived from nine human induced pluripotent stem cell (iPSC) lines belonging to three different ethnic groups, Black or African American, Latino or Hispanic, and Non-Hispanic White. We demonstrated that the panel of iPSC-derived hepatocytes manifested diversity in hepatic function assays, in global and hepatic gene expressions, and in cytotoxic responses to four well know hepatotoxicants with distinct mechanisms of toxicity: acetaminophen, troglitazone, diglycolic acid, and usnic acid. However, due to the unavailability of model compounds with ethnicity specific toxicity as well as the small number of individuals in each ethnic group ( = 3), ethnic-specific effects were not observed using the model.
个体对化学物质反应的差异通常通过使用10倍的默认“不确定性”因子来解决。直到最近，才出现了一些模型来定量评估特定化学物质在人群中的个体间变异性。在当前的研究中，我们试图建立一个模型，使用来自属于三个不同种族（黑人或非裔美国人、拉丁裔或西班牙裔、非西班牙裔白人）的九条人类诱导多能干细胞（iPSC）系的一组肝细胞，来评估肝毒性测试中的人群变异性。我们证明，iPSC衍生的肝细胞组在肝功能测定、全局和肝脏基因表达以及对四种具有不同毒性机制的知名肝毒性物质（对乙酰氨基酚、曲格列酮、二乙醇酸和扁枝衣酸）的细胞毒性反应中表现出多样性。然而，由于缺乏具有种族特异性毒性的模型化合物，以及每个种族组中的个体数量较少（n = 3），使用该模型未观察到种族特异性效应。
