Impact of sex differences on the induction and evolution of clinical signs of an end-stage liver disease rat model

Abstract

Background: Historically, preclinical studies with rat models have been carried out only with male animals. Current regulations require sex parity in experimental procedures. Several studies have shown significant sex differences in rat models of liver fibrosis, but there is no data available in end-stage liver disease. The aim was to describe sex-related differences in a carbon tetrachloride (CCl4)-induced rat model of cirrhosis with ascites. Methods: Fifty-two rats, 26 of each sex, fed ad libitum with phenobarbital-enriched drinking water (5 mmol/l). CCl4was administered orally weekly, adjusting doses to weight changes after CCl4administration until ascites development. Results: Median time to ascites development was significantly higher in females (19 vs. 10 weeks). Males showed significantly greater weight changes 48 h after CCl4administration. The cumulative dose of CCl4was significantly higher in females, both at the time of diagnosis of ascites (10.7 vs. 1.5 ml) and at week 10 (median time to ascites development in males) (3.9 vs. 1.5 ml). There were no significant sex differences in model associated mortality (31% males vs. 27% females). Conclusions: Sex differences have a significant impact on CCl4-induced end-stage liver disease; classical models should be redesigned to appropriately encompass both sexes.