肠道器官样本可能作为毒性测试的替代模型。然而，器官样本中特定形态改变与化学诱导毒性之间的联系尚待确定。本文中，我们制备了C57BL/6小鼠肠道器官样本，并对化学诱导毒性进行了形态学分析。形态学上的改变包括大囊状结构、增生型器官样本、小囊状结构以及凸出缺失型器官样本，这些改变在浓度依赖下对四种金属（类）即镉（Cd）、铅（Pb）、六价铬（Cr-VI）和无机三价砷（iAs-III）的处理产生反应。需要注意的是，器官样本形态学上的异常形态率改变与特定的肠道毒性效应相关，包括细胞活力和分化的降低，细胞凋亡的诱导、粘液生成功能的障碍以及上下皮层结构的损伤。基准剂量（BMDL10）值的形态学改变（0.007-0.195μM）低于常规生物测定的值（0.010-0.907μM）。我们还确定了肠道器官在Cd、Pb、Cr-VI或iAs-III处理下的形态特征是金属特异性的，并受到Wnt、骨形成蛋白、细胞凋亡诱导和Notch信号通路的介导。总之，这些发现为器官样本中形态学改变与特定毒性端点的相关性提供了新的见解，并将特定形态学改变作为肠毒性的潜在指标进行了识别。©2023年，本文作者独家授权Springer-Verlag GmbH Germany及Springer Nature出版。

Intestinal organoid may serve as an alternative model for toxicity testing. However, the linkage between specific morphological alterations in organoids and chemical-induced toxicity has yet to be defined. Here, we generated C57BL/6 mouse intestinal organoids and conducted a morphology-based analysis on chemical-induced toxicity. Alterations in morphology were characterized by large spheroids, hyperplastic organoids, small spheroids, and protrusion-loss organoids, which responded in a concentration-dependent manner to the treatment of four metal(loid)s including cadmium (Cd), lead (Pb), hexavalent chromium (Cr-VI), and inorganic trivalent arsenic (iAs-III). Notably, alterations in organoid morphology characterized by abnormal morphology rate were correlated with specific intestinal toxic effects, including reduction in cell viability and differentiation, induction of apoptosis, dysfunction of mucus production, and damage to epithelial barrier upon repeated administration. The benchmark dose (BMDL10) values of morphological alterations (0.007-0.195 μM) were lower than those of conventional bioassays (0.010-0.907 μM). We also established that the morphologic features of organoids upon Cd, Pb, Cr-VI, or iAs-III treatment were metal specific, and mediated by Wnt, bone morphogenetic protein, apoptosis induction, and Notch signaling pathways, respectively. Collectively, these findings provide novel insights into the relevance of morphological alterations in organoids to specific toxic endpoints and identify specific morphological alterations as potential indicators of enterotoxicity.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.