Liver pathophysiology of Sprague-Dawley rat models of intrahepatic cholestasis of pregnancy induced by different sex hormones

Abstract:

Objective To explore the pathogenesis of intrahepatic cholestasis of pregnancy（ICP） in rats induced by either estradiol or progesterone，through determining the levels of liver damage，bile acid profiles，inflammatory factors，and oxidative stress.Methods ICP models were established by subcutaneous injection of either estradiol or progesterone in the neck of Sprague-Dawley（SD） rats during pregnancy. The models were evaluated by measuring the levels of TBA（serum total bile acid），ALT（alanine aminotransferase），AST（aspartate aminotransferase），and ALP（alkaline phosphatase）. Liver injury was evaluated through pathological section observation. The bile acid profiles of the liver were analyzed by liquid chromatography-mass spectrometry. The transcription levels of inflammatory cytokines（tumor necrosis factor-α[TNF-α]，interleukin[IL]-1β，and IL-6） in the liver were measured using RT-qPCR. The levels of oxidative and antioxidative markers（malondialdehyde[MDA]，glutathione[GSH]，and superoxide dismutase[SOD]） were determined using commercial kits. The mRNA and protein levels of antioxidative stress markers（nuclear factor erythroid 2-related factor 2[NRF2]，glutamate-cysteine ligase modifier subunit[GCLM]，glutamate-cysteine ligase catalytic subunit[GCLC]，NAD（P）H quinone oxidoreductase-1[NQO1]，and heme oxygenase-1[HO-1]） in the liver were determined using RT-qPCR and Western blotting，respectively.Results The levels of serum total bile acid，ALT，AST，and ALP in the estradiol group and progesterone group were significantly higher than those in the control group. HE staining showed narrower hepatic sinusoids and cholestasis in the estradiol group and hepatocyte swelling and mild hepatic steatosis in the progesterone group. The bile acid profiles were significantly different between the groups. In the estradiol group，the levels of TNF-α，IL-1β，IL-6，and MDA in the liver were significantly increased，while the levels of GSH and SOD as well as the mRNA and protein levels of NRF2，GCLM，GCLC and NQO1 were significantly decreased，with no significant changes in the progesterone group.Conclusion Both estrogen and progesterone induce ICP in rats. Estrogen can inhibit the NRF2-GCLM and NRF2-GCLC pathways to aggravate liver injury，while progesterone has no such effect.