The synthetic toxin biliatresone causes biliary atresia in mice

Laboratory Investigation volume 100, pages1425–1435(2020)Cite this article

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Abstract

Exposure to environmental toxins may be responsible for biliary atresia. The focus of this study was to investigate the effect of biliatresone on the development of the hepatobiliary system in mice. We successfully synthesized biliatresone with a purity of 98% and confirmed its biliary toxicity. Exposure to high doses of biliatresone caused abortion or death in pregnant mice. Neonatal mice injected with biliatresone developed clinical signs of biliary obstruction, and dysplasia or the absence of extrahepatic biliary tract lumen, which confirmed the occurrence of biliary atresia. In the portal tract of biliary atresia mice, signs of infiltration of inflammatory cells and liver fibrosis were observed. The signature of extrahepatic biliary gene expression in these mice mainly involved the cell adhesion process, and hepatic RNA-seq was highly linked to transcriptional evidence of oxidative stress. When compared with the control group, hepatic glutathione levels were markedly reduced after biliatresone injection. Taken together, these data confirm that biliatresone causes severe developmental abnormalities of the hepatobiliary system in mice. Furthermore, decreased levels of glutathione may play a mechanistic role in the pathogenesis of liver fibrosis in biliatresone-induced experimental biliary atresia.

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Fig. 1: Biliatresone induced clinical manifestations of BA in neonatal mice.
Fig. 2: Biliatresone caused developmental abnormalities of the hepatobiliary system in mice.
Fig. 3: Reduced staining of cellular tubulin for CK19+ biliary epithelial cells of the gallbladder in biliatresone-induced BA mice.
Fig. 4: Activation of immune cells in the liver of biliatresone-induced BA models. Distribution of CD4+ and CD8+ T cells, and F4/80+ macrophages in the liver of biliatresone-induced BA models and controls at 14 days post injection.
Fig. 5: Extrahepatic biliary gene expression signature for the biliatresone-induced mouse model of BA at 14 days post injection.
Fig. 6: Hepatic gene expression signature for the biliatresone-induced mouse model of BA at 14 days post injection.

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Acknowledgements

This study received financial support from Shanghai Key Disciplines (no. 2017ZZ02022), Shanghai Municipal Key Clinical Specialty (no. shslczdzk05703), National Natural Science Foundation of China (no. 81770519, no. 81771633, no. 81873545 and no. 81974059), The Science Foundation of Shanghai (no. 18411969100 and no. 19ZR1406600), and Children’s National Medical Center (no. EK1125180104, no. EKYY20180204, EK112520180211 and no. EK112520180310).

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  1. Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China

    Yifan Yang, Junfeng Wang, Yong Zhan, Gong Chen, Zhen Shen, Shan Zheng & Rui Dong

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  1. Yifan Yang
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Yang, Y., Wang, J., Zhan, Y. et al. The synthetic toxin biliatresone causes biliary atresia in mice. Lab Invest 100, 1425–1435 (2020). https://doi.org/10.1038/s41374-020-0467-7

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