Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Center for Engineering MechanoBiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2024 Apr 5;19(4):e0301824. doi: 10.1371/journal.pone.0301824. eCollection 2024.
Biliary atresia is a neonatal disease characterized by damage, inflammation, and fibrosis of the liver and bile ducts and by abnormal bile metabolism. It likely results from a prenatal environmental exposure that spares the mother and affects the fetus. Our aim was to develop a model of fetal injury by exposing pregnant mice to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock, and then to determine whether there was a hepatobiliary phenotype in their pups. Pregnant mice were treated orally with 15 mg/kg/d biliatresone for 2 days. Histology of the liver and bile ducts, serum bile acids, and liver immune cells of pups from treated mothers were analyzed at P5 and P21. Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal. However, serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at P21. These results suggest that prenatal exposure to low doses of an environmental toxin can cause subclinical disease including liver inflammation and aberrant bile metabolism even in the absence of histological changes. This finding suggests a wide potential spectrum of disease after fetal biliary injury.
先天性胆道闭锁是一种新生儿疾病，其特征为肝脏和胆管的损伤、炎症和纤维化，以及异常的胆汁代谢。它可能是由一种产前环境暴露引起的，这种暴露对母亲没有影响，但会影响胎儿。我们的目的是通过使怀孕的老鼠暴露于低剂量的胆甾烯酮（一种与家畜先天性胆道闭锁有关的植物毒素）来建立胎儿损伤模型，然后确定其幼崽是否存在肝胆表型。怀孕的老鼠每天经口接受 15mg/kg 的胆甾烯酮治疗 2 天。用治疗母亲的幼崽的肝脏和胆管组织学、血清胆汁酸和肝脏免疫细胞来分析 P5 和 P21 时的情况。在这两个时间点，幼崽均未表现出组织学肝或胆管损伤或纤维化的证据。此外，生长正常。然而，P5 时甘氨胆酸的血清水平升高，表明胆汁代谢异常，并且血清胆汁酸谱通过 P21 变得越来越异常，胆汁酸的甘氨酸结合增强。在 P21 时还观察到肝脏中免疫细胞的激活。这些结果表明，即使没有组织学变化，产前暴露于低剂量的环境毒素也会导致包括肝脏炎症和异常胆汁代谢在内的亚临床疾病。这一发现表明，胎儿胆道损伤后可能存在广泛的潜在疾病谱。
