Identification of a plant isoflavonoid that causes biliary atresia.
Identification of a plant isoflavonoid that causes biliary atresia.
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DOI：
10.1126/scitranslmed.aaa1652
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发表时间：
2015-05-06
影响因子：
17.1
通讯作者：
Pack M
中科院分区：
文献类型：
--
作者：
Lorent K;Gong W;Koo KA;Waisbourd-Zinman O;Karjoo S;Zhao X;Sealy I;Kettleborough RN;Stemple DL;Windsor PA;Whittaker SJ;Porter JR;Wells RG;Pack M
胆道闭锁（BA）是一种病因不明的快速进展性和破坏性纤维化疾病，影响新生儿肝外胆管树。流行病学研究表明，病毒或毒素等环境因素是导致这种疾病的原因，尽管尚未明确确定。澳大利亚牲畜中数起自然发生的 BA 爆发与怀孕动物在干旱条件下摄入不寻常的植物有关。我们对斑马鱼进行了胆汁分泌测定，从近期 BA 爆发涉及的精神障碍物种中分离出一种以前未描述过的异黄酮类化合物胆阿曲酮。这种化合物会选择性破坏斑马鱼幼虫的肝外胆管系统，但不会破坏肝内胆管系统。一种增强胆阿曲松毒性的突变映射到斑马鱼基因组的一个区域，该区域与已确定的人类 BA 易感基因座具有保守同线性。该毒素还导致培养的新生小鼠肝外胆管细胞纤毛丢失，并破坏胆管细胞球体中的细胞极性和单层完整性。总之，这些发现提供了直接证据表明 BA 可能是由围产期暴露于环境毒素引起的。
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.