PUBLICATION
Identification of a plant isoflavonoid that causes biliary atresia
- Authors
- Lorent, K., Gong, W., Koo, K.A., Waisbourd-Zinman, O., Karjoo, S., Zhao, X., Sealy, I., Kettleborough, R.N., Stemple, D.L., Windsor, P.A., Whittaker, S.J., Porter, J.R., Wells, R.G., Pack, M.
- ID
- ZDB-PUB-150508-10
- Date
- 2015
- Source
- Science Translational Medicine 7: 286ra67 (Journal)
- Registered Authors
- Kettleborough, Ross, Lorent, Kristin, Pack, Michael, Stemple, Derek L.
- Keywords
- none
- MeSH Terms
-
- Amaranthaceae/chemistry*
- Animals
- Australia
- Biliary Atresia/etiology*
- Biliary Atresia/pathology
- Biliary Atresia/veterinary
- Biological Assay
- Cattle
- Disease Models, Animal
- Exome
- Flavonoids/chemistry*
- Genetic Predisposition to Disease
- Humans
- Immunity, Innate
- Mice
- Microscopy, Confocal
- Mutation
- Plant Extracts/chemistry*
- Rats
- Sheep
- Zebrafish
- PubMed
- 25947162 Full text @ Sci. Transl. Med.
Citation
Lorent, K., Gong, W., Koo, K.A., Waisbourd-Zinman, O., Karjoo, S., Zhao, X., Sealy, I., Kettleborough, R.N., Stemple, D.L., Windsor, P.A., Whittaker, S.J., Porter, J.R., Wells, R.G., Pack, M. (2015) Identification of a plant isoflavonoid that causes biliary atresia. Science Translational Medicine. 7:286ra67.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping