title: Identification of a plant isoflavonoid that causes biliary atresia.
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.
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lorent
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Weilong
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Biological Sciences, University of the Sciences, Philadelphia, PA 19104, USA.
authors.forename: Kyung A
authors.initials: KA
authors.lastname: Koo
authors.affiliation: 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.
authors.forename: Orith
authors.initials: O
authors.lastname: Waisbourd-Zinman
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Karjoo
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Sealy
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Ross N
authors.initials: RN
authors.lastname: Kettleborough
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.affiliation: Faculty of Veterinary Science, University of Sydney, Camden, New South Wales 2570, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Windsor
authors.affiliation: Hume Livestock Health and Pest Authority, Albury, New South Wales 2640, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Whittaker
authors.affiliation: Department of Biological Sciences, University of the Sciences, Philadelphia, PA 19104, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Porter
authors.affiliation: 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.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Wells
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
mesh_terms: D027703:Amaranthaceae / Q000737:chemistry*; D000818:Animals; D001315:Australia; D001656:Biliary Atresia / Q000209:etiology* / Q000473:pathology / Q000662:veterinary; D001681:Biological Assay; D002417:Cattle; D004195:Disease Models, Animal; D059472:Exome; D005419:Flavonoids / Q000737:chemistry*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D010936:Plant Extracts / Q000737:chemistry*; D051381:Rats; D012756:Sheep; D015027:Zebrafish
chemical_list: D005419:Flavonoids; D010936:Plant Extracts