市原 佐保子

<b>Introduction:</b> 1,2-Dichloropropane (1,2-DCP) has been used as an intermediate in production for other chemicals and as a paint remover. IARC reclassified it as carcinogenic to humans (Group 1) according to the epidemiological studies of cholangiocarcinoma among offset color proof-printing workers exposed to 1,2-DCP in Japan. The present study investigated hepatotoxicity and proliferation in the bile duct induced by exposure to 1,2-DCP and role of P450 in its toxicity by inhibiting P450 activity using 1-aminobenzotriazole (1-ABT).<br><b>Methods: </b>42 male C57BL/6JJcl mice were randomly divided into 7 groups of six each. Four groups of mice administrated subcutaneously with 1-ABT at 50mg/kg were exposed to 1,2-DCP at 0, 50, 250 and 1250 ppm, respectively via inhalation route, 8hs per day for 4 weeks. The other three groups administered with saline were exposed to 1,2-DCP at 0, 50 and 250 ppm, respectively. Organ samples were collected under anesthesia at the end of the experiment. BrdU was injected intraperitoneally to the mice one hour prior to dissection for observation of proliferation in bile duct epithelial cells.<br><b>Results:</b> Serious hepatic pathological changes were found in the groups of 1250 ppm 1,2-DCP with 1-ABT injection and 250 ppm 1,2-DCP without 1-ABT injection, including massive necrosis, inflammation, and hepatocyte degeneration. BrdU labeling index tended to increase with exposure levels of 1,2-DCP in the groups without 1-ABT treatment, but this increase was suppressed by administration with 1-ABT.<br><b>Conclusions:</b> 1-ABT could reduce liver damage induced by 1,2-DCP exposure, indicating that P450 plays an important role in the hepatotoxicity of 1,2-DCP. P450-mediated metabolism of 1,2-DCP might contribute to proliferation in bile duct epithelial cells induced by exposure to 1,2-DCP.

Metal oxide nanoparticles are now widely used in the cosmetics and, electronics. Previous studies investigated pulmonary effects of metal oxide nanoparticles, but their effects on cardiovascular system remain elusive. The present study investigated the effects of exposure to metal oxide nanoparticles on the angiogenesis using transgenic zebrafish and human umbilical vein endothelial cells (HUVECs). The study also examined the potential mechanisms and signaling pathways that may be involved in those effects. We used fli1: eGFP Zebrafish (Danio rerio) transgenic zebrafish and exposed to nano-sized titanium dioxide (TiO<SUB>2</SUB>), silica dioxide (SiO<SUB>2</SUB>), and copper oxide (CuO) at the concentration of 1 and 100 miucrogram/ml from 1 dpf (day-after-fertilization) to 5 dpf. Angiogenesis were evaluated at the end of the exposure (after 5dpf) by ImageXpress Microscope and then endothelial cells were separated by FACS (Fluorescence Activated Cell Sorter).Exposure to CuO reduced angiogenesis in the ventral vessels of transgenic zebrafish. HUVECs were cultured and exposed to metal oxide nanoparticles for 24 hours. MTS assay was performed to assess cell viability. The exposure to CuO reduced the cell viability in a dose-dependent manner. Moreover, we analyzed the expression of vascular endothelial growth factor (VEGF) and VEGF receptors in the endothelial cells of zebrafish and HUVECs. The study showed nano-sized CuO might inhibit the angiogenesis in zebrafish and HUVECs.