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.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012;21:175–84.
Garcia-Barceló MM, Yeung MY, Miao XP, Tang CS, Cheng G, So MT, et al. Genome-wide association study identifies a susceptibility locus for biliary atresia on 10q24.2. Hum Mole Genet. 2010;19:2917–25.
Leyva-Vega M, Gerfen J, Thiel BD, Jurkiewicz D, Rand EB, Pawlowska J, et al. Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3. Am J Med Genet A. 2010;152A:886–95.
Rurarz M, Czubkowski P, Chrzanowska K, Cielecka-Kuszyk J, Marczak A, Kamińska D, et al. Biliary atresia in children with aberrations involving chromosome 11q. J Pediatr Gastroenterol Nutr. 2014;58:e26–e29.
Riepenhoff-Talty M, Schaekel K, Clark HF, Mueller W, Uhnoo I, Rossi T, et al. Group a rotaviruses produce extrahepatic biliary obstruction in orally inoculated newborn mice. Pediatr Res. 1993;33:394–9.
Mack C. The pathogenesis of biliary atresia: evidence for a virus-induced autoimmune disease. Semin Liver Dis. 2007;27:233–42.
Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM, Narkewicz MR, et al. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology. 1998;27:1475–82.
Petersen C, Davenport M. Aetiology of biliary atresia: what is actually known? Orphanet J Rare Dis. 2013;8:128.
Petersen C. Biliary atresia: the animal models. Semin Pediatr Surg. 2012;21:185–91.
Rauschenfels S, Krassmann M, Al-Masri AN, Verhagen W, Leonhardt J, Kuebler JF, et al. Incidence of hepatotropic viruses in biliary atresia. Eur J Pediatr. 2009;168:469–76.
Mack CL, Feldman AG, Sokol RJ. Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis. 2012;32:307–16.
Harper P, Plant JW, Ungers DB. Congenital biliary atresia and jaundice in lambs and calves. Aust Vet J. 1990;67:18–22.
Lorent K, Gong W, Koo KA, Waisbourd-Zinman O, Karjoo S, Zhao X, et al. Identification of a plant isoflavonoid that causes biliary atresia. Sci Transl Med. 2015;7:286ra67.
Estrada MA, Zhao X, Lorent K, Kriegermeier A, Nagao SA, Berritt S, et al. Synthesis and structure–activity relationship study of biliatresone, a plant isoflavonoid that causes biliary atresia. ACS Med Chem Lett. 2018;9:61–4.
Dong R, Yang Y, Shen Z, Zheng C, Jin Z, Huang Y, et al. Forkhead box A3 attenuated the progression of fibrosis in a rat model of biliary atresia. Cell Death Dis. 2017;8:e2719.
Mack CL, Tucker RM, Sokol RJ, Karrer FM, Kotzin BL, Whitington PF, et al. Biliary atresia is associated with cd4+ th1 cell–mediated portal tract inflammation. Pediatr Res. 2004;56:79–87.
Bessho K, Mourya R, Shivakumar P, Walters S, Magee JC, Rao M, et al. Gene expression signature for biliary atresia and a role for Interleukin-8 in pathogenesis of experimental disease. Hepatology. 2014;60:211–23.
Zhao X, Lorent K, Benjamin JW, Marchione DM, Gillespie K, Waisbourd-Zinman O, et al. Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish. Hepatology. 2016;64:894–907.
Zong Y, Stanger BZ. Molecular mechanisms of liver and bile duct development. Wiley Interdiscip Rev Dev Biol. 2012;1:643–55.
Li Z, White P, Tuteja G, Rubins N, Sackett S, Kaestner KH. Foxa1 and Foxa2 regulate bile duct development in mice. J Clin invest. 2009;119:1537–45.
Lertudomphonwanit C, Mourya R, Fei L, Zhang Y, Gutta S, Yang L, et al. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Sci Transl Med. 2017;9:eaan8462.
Jiang J, Wang J, Shen Z, Lu X, Chen G, Huang Y, et al. Serum mmp-7 in the diagnosis of biliary atresia. Pediatrics. 2019;144:e20190902.
Allen SR, Jafri M, Donnelly B, McNeal M, Witte D, Bezerra J, et al. Effect of rotavirus strain on the murine model of biliary atresia. J Virol. 2007;81:1671–9.
Glaser SS, Gaudio E, Miller T, Miller T, Alvaro D, Alpini G. Cholangiocyte proliferation and liver fibrosis. Expert Rev Mol Med. 2009;11:e7.
Lichtman SN, Sartor RB. Duct proliferation following biliary obstruction in the rat. Gastroenterology. 1991;100:1785–7.
Waisbourd-Zinman O, Koh H, Tsai S, Lavrut P-M, Dang C, Zhao X, et al. The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17. Hepatology. 2016;64:880–93.
Luo ZH, Shivakumar P, Mourya R, Gutta S, Bezerra JA. Gene expression signatures associated with survival times of pediatric patients with biliary atresia identify potential therapeutic agents. Gastroenterology. 2019;157:1138–52.
Ye ZW, Zhang J, Townsend DM, Tew KD. Oxidative stress, redox regulation and diseases of cellular differentiation. Biochim Biophys Acta. 2015;1850:1607–21.
Lu SC. Glutathione synthesis. Biochim Biophys Acta. 2013;1830:3143–53.
Yang H, Ramani K, Xia M, Ko KS, Li TW, Oh P, et al. Dysregulation of glutathione synthesis during cholestasis in mice: Molecular mechanisms and therapeutic implications. Hepatology. 2009;49:1982–91.
Ramani K, Tomasi ML, Yang H, Ko K, Lu SC. Mechanism and significance of changes in glutamate-cysteine ligase expression during hepatic fibrogenesis. J Biol Chem. 2012;287:36341–55.
Yang H, Ko K, Xia M, Li TW, Oh P, Li J, et al. Induction of avian musculoaponeurotic fibrosarcoma proteins by toxic bile acid inhibits expression of GSH synthetic enzymes and contributes to cholestatic liver injury in mice. Hepatology. 2010;51:1291–301.
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).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
A novel model of injured liver ductal organoids to investigate cholangiocyte apoptosis with relevance to biliary atresia
Pediatric Surgery International (2020)
Frontiers in Medicine (2020)