基本情報
研究キーワード
6経歴
3-
2017年4月 - 現在
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2009年4月 - 2017年3月
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2004年1月 - 2009年3月
学歴
2-
- 2001年3月
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- 1990年3月
論文
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Toxicology research 5(6) 1522-1529 2016年11月1日 査読有り1-Bromopropane (1BP) is widely used as an alternative to ozone-depleting solvents. The present study investigated the role of P450s in 1BP-induced male reproductive toxicity. Mice co-treated with 1-aminobenzotriazole (ABT), a non-selective P450 inhibitor, were exposed to 1BP at 0, 50, 250, or 1200 ppm, while saline-treated control mice were exposed to 1BP at 0, 50, or 250 ppm, for 4 weeks. In the saline-treated mice, exposure to 1BP at 250 ppm decreased the sperm count and sperm motility. Histopathological examination showed that exposure to 1BP at 50 and 250 ppm increased the number of elongated spermatids retained at the basal region of stage IX, X and XI seminiferous tubules, while exposure to 1BP at 250 ppm increased the number of periodic acid-Schiff (PAS)-positive round structures in stage IX, X, and XI seminiferous tubules. Co-treatment with ABT prevented the above changes induced by exposure to 1BP at 50 or 250 ppm. However, ABT-treated mice exposed to 1BP in the 1200 ppm group showed decreases in the weights of reproductive organs, epididymal sperm count and motility, increases in epididymal sperm with abnormal heads, retained spermatids and PAS-positive round structures in stages IX-XI, depletion of spermatogenic cells in part of the seminiferous tubules, and a small number of round spermatids in stage VII seminiferous tubules. The results at 50 and 250 ppm of 1-BP exposure indicate that P450s play important roles in 1BP-induced testicular toxicity. The control of P450 activity reduced 1BP-induced male reproductive toxicities including spermiation failure, reduction of epididymal sperm count and motility, and formation of PAS-positive round structures at postspermiation stages.
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Particle and fibre toxicology 13(1) 54-54 2016年10月13日 査読有りBACKGROUND: The use of carbon nanotubes has increased lately. However, the cardiovascular effect of exposure to carbon nanotubes remains elusive. The present study investigated the effects of pulmonary exposure to single-walled carbon nanotubes (SWCNTs) and double-walled carbon nanotubes (DWCNTs) on atherosclerogenesis using normal human aortic endothelial cells (HAECs) and apolipoprotein E-deficient (ApoE-/-) mice, a model of human atherosclerosis. METHODS: HAECs were cultured and exposed to SWCNTs or DWCNTs for 16 h. ApoE-/- mice were exposed to SWCNTs or DWCNTs (10 or 40 μg/mouse) once every other week for 10 weeks by pharyngeal aspiration. RESULTS: Exposure to CNTs increased the expression level of adhesion molecule (ICAM-1) and enhanced THP-1 monocyte adhesion to HAECs. ApoE-/- mice exposed to CNTs showed increased plaque area in the aorta by oil red O staining and up-regulation of ICAM-1 expression in the aorta, compared with vehicle-treated ApoE-/- mice. Endothelial progenitor cells (EPCs) are mobilized from the bone marrow into the circulation and subsequently migrate to the site of endothelial damage and repair. Exposure of ApoE-/- mice to high-dose SWCNTs or DWCNTs reduced the colony-forming units of EPCs in the bone marrow and diminished their migration function. CONCLUSION: The results suggested that SWCNTs and DWCNTs enhanced atherosclerogenesis by promoting monocyte adhesion to endothelial cells and inducing EPC dysfunction.
