TY - JOUR
T1 - Identification of a plant isoflavonoid that causes biliary atresia
AU - Lorent, Kristin
AU - Gong, Weilong
AU - Koo, Kyung A.
AU - Waisbourd-Zinman, Orith
AU - Karjoo, Sara
AU - Zhao, Xiao
AU - Sealy, Ian
AU - Kettleborough, Ross N.
AU - Stemple, Derek L.
AU - Windsor, Peter A.
AU - Whittaker, Stephen J.
AU - Porter, John R.
AU - Wells, Rebecca G.
AU - Pack, Michael
PY - 2015/5/6
Y1 - 2015/5/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84928975439&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/scitranslmed.aaa1652
DO - https://doi.org/10.1126/scitranslmed.aaa1652
M3 - مقالة
C2 - 25947162
SN - 1946-6234
VL - 7
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 286
ER -