Biliatresone induces cholangiopathy in C57BL/6J neonates

Abstract

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.

Environmental Toxin Biliatresone-Induced Biliary Atresia-like Abnormal Cilia and Bile Duct Cell Development of Human Liver Organoids

“…Biliatresone, a plant isoflavonoid-related 1,2-diaryl-2-propenone, has been implicated in BA-like syndrome outbreaks in Australian livestock [ 13 , 16 ]. It also causes bile duct destruction in zebrafish [ 13 ], mouse cholangiocyte spheroids [ 17 , 18 ], ex vivo bile duct culture [ 18 ], and mouse neonates [ 19 , 20 ]. However, evidence of the adverse effect of biliatresone on the growth of human cholangiocytes is still lacking.…”

“…The toxin biliatresone, a naturally occurring isoflavonoid-related 1,2-diaryl-2-propenone found in Dysphania glomulifera and D. littoralis , has been implicated in BA-like syndrome outbreaks in Australian livestock [ 13 , 16 ]. It also causes bile duct destruction in zebrafish [ 13 ], mouse cholangiocyte spheroids [ 17 , 18 ], ex vivo bile duct culture [ 18 ] and mouse neonates [ 19 , 20 ]. Biliatresone contains a reactive α-methylene ketone group, is highly electrophilic, and binds to reduced glutathione (GSH) [ 21 , 22 , 23 ].…”

Experimental models of biliatresone-induced biliary atresia

“…Recently, the toxic effect of biliatresone was also confirmed in C57BL/6J mice, where the animals displayed the etiopathogenesis (jaundice, growth retardation, claycolored feces, bilirubin increase, extrahepatic obliteration) of human BA (Schmidt et al, 2023), indicating that the onset of BA induced by biliatresone is independent of the immunological background. These studies showed that biliatresone generates abnormalities observed in the hepatobiliary system in newborn mice, which are similar to human BA, reaffirming that redox stress signaling may be important in mediating the response to biliatresone-induced damage.…”