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Toxicology letters 258 249-258 2016年9月6日 査読有りNeurotoxicity of 1-bromopropane (1-BP) has been reported in both human cases and animal studies. To date, neurotoxicity of 1-BP has been induced in rats but not in mice due to the lethal hepatotoxicity of 1-BP. Oxidization by cytochromes P450 and conjugation with glutathione (GSH) are two critical metabolism pathways of 1-BP and play important roles in toxicity of 1-BP. The aim of the present study was to establish a murine model of 1-BP neurotoxicity, by reducing the hepatotoxicity of 1-BP with 1-aminobenzotriazole (1-ABT); a commonly used nonspecific P450s inhibitor. The results showed that subcutaneous or intraperitoneal injection of 1-ABT at 50mg/kg body weight BID (100mg/kg BW/day) for 3days, inhibited about 92-96% of hepatic microsomal CYP2E1 activity, but only inhibited about 62-64% of CYP2E1 activity in brain microsomes. Mice treated with 1-ABT survived even after exposure to 1200ppm 1-BP for 4 weeks and histopathological studies showed that treatment with 1-ABT protected mice from 1-BP-induced hepatic necrosis, hepatocyte degeneration, and hemorrhage. After 4-week exposure to 1-BP, the brain weight of 1-ABT(+)/1200ppm 1-BP group was decreased significantly. In 1-ABT-treated groups, expression of hippocampal Ran protein and cerebral cortical GRP78 was dose-dependently increased by exposure to 1-BP. We conclude that the control of hepatic P450 activity allows the observation of effects of 1-BP on the murine brain at a higher concentration by reduction of hepatotoxicity. The study suggests that further experiments with liver-specific control of P450 activity using gene technology might provide better murine models for 1-bromopropane-induced neurotoxicity.
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International journal of molecular sciences 17(4) 576-576 2016年4月16日 査読有りTitanium dioxide (TiO₂) nanoparticles are widely used in cosmetics, sunscreens, biomedicine, and food products. When used as a food additive, TiO₂ nanoparticles are used in significant amounts as white food-coloring agents. However, the effects of TiO₂ nanoparticles on the gastrointestinal tract remain unclear. The present study was designed to determine the effects of five TiO₂ particles of different crystal structures and sizes in human epithelial colorectal adenocarcinoma (Caco-2) cells and THP-1 monocyte-derived macrophages. Twenty-four-hour exposure to anatase (primary particle size: 50 and 100 nm) and rutile (50 nm) TiO₂ particles reduced cellular viability in a dose-dependent manner in THP-1 macrophages, but in not Caco-2 cells. However, 72-h exposure of Caco-2 cells to anatase (50 nm) TiO₂ particles reduced cellular viability in a dose-dependent manner. The highest dose (50 µg/mL) of anatase (100 nm), rutile (50 nm), and P25 TiO₂ particles also reduced cellular viability in Caco-2 cells. The production of reactive oxygen species tended to increase in both types of cells, irrespective of the type of TiO₂ particle. Exposure of THP-1 macrophages to 50 µg/mL of anatase (50 nm) TiO₂ particles increased interleukin (IL)-1β expression level, and exposure of Caco-2 cells to 50 µg/mL of anatase (50 nm) TiO₂ particles also increased IL-8 expression. The results indicated that anatase TiO₂ nanoparticles induced inflammatory responses compared with other TiO₂ particles. Further studies are required to determine the in vivo relevance of these findings to avoid the hazards of ingested particles.
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Journal of Nanoparticle Research 18(3) 1-14 2016年3月1日 査読有り© 2016, Springer Science+Business Media Dordrecht. Titanium dioxide (TiO2) particles are used for surface coating and in a variety of products such as inks, fibers, food, and cosmetics. The present study investigated possible respiratory and cardiovascular effects of TiO2 particles in workers exposed to this particle at high concentration in a factory in China. The diameter of particles collected on filters was measured by scanning electron microscopy. Real-time size-dependent particle number concentration was monitored in the nostrils of four workers using condensation particle counter and optical particle counter. Electrocardiogram was recorded using Holter monitors for the same four workers to record heart rate variability. Sixteen workers underwent assessment of the respiratory and cardiovascular systems. Mass-based individual exposure levels were also measured with personal cascade impactors. The primary particle diameter ranged from 46 to 562 nm. Analysis of covariance of the pooled data of the four workers showed that number of particles with a diameter <300 nm was associated positively with total number of N–N and negatively with total number of increase or decrease in successive RR intervals greater than 50 ms (RR50+/−) or percentage of RR 50+/− that were parameters of parasympathetic function. The total mass concentration was 9.58–30.8 mg/m3 during work, but significantly less before work (0.36 mg/m3). The clear abnormality in respiratory function was not observed in sixteen workers who had worked for 10 months to 13 years in the factory. The study showed that exposure to particles with a diameter <300 nm might affect HRV in workers handling TiO2 particles. The results highlight the need to investigate the possible impact of exposure to nano-scaled particles on the autonomic nervous system.
