Differences in the progression of liver disease in male and female rats induced by TAA: considerations in the development of pharmacological therapies

Introduction and Objectives

Thioacetamide (TAA) is a hepatotoxic agent that causes fibrosis, cirrhosis, and cancer. Various doses and regimens of TAA have been tested in different murine models to validate hepatoprotective compounds. To date, only two studies have reported differences in TAA susceptibility according to sex in murine models. To compare the progression of liver disease in male and female Wistar rats induced by TAA.

Materials and Patients

Male and female Wistar rats (250 g) were grouped into two conditions: treated with thioacetamide (TAA) and saline solution (CT) intraperitoneally. TAA group (n=12, males=6, females=6): dose 200 mg/kg/3 times per week for 6 weeks; CT group (n=12, males=6, females=6): rats treated with saline solution. Water and food were provided ad libitum, and the animals were monitored daily, with weight recorded weekly. At the end of the treatment, euthanasia was performed with pentobarbital, and an exploratory laparotomy and liver recovery were conducted, with photographic records and macroscopic descriptions for each rat. Statistical analysis and mortality curve were performed using a two-way ANOVA and Log-Rank test.

Results

TAA administration caused weight loss in female rats during the first 2 weeks of treatment, but they showed recovery and stabilization from the third week onwards, while males showed progressive weight gain. Unexpectedly, the mortality rate in males by the third week was 66.6%, which remained until the sixth week, compared to 0% mortality in females and control animals. Macroscopic analysis of TAA-treated animals showed no alterations in adjacent organs but revealed evident morphological changes in liver tissue in males, such as heterogeneous dark brown coloration, irregular edges, and tissue nodulation. In contrast, female rats showed more discreet morphological changes of damage after 6 weeks of treatment.

Conclusions

The TAA model in Wistar rats demonstrated greater susceptibility to damage in male rats than in female rats. These findings should be considered in future studies, such as exploring new pharmacological therapies and/or biomarker development.

Ethical statement: The protocol was approved by the Ethics and Research Committees of the "Dr. Eduardo Liceaga" General Hospital of Mexico (CI/314/15) and the Faculty of Medicine of UNAM (DI 115/2015).

Declaration of interests: None.

Funding: Partial funding was received by Medifarma S.A. de C.V