2. Academic Validation
  3. Identification of a plant isoflavonoid that causes biliary atresia

Identification of a plant isoflavonoid that causes biliary atresia

  • Sci Transl Med. 2015 May 6;7(286):286ra67. doi: 10.1126/scitranslmed.aaa1652.
Kristin Lorent 1,  Weilong Gong 1,  Kyung A Koo 2,  Orith Waisbourd-Zinman 3,  Sara Karjoo 4,  Xiao Zhao 1,  Ian Sealy 5,  Ross N Kettleborough 5,  Derek L Stemple 5,  Peter A Windsor 6,  Stephen J Whittaker 7,  John R Porter 2,  Rebecca G Wells 8,  Michael Pack 9
Affiliations

Affiliations

  • 1 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Department of Biological Sciences, University of the Sciences, Philadelphia, PA 19104, USA.
  • 3 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • 4 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 5 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 6 Faculty of Veterinary Science, University of Sydney, Camden, New South Wales 2570, Australia.
  • 7 Hume Livestock Health and Pest Authority, Albury, New South Wales 2640, Australia.
  • 8 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. rgwells@mail.med.upenn.edu mpack@mail.med.upenn.edu.
  • 9 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. rgwells@mail.med.upenn.edu mpack@mail.med.upenn.edu.
PMID: 25947162 DOI: 10.1126/scitranslmed.aaa1652
Abstract

Biliary atresia (BA) is a rapidly progressive and destructive fibrotic disorder of unknown etiology affecting the extrahepatic biliary tree of neonates. Epidemiological studies suggest that an environmental factor, such as a virus or toxin, is the cause of the disease, although none have been definitively established. Several naturally occurring outbreaks of BA in Australian livestock have been associated with the ingestion of unusual Plants by pregnant Animals during drought conditions. We used a biliary secretion assay in zebrafish to isolate a previously undescribed isoflavonoid, biliatresone, from Dysphania species implicated in a recent BA outbreak. This compound caused selective destruction of the extrahepatic, but not intrahepatic, biliary system of larval zebrafish. A mutation that enhanced biliatresone toxicity mapped to a region of the zebrafish genome that has conserved synteny with an established human BA susceptibility locus. The toxin also caused loss of cilia in neonatal mouse extrahepatic cholangiocytes in culture and disrupted cell polarity and monolayer integrity in cholangiocyte spheroids. Together, these findings provide direct evidence that BA could be initiated by perinatal exposure to an environmental toxin.

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