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Scientific Reports 5 17855 2015年12月9日 査読有りJapan has often been viewed as an Asian country that possesses a genetically homogenous community. The basis for partitioning the country into prefectures has largely been geographical, although cultural and linguistic differences still exist between some of the districts/prefectures, especially between Okinawa and the mainland prefectures. The Major Histocompatibility Complex (MHC) region has consistently emerged as the most polymorphic region in the human genome, harbouring numerous biologically important variants nevertheless the presence of population-specific long haplotypes hinders the imputation of SNPs and classical HLA alleles. Here, we examined the extent of genetic variation at the MHC between eight Japanese populations sampled from Okinawa, and six other prefectures located in or close to the mainland of Japan, specifically focusing at the haplotypes observed within each population, and what the impact of any variation has on imputation. Our results indicated that Okinawa was genetically farther to the mainland Japanese than were Gujarati Indians from Tamil Indians, while the mainland Japanese from six prefectures were more homogeneous than between northern and southern Han Chinese. The distribution of haplotypes across Japan was similar, although imputation was most accurate for Okinawa and several mainland prefectures when population-specific panels were used as reference.
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DIABETOLOGIA 58(12) 2781-2790 2015年12月 査読有りAims/hypothesis To investigate epigenetic regulation of the plasma concentration of resistin, we performed an epigenome-wide association study for this variable and DNA methylation (DNAm) in an elderly Japanese cohort and then assessed the relation of single nucleotide polymorphisms (SNPs) associated with the plasma resistin concentration to DNAm level at identified sites. Methods The association of plasma resistin level with DNAm status was examined in 191 nondiabetic elderly men with the Illumina Infinium HumanMethylation450 BeadChip array. The association between DNAm status at specific sites in the flanking region of the resistin gene (RETN) and RETN mRNA abundance was then evaluated with a public data set for 1202 monocyte samples from a multi-ethnic cohort. Finally, the association of DNAm status and SNPs in the promoter region of RETN was assessed in two cohorts comprising a total of 478 Japanese individuals. Results DNAm status at cg02346997 located in the RETN promoter region showed a negative genome-wide significant association with the plasma resistin level (p = 6.02 x 10(-10)). Four DNAm sites in the RETN promoter region including cg02346997 (p = 4.23 x 10(-70)) showed a negative genome-wide significant association with RETN mRNA abundance in monocytes. Furthermore, the number of minor alleles of the RETN promoter SNPs rs34861192 and rs3219175 was negatively associated with DNAm level at cg02346997 (p = 4.43 x 10(-17)). Conclusions/interpretation Our results suggest that RETN promoter SNPs might influence the circulating resistin level through an effect on DNAm at cg02346997 and on RETN mRNA abundance in monocytes.
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NATURE GENETICS 47(11) 1282-+ 2015年11月 査読有りWe carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
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Journal of nanoscience and nanotechnology 15(3) 2140-7 2015年3月 査読有りThe present study investigated the effects of exposure to metal oxide nanoparticles on vasculogenesis/angiogenesis using transgenic zebrafish. The study also examined the potential mechanisms involved in those effects using human umbilical vein endothelial cells (HUVEC). TG (nacre/fli1:EGFP) zebrafish were exposed to nano-sized titanium dioxide (TiO2), silica dioxide (SiO2), and copper oxide (CuO) particles at 0.01, 1 and 100 µg/ml concentrations from 1 to 5 dpf (day-post-fertilization). Angiogenesis was evaluated morphologically at the end of exposure. Exposure to CuO nanoparticles reduced the number of transversely-running subintestinal vessels in TG zebrafish. Exposure to CuO nanoparticles down-regulated the expression of vascular endothelial growth factor (VEGF) and VEGF receptor in endothelial cells sorted by Fluorescence Activated Cell Sorter (FACS). Exposure of HUVEC to CuO nanoparticles reduced cell viability and increased apoptotic index in a dose-dependent manner. The results suggested that CuO nanoparticles inhibit vasculogenesis through reduction of VEGF expression and induction of apoptosis.
