市原 佐保子

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<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.

1-Bromopropane was introduced as an alternative to ozone layer-depleting solvents such as chlorofluorocarbons and 1,1,1-trichloroethane. However, a dozen human cases have been reported with symptoms and signs of toxicity to 1-bromopropane including numbness, diminished vibration sense in the lower extremities as well as ataxic gait. An epidemiological study also demonstrated dose-dependent prolongation of distal latency and decrease in vibration sense in the lower extremities. The initial animal experiments helped to identify and analyze the initial human case of 1-bromopropane toxicity. However, animal data that can explain the central nervous system disorders in humans are limited. Nonetheless, animal data should be carefully interpreted especially in a high-order function of the central nervous system or neurological signs such as ataxia that is influenced by fundamental anatomical/physiological differences between humans and animals. Enzymatic activity in the liver may explain partly the difference in the susceptibility between humans and animals, but further studies are needed to clarify the biological factors that can explain the difference and commonality among the species. © 2011.

Breast cancer can be classified into several subtypes based on gene expression profiling. Basal-like breast carcinoma (BLC) has a triple negative phenotype, that is, the subtype lacks the estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2). It has been recently reported that CD109, a glycosylphosphatidylinositol (GPI)-anchored cell surface protein, is a new breast myoepithelial marker. In the present study CD109 expression was investigated in invasive ductal carcinomas (IDC) of the breast on immunohistochemistry. Eighty-eight formalin-fixed, paraffin-embedded breast carcinoma sections were immunostained with anti-CD109, anti-cytokeratin 5/6 (CK5/6), anti-calponin, anti-vimentin and anti-p63 antibodies. CD109 expression was detected in 18 of 30 basal-like breast carcinomas (BLC) but not in other types of 53 IDC (non-BLC) that were positive for ER, PgR and/or HER2. The percentage of CD109-positive tissues (60%) in BLC was similar to that of CK5/6 (63%) and higher than that of other myoepithelial markers including p63 (23%), calponin (33%) and vimentin (33%). Statistical analysis indicated that the CD109-positive group in BLC, but not the CK5/6-positive group in BLC, was associated with reduced fat invasion (P < 0.05). These findings indicate that CD109 is a useful diagnostic marker for BLC and that CD109 expression may affect biological properties of cancer cells.

Obesity is a multifactorial and heterogeneous condition that results from alterations of various genes, each having a partial and additive effect. The inheritance pattern of obesity is thus complex, and environmental factors play an important role in promoting or delaying its development. The identification of susceptibility genes and genetic variants for obesity requires various methodological approaches. Obesity is classified into three main categories on the basis of genetic etiology: monogenic, syndromic, and polygenic obesity. Here we review monogenic and syndromic obesity. We also review the linkage analysis studies followed by the candidate gene approaches and genome-wide association studies. Identification of the underlying genetic causes of obesity will likely provide a basis both for the development of new therapeutic agents and for the personalized prevention of this condition.