Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70(-/-) mice with human-like bile acids

BACKGROUND: Cyp2c70(-/-) mice with a human-like bile acid (BA) composition display features of neonatal cholestasis. We assessed whether perinatal ursodeoxycholic acid (UDCA) exposure prevents neonatal cholestasis in Cyp2c70(-/-) mice and reduces cholangiopathy development later in life. METHODS: Cyp2c70(+/-) males were crossed with Cyp2c70(+/-) females fed either a regular chow diet or a 0.1% UDCA-containing diet during breeding, gestation, and suckling. Cholestasis and liver function parameters were assessed in their Cyp2c70(-/-) and wild-type offspring at 3 and 8 weeks of age. RESULTS: Three-week-old Cyp2c70(-/-) pups showed features of neonatal cholestasis, including elevated plasma BAs and transaminases, which were completely prevented in Cyp2c70(-/-) pups upon perinatal UDCA exposure. In addition, UDCA administration to the dams corrected altered hepatic gene expression patterns in Cyp2c70(-/-) pups, reduced markers of fibrogenesis and inflammation, and prevented cholangiocyte proliferation. Yet, these beneficial effects of perinatal UDCA exposure were not retained into adulthood upon discontinuation of treatment. CONCLUSION: Perinatal exposure of Cyp2c70(-/-) mice to UDCA has beneficial effects on liver function parameters, supporting a direct role of BA hydrophobicity in the development of neonatal cholestasis in these mice. However, prevention of neonatal cholestasis in Cyp2c70(-/-) mice has no long-lasting effects on liver pathophysiology. IMPACT: This is the first study showing that perinatal UDCA exposure prevents features of neonatal cholestasis that are observed in mice with a human-like bile acid composition, i.e., Cyp2c70(-/-) mice. Perinatal UDCA exposure of Cyp2c70(-/-) pups leads to UDCA enrichment in their circulating bile acid pool and, consequently, to a reduced hydrophobicity of biliary bile acids. Perinatal UDCA exposure of Cyp2c70(-/-) pups has no long-lasting effects on the development of cholangiopathy after discontinuation of treatment. The results in this study expand current knowledge regarding acute and long-lasting effects of UDCA treatment in early life.