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Toxicology and applied pharmacology 282(2) 151-60 2015年1月15日 査読有り1-Bromopropane (1-BP) is neurotoxic in both experimental animals and human. To identify phosphorylated modification on the unrecognized post-translational modifications of proteins and investigate their role in 1-BP-induced neurotoxicity, changes in hippocampal phosphoprotein expression levels were analyzed quantitatively in male F344 rats exposed to 1-BP inhalation at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks. Hippocampal protein extracts were analyzed qualitatively and quantitatively by Pro-Q Diamond gel staining and SYPRO Ruby staining coupled with two-dimensional difference in gel electrophoresis (2D-DIGE), respectively, as well as by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to identify phosphoproteins. Changes in selected proteins were further confirmed by Manganese II (Mn(2+))-Phos-tag SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Bax and cytochrome c protein levels were determined by western blotting. Pro-Q Diamond gel staining combined with 2D-DIGE identified 26 phosphoprotein spots (p<0.05), and MALDI-TOF/MS identified 18 up-regulated proteins and 8 down-regulated proteins. These proteins are involved in the biological process of response to stimuli, metabolic processes, and apoptosis signaling. Changes in the expression of phosphorylated 14-3-3 θ were further confirmed by Mn(2+)-Phos-tag SDS-PAGE. Western blotting showed overexpression of Bax protein in the mitochondria with down-regulation in the cytoplasm, whereas cytochrome c expression was high in the cytoplasm but low in the mitochondria after 1-BP exposure. Our results suggest that the pathogenesis of 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process. Phosphoproteins identified in this study can potentially serve as biomarkers for 1-BP-induced neurotoxicity.
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Toxicology reports 2 692-701 2015年 査読有りZinc oxide (ZnO) nanoparticles have been widely used in industry, cosmetics, and biomedicine. Recent studies suggested that these nanoparticles could have a major impact on the cardiovascular system. Endothelial progenitor cells (EPCs) contribute to postnatal endothelial repair and regeneration. The present study dissected the effects of ZnO nanoparticles on vasculogenesis using human endothelial colony forming cells (ECFCs), which participate in post-natal vasculogenesis. Two types of ZnO particles were used (nano and micro), in addition to zinc chloride solutions with zinc ion concentrations equal to those in ZnO nanoparticles. Twenty-four-hour exposure induced cytotoxicity in a dose-dependent manner and increased ECFCs apoptosis in all groups. The exposure also reduced the functional capacity of ECFCs on Matrix gel to form tubules, compared with the control cells. These effects were associated with downregulation of expression of vascular endothelial growth factor receptor, VEGFR2 and CXC chemokine receptor, CXCR4. The results suggest that ZnO nanoparticles suppress vasculogenesis from ECFCs through downregulation of the expression of receptors related to vasculogenesis. These effects are based the concentration of released Zn(II).
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Journal of occupational health 57(6) 548-54 2015年 査読有りOBJECTIVES: It has been reported that 1,2-Dichloropropane (DCP) induced cholangiocarcinoma (CCA) in offset color proof-printing workers. However, exposure to DCP by inhalation or gavage for 2 year did not induce CCA in mice and rats. The present study mapped the hepatic distribution of GST, which is known to activate dihalogenated alkanes, and proliferative and fibrotic changes in bile ducts in various species to find the most appropriate animal model of DCP-induced CCA. METHODS: First, 12 each of C57BL/6J mice, Balb/cA mice, F344 rats, Syrian hamsters, and guinea pigs were divided into four equal groups and exposed to DCP at 0, 300, 1,000, or 3,000 ppm 8 hours/day for 7 days. Second, 32 Balb/cA mice and 32 Syrian hamsters were each divided into four equal groups and exposed to DCP at 0, 200, 400, and 800 ppm 6 hours/day for 14 days. After the last exposure, the animals were decapitated, and the livers were dissected out for histopathological evaluation. Immunostaining was conducted to determine the distribution of GSTT1, GSTM1, and GSTPi, as well as the expression of proliferation marker Ki67. RESULTS: GSTT1, GSTM1, and GSTPi were expressed in both hepatocytes and bile duct cells in all control and exposed animals. There was no clear difference in the expression of Ki67 between the exposed groups and the control. No fibrotic changes were observed in any species or strains examined. CONCLUSIONS: Expression of GSTT1 or other GST isozymes might not explain the difference in sensitivity of hepatocytes and the bile duct to DCP between humans and rodents.
