ABSTRACT
Background Mitochondrial dynamin-related protein 1 (DRP1) regulates mitochondrial division and plays an important role in maintaining hepatocyte function. However, the role of DRP1 in cadmium exposure-induced maternal liver damage in pregnant mice remains unclear. Objective To investigate the role and mechanism of DRP1 in maternal liver damage induced by cadmium exposure during pregnancy. Methods This study consisted of animal experiments and cell experiments. (1) Animal experiments. Mice at 14 days of gestation were randomly divided into three groups: a control group, a low-dose cadmium group (LCd group: 2.5 mg·kg−1), and a high-dose cadmium group (HCd group: 5 mg·kg−1). The pregnant mice were intraperitoneally injected with cadmium chloride (CdCl2) for 6 and 24 h in the next morning. The weights of pregnant mice, uterus, maternal liver, and fetal mice were recorded after sacrifice. Serum and liver of pregnant mice were collected, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were detected, and liver tissues were stained with HE to observe changes in liver function and liver tissue structure. The expressions of oxidative phosphorylation-related proteins, hypoxia inducible factor-1α (HIF-1α) and DRP1 proteins in liver of pregnant mice were detected by Western blotting. (2) Cell experiments. AML12 cells were treated with CdCl2 (10 μmol·L−1) for 0, 2, 6, 12, and 24 h. The expressions of oxidative phosphorylation-related proteins, DRP1, and hypoxia inducible factor-1α (HIF-1α) proteins were detected. AML12 cells were pretreated with DRP1 inhibitor Mdivi-1 for 1 h and then CdCl2 (10 μmol·L−1) for 12 h to detect the expression of oxidative phosphorylation-related proteins and DRP1 protein. AML12 cells were treated with Hif-1α siRNA for 48 h and CdCl2 (10 μmol·L−1) for 6 h to detect the expression of HIF-1α and DRP1 proteins. Results The results of animal experiments showed that cadmium exposure in pregnant mice had no effects on maternal liver weight and liver coefficient. However, the histomorphological changes and necrosis in hepatocytes were observed. Compared with the control group, the serum ALT and AST levels of pregnant mice in the LCd group were significantly increased after 6 h (P＜0.05), and the levels in the HCd group were significantly increased after 6 and 24 h (P＜0.05). Cadmium exposure during pregnancy significantly up-regulated HIF-1α and DRP1 expressions and down-regulated the expressions of oxidative phosphorylation-related proteins in maternal livers. In vitro cell experiments showed that the expressions of oxidative phosphorylation-related proteins was significantly decreased and HIF-1α and DRP1 protein expressions were significantly increased in the AML12 cells treated with CdCl2 for 6 h. Mdivi-1 pretreatment significantly antagonized the inhibitory effect of cadmium on the expressions of oxidative phosphorylation-related proteins in AML12 cells, while Hif-1α siRNA pretreatment significantly antagonized the up-regulative effect of cadmium on DRP1 expression in AML12 cells. Conclusion Cadmium exposure in pregnant mice may up-regulate DRP1 expression by activating HIF-1α signaling, then inhibit oxidative phosphorylation level of hepatic cells, and ultimately lead to maternal liver damage.
ABSTRACT
Objective To studying the MR findings and pathology of peripheral small intrahepatic cholangiocarcinoma and improving the understanding of peripheral small cholangiocarcinoma with no-bile duct dilatation. Methods A retrospective analysis of 12 patients with intrahepatic peripheral cholangiocarcinoma which were confirmed by surgery and pathology, all patients were examined by abdominal MRI without and with contrast. Correlation was made with gross pathology and surgical pathological specimen. Results On T1WI, there were 4 cases of complex low signal intensity and 8 cases of low signal intensity. On T2WI, there were 8 cases of high signal intensity and 4 cases of complex high signal intensity. Enhanced MRI showed: marked nidus enhancement on arterial phase in 1 case, and the pathological diagnosis was poorly differentiated adenocarcinoma. Inhomogeneous enhancement or annular enhancement were seen in 10 cases on arterial phase, 3 of these cases showed thin annular enhancement on arterial phase, low signalintensity on portal venous phase and isointensity on delayed phase. One case showed delayed enhancement. Thick circular enhancement correlated with pathological changes of survival of tumor cells, center areas correlated with fibrous connective tissue, and a small amount of necrotic tissue. Island-like enhancement or inhomogeneous enhancement were seen in 3 cases. Corresponding pathological changes consisted of tumor tissue and a small amount of fibrous connective tissue, as well as somenecrotic tissue. In 1 case, no enhancement was seen on all three phases and pathological changes showed cystic changes, hemorrhage, necrosis, with survival tumor cells seen between cyst and normal liver tissue. Conclusions MRI scanning of peripheral small cholangiocarcinoma lacked characteristic features, but dynamic contrast-enhanced MR had certain specific findings. Due to different pathology, the fibrous tissue, necrotic tissue and survival tumor tissue components were exhibited different imaging findings.