TY - JOUR
T1 - Morphological alterations in C57BL/6 mouse intestinal organoids as a tool for predicting chemical-induced toxicity
AU - Wang, Ziwei
AU - Chen, Shen
AU - Pang, Yaqin
AU - Ye, Lizhu
AU - Zhang, Qi
AU - Jiang, Xinhang
AU - Zhang, Rui
AU - Li, Miao
AU - Guo, Zhanyu
AU - Jiang, Yue
AU - Li, Daochuan
AU - Xing, Xiumei
AU - Chen, Liping
AU - Aschner, Michael
AU - Chen, Wen
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
KW - Intestinal organoids
KW - Intestinal toxicity
KW - Metal(loid) exposure
KW - Morphological alterations
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U2 - 10.1007/s00204-023-03451-1
DO - 10.1007/s00204-023-03451-1
M3 - Article
C2 - 36806895
AN - SCOPUS:85148428429
SN - 0340-5761
VL - 97
SP - 1133
EP - 1146
JO - Archives of Toxicology
JF - Archives of Toxicology
IS - 4
ER -