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International journal of molecular sciences 16(1) 660-76 2014年12月30日 査読有りZinc oxide (ZnO) nanoparticles are widely used in various products, and the safety evaluation of this manufactured material is important. The present study investigated the inflammatory and fibrotic effects of pulmonary exposure to ZnO nanoparticles in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by constant subcutaneous infusion of bleomycin (BLM). Female C57BL/6Jcl mice were divided into BLM-treated and non-treated groups. In each treatment group, 0, 10, 20 or 30 µg of ZnO nanoparticles were delivered into the lungs through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and the lungs were sampled at Day 10 or 14 after administration. Pulmonary exposure by a single bolus of ZnO nanoparticles resulted in severe, but transient inflammatory infiltration and thickening of the alveolar septa in the lungs, along with the increase of total and differential cell counts in BLAF. The BALF level of interleukin (IL)-1β and transforming growth factor (TGF)-β was increased at Day 10 and 14, respectively. At Day 10, the synergistic effect of BLM and ZnO exposure was detected on IL-1β and monocyte chemotactic protein (MCP)-1 in BALF. The present study demonstrated the synergistic effect of pulmonary exposure to ZnO nanoparticles and subcutaneous infusion of BLM on the secretion of pro-fibrotic cytokines in the lungs.
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Toxicology and applied pharmacology 278(1) 16-25 2014年7月1日 査読有りMetal oxide nanoparticles are widely used in industry, cosmetics, and biomedicine. However, the effects of exposure to these nanoparticles on the cardiovascular system remain unknown. The present study investigated the effects of nanosized TiO2 and ZnO particles on the migration and adhesion of monocytes, which are essential processes in atherosclerogenesis, using an in vitro set-up of human umbilical vein endothelial cells (HUVECs) and human monocytic leukemia cells (THP-1). We also examined the effects of exposure to nanosized metal oxide particles on macrophage cholesterol uptake and foam cell formation. The 16-hour exposure to ZnO particles increased the level of monocyte chemotactic protein-1 (MCP-1) and induced the migration of THP-1 monocyte mediated by increased MCP-1. Exposure to ZnO particles also induced adhesion of THP-1 cells to HUVECs. Moreover, exposure to ZnO particles, but not TiO2 particles, upregulated the expression of membrane scavenger receptors of modified LDL and increased cholesterol uptake in THP-1 monocytes/macrophages. In the present study, we found that exposure to ZnO particles increased macrophage cholesterol uptake, which was mediated by an upregulation of membrane scavenger receptors of modified LDL. These results suggest that nanosized ZnO particles could potentially enhance atherosclerogenesis and accelerate foam cell formation.
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EXPERIMENTAL DERMATOLOGY 23(6) 424-425 2014年6月 査読有りThe incidence of cutaneous malignant melanoma is increasing at a greater rate than that of any other cancer in the world. However, an effective therapy for malignant melanoma has not been established. Recently, some studies have shown an antitumor effect of non-equilibrium atmospheric pressure plasmas (NEAPPs) in vitro. Here, we examined the in vivo effect of NEAPP on cell cycle regulators, key elements for malignant transformation, in spontaneously developed benign melanocytic tumors in a hairless animal model. NEAPP irradiation decreased expression levels of cell cycle promoters, Cyclin D1, E1 and E2, and increased expression level of a cell cycle repressor, p27KIP1. Cyclin D1, E1 and E2 and p27KIP expression levels were associated with malignant transformation of the benign tumor in the animal model. Our results suggest that NEAPP irradiation suppresses malignant transformation of a benign melanocytic tumor via control of the expression levels of cell cycle regulators.
