Biliary Atresia Animal Models: Is the Needle in a Haystack?

Pal, Nutan; Joy, Parijat S.; Sergi, Consolato

doi:10.3390/ijms23147838

Cited by 6 publications

(4 citation statements)

References 111 publications

(143 reference statements)

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“…Since BA only occurs in newborns, it can be assumed that the vulnerability in humans is developmental and exposure to a toxin, such as biliatresone leads to the development of BA. These results are consistent with the murine Rhesus-Rotavirus (RRV) model and the dose-and time dependent morphological disruption of the www.nature.com/scientificreports/ EHBD in zebrafish after biliatresone exposition 1,32 . The virus kind, virus quantity and injection time point have been reported as being critical in the RRV model for the induction of BA-like phenotype 33,34 .…”

Section: Discussionsupporting

confidence: 85%

Biliatresone induces cholangiopathy in C57BL/6J neonates

Schmidt

Hagens

Schuppert

et al. 2023

Sci Rep

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Exposure to plant toxins or microbiota that are able to digest common food ingredients to toxic structures might be responsible for biliary atresia (BA). An isoflavonoid, biliatresone is known to effectively alter the extrahepatic bile duct (EHBD) development in BALB/c mice. Biliatresone causes a reduction of Glutathione (GSH) levels, SOX17 downregulation and is effectively countered with N-Acetyl-L-cysteine treatment in vitro. Therefore, reversing GSH-loss appears to be a promising treatment target for a translational approach. Since BALB/c mice have been described as sensitive in various models, we evaluated the toxic effect of biliatresone in robust C57BL/6J mice and confirmed its toxicity. Comparison between BALB/c and C57BL/6J mice revealed similarity in the toxic model. Affected neonates exhibited clinical symptoms of BA, such as jaundice, ascites, clay-colored stools, yellow urine and impaired weight gain. The gallbladders of jaundiced neonates were hydropic and EHBD were twisted and enlarged. Serum and histological analysis proved cholestasis. No anomalies were seen in the liver and EHBD of control animals. With our study we join a chain of evidence confirming that biliatresone is an effective agent for cross-lineage targeted alteration of the EHBD system.

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Section: Discussionsupporting

confidence: 85%

Biliatresone induces cholangiopathy in C57BL/6J neonates

Schmidt

Hagens

Schuppert

et al. 2023

Sci Rep

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“…Animal models serve as an important tool for both etiological and damage mechanism studies of BA [ 27 ]. Although there is still a lack of direct evidence that biliatresone is the cause of human BA, the discovery of biliatresone does provide the possibility to establish animal models induced by environmental toxins, thus drawing a more complete map of the bile duct injury mechanism in BA.…”

Section: Introductionmentioning

confidence: 99%

Biliatresone: progress in biliary atresia study

et al. 2022

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Background Biliary atresia (BA) is one of the main causes of neonatal end-stage liver disease. Without timely diagnosis and treatment, most children with BA will develop irreversible liver fibrosis within the first two months. While current theorized causes of BA include viral infection, immune disorders, and genetic defects, the comprehensive etiology is still largely unknown. Recently, biliatresone attracted much interest for its ability to induce BA in both zebrafish and mice, so we summarized the latest progress of biliatresone research in BA and tried to answer the question of whether it could provide further clues to the etiology of human BA. Data sources We conducted a PubMed search for any published articles related to the topic using search terms including “biliary atresia”, “biliatresone”, “GSH”, and “HSP90”. Relevant data were extracted from the original text or supplementary materials of the corresponding articles. Results Biliatresone had shown its unique toxicity in multiple species such as zebrafish and mice, and pathogenic factors involved included glutathione (GSH), heat shock protein 90 (HSP90) and the related pathways. In combination with epidemiological evidence and recent studies on the intestinal flora in biliary atresia, a new pathogenic hypothesis that the occurrence of biliary atresia is partly due to biliatresone or its structure-like compounds depositing in human body via vegetables or/and the altered intestinal flora structure can be tentatively established. Conclusions Based on the existing evidence, we emphasized that GSH and HSP90 are involved in the development of BA, and the maternal diet, especially higher vegetable intake of Asian women of childbearing age, accompanied by the altered intestinal flora structure, may contribute to the occurrence of biliary atresia and the higher incidence in the Asia group. However, the evidence from large sample epidemiological research is necessary.

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“…This is likely in part because mice are less prone to develop cholestatic diseases than humans [14], but the rarity of BA and the presence of abnormal direct/conjugated bilirubin at birth in many healthy babies who do not develop BA suggests an additional possibility: that the environmental insult responsible for BA causes persistent disease in a minority of cases. If this were the case, finding a BA-afflicted mouse pup even after exposure of the mother to a physiologically-relevant concentration of a toxin or virus might be infrequent [15]. Our aim here was to determine – as a means of understanding the full spectrum of changes in toxic fetal biliary injury – whether exposing mothers to low doses of biliatresone would generate a mild phenotype.…”

Section: Discussionmentioning

confidence: 99%

Biliatresone treatment of pregnant mice causes changes in bile metabolism and liver inflammation in their offspring

Gupta

Diamond

et al. 2023

Preprint

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Background & AimsBiliary atresia is a neonatal disease characterized by bile duct and liver damage, fibrosis, inflammation and abnormal bile metabolism. It appears to result from a prenatal exposure that spares the mother and affects the fetus. Our aim was to define the phenotype in neonatal mice after maternal exposure to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock.MethodsPregnant mice were treated orally with low-doses of biliatresone. Histological changes, bile acid profiles and immune profiles were analyzed in postnatal day 5 and 21 pups born to treated mothers.ResultsThe pups of mothers treated with this dose of biliatresone had no evidence of significant liver or ductular injury or fibrosis at postnatal day 5 or 21 and they grew normally. However, serum levels of glycocholic acid were elevated at postnatal day 5, suggesting altered bile metabolism, and bile metabolism became increasingly abnormal through postnatal day 21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at postnatal day 21.ConclusionPrenatal exposure to low doses of an environmental toxin can cause liver inflammation and aberrant bile metabolism even in the absence of histological changes.Lay summaryPrenatal exposure to low doses of an environmental toxin can cause changes in bile metabolism in neonatal mice.

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Biliary Atresia Animal Models: Is the Needle in a Haystack?

Cited by 6 publications

References 111 publications

Biliatresone induces cholangiopathy in C57BL/6J neonates

Biliatresone induces cholangiopathy in C57BL/6J neonates

Biliatresone: progress in biliary atresia study

Biliatresone treatment of pregnant mice causes changes in bile metabolism and liver inflammation in their offspring

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