BackgroundCyp2c70-/-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 inCyp2c70-/-mice and reduces cholangiopathy development later in life.MethodsCyp2c70+/-males were crossed withCyp2c70+/-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 theirCyp2c70-/-and wild-type offspring at 3 and 8 weeks of age.ResultsThree-week-oldCyp2c70-/-pups showed features of neonatal cholestasis, including elevated plasma BAs and transaminases, which were completely prevented inCyp2c70-/-pups upon perinatal UDCA exposure. In addition, UDCA administration to the dams corrected altered hepatic gene expression patterns inCyp2c70-/-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.ConclusionPerinatal exposure ofCyp2c70-/-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 inCyp2c70-/-mice has no long-lasting effects on liver pathophysiology.ImpactThis 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 ofCyp2c70-/-pups leads to UDCA enrichment in their circulating bile acid pool and, consequently, to a reduced hydrophobicity of biliary bile acids.Perinatal UDCA exposure ofCyp2c70-/-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.