In an attempt to determine the effect of a toxic insult occurringin uteroon the developing liver, fetal amniotic cavities of timed-pregnant (16-day) Sprague-Dawley rats were injected with varying concentrations of E.coliendotoxin. Controls were sham-operated or saline-injected fetal rats. Five days after injection, the pregnant animals were killed;14C-Ieucine was injected subcutaneously into the newborns, and their livers were removed, prepared for histo-logic examination and for analysis of radiolabeled protein incorporation. A significant increase in the number of hepatic giant cells (giant cells/mm2) was noted in fetal rats injected with endotoxin compared to the controls (P < 0.01). In addition, the incorporation of14C-leucine into total liver protein and immuno-precipitable albumin of endotoxin-injected fetuses was significantly lower than that of control animals (P < 0.01 and P < 0.02, respectively). In contrast,14C-leucine incorporation into immuno-precipitable α-fetoprotein was significantly greater in endotoxin-injected fetuses than in controls (P < 0.02). Also, serum α-fetoprotein levels were significantly (P < 0.01) higher in the endotoxin-injected fetuses.These data suggest that intrauterine insult with endotoxin during late fetal development results in hepatotoxicity manifested as giant cell induction and disrupted protein metabolism. The changes (hepatic giant cell response and elevated serum levels of α-fetoprotein) in rat liver parallel those reported in human newborns with neonatal hepatitis syndrome. Therefore, it may be suggested that the endotoxin-injected fetal rat may represent an appropriate animal model for the study of the pathogenesis of neonatal hepatitis in man.SpeculationThe development of an animal model for neonatal hepatitis syndrome may ultimately provide the basis for a better understanding of the pathogenetic mechanisms responsible for both morphologic and biochemical abnormalities noted in this spectrum of hepatobiliary diseases. Of particular importance is the more precise characterization of the hepatic giant cell frequently demonstrated in neonatal hepatitis. This cell type could contribute to the pathogenesis of hepatitis by releasing secretions that help to regulate changes in the hepatic cellular environment such as proteolysis, inflammatory cell infiltration, or disruption of the biliary tract epithelial surface, and thereby, contribute to the various manifestations of disease. Furthermore, there could be modification of these tissue reactions by coexisting genetic factors such as renewed synthesis of fetoprotein after reversion of fetal hepatocytes to an earlier stage of development. The synthesis and release of this developmental protein may also be of importance in immunoregulation during intrauterine existence.