TCDD promotes liver fibrosis through disordering systemic and hepatic iron homeostasis

Abstract

2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental pollutant which can cause severe health problems, such as fibrosis. However, the toxic effects and related mechanism of TCDD on the liver remain largely unknown. In this study, we established a liver fibrosis mouse model upon exposure of TCDD, as evidenced by increased collagen I, tumor growth factor β1 (TGFβ1), α-smooth muscle actin (α-SMA), and Masson staining. Meanwhile, there was also a significant increase of inflammatory factors and TUNEL-positive hepatocytes in liver, indicating that liver inflammation and hepatic cell apoptosis occurred. In addition, increased serum and liver iron were concomitant with liver injury induced by TCDD. We further investigated the mechanism underlying TCDD-induced hepatocyte apoptosis through apoptosis polymerase chain reaction array, and found that a crucial apoptosis-related gene, cell death-inducing DFF45-like effector b (Cideb), was significantly increased in primary hepatocytes from TCDD-exposed mice, and accompanied by liver iron deposition in hepcidin knockout mice. Therefore, Cideb depletion could effectively attenuated TCDD or iron induced cell death related genes expression. In conclusion, our results showed that iron-induced Cideb expression played a critical role in promoting TCDD-induced hepatocyte apoptosis and liver fibrosis, which provide a novel mechanism for understanding TCDD-induced liver injury.

Keywords: Cideb; Hepatocyte apoptosis; Iron deposition; Liver fibrosis; TCDD.