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EUROPEAN JOURNAL OF DERMATOLOGY 24(3) 392-394 2014年5月 査読有り
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MOLECULAR MEDICINE REPORTS 9(3) 808-812 2014年3月 査読有りWe have previously shown that the CT polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with myocardial infarction. Considering that dyslipidemia is a significant risk factor for coronary heart disease, it was hypothesized that the association between rs6929846 of BTN2A1 and myocardial infarction may be attributable, at least in part, to its effect on the susceptibility to dyslipidemia. The purpose of the present study was to examine a possible association of rs6929846 of BTN2A1 with dyslipidemia in community-dwelling individuals. The study subjects were comprised of 5,958 community-dwelling individuals (2,909 subjects with dyslipidemia and 3,049 controls) who were recruited into a population-based cohort study in Inabe, Japan. Dyslipidemia was defined by a serum concentration of triglycerides of 1.65 mmol/l, a serum high-density lipoprotein-cholesterol concentration of <1.04 mmol/l or a serum low-density lipoprotein (LDL)-cholesterol concentration of 3.64 mmol/l. A comparison of the allele frequencies or genotype distributions by the (2) test revealed that rs6929846 of BTN2A1 was significantly associated with dyslipidemia (P<0.05). A multivariable logistic regression analysis adjusted for age, gender, body mass index, smoking status and the prevalence of diabetes mellitus revealed that rs6929846 of BTN2A1 was significantly (dominant model; P=2.4x10(-4); odds ratio, 1.29) associated with dyslipidemia, with the minor T allele representing a risk for this condition. Among all the individuals, the serum concentrations of total cholesterol, triglycerides and LDL-cholesterol were significantly greater for individuals in the combined CT and TT genotype groups than for those with the CC genotype. BTN2A1 may thus be a susceptibility gene for dyslipidemia in community-dwelling individuals.
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HUMAN MOLECULAR GENETICS 23(4) 1108-1119 2014年2月 査読有りBlood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P 3.0 10(14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P 1.2 10(7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P 6.8 10(165)), ADIPOQ (P 1.8 10(22)), PEPD (P 3.6 10(12)), CMIP (P 2.1 10(10)), ZNF664 (P 2.3 10(7)) and GPR109A (P 7.4 10(6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (P-initial 0.020; P-conditional 7.0 10(7)). We further confirmed the independence of two pairs of closely located loci (2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P 3.3 10(4)), high density lipoprotein cholesterol (HDL-C, P 4.9 10(4)) and body mass index (BMI)-adjusted waisthip ratio (P 9.8 10(3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
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Diabetology & metabolic syndrome 6(1) 8-8 2014年1月27日 査読有りBACKGROUND: The etiology of the metabolic syndrome is complex, and is determined by the interplay of both genetic and environmental factors. The present study was designed to identify genes and proteins in the adipose tissues with altered expression in the spontaneously hypertensive/NIH -corpulent rat, SHR/NDmcr-cp (CP) and to find possible molecular targets associated with the pathogenesis or progression of obesity related to the metabolic syndrome. METHODS: We extracted RNAs and proteins from the epididymal adipose tissues in CP, SHR/Lean (Lean), and Wistar Kyoto (WKY) rats and performed microarray analysis and two-dimensional difference in gel electrophoresis (2D-DIGE) linked to a matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS). RESULTS: The results showed different mRNA and protein expression levels in the adipose tissue: oligo DNA microarray identified 33 genes that were significantly (P < 0.01) up-regulated and 17 genes significantly down-regulated in CP compared with WKY and Lean rats at both 6 and 25 weeks of age. The affected genes-proteins were associated with lipolytic enzymes stimulated by peroxisome proliferator-activated receptor (PPAR) signaling. Further analysis using the 2D-DIGE connected with MALDI-TOF/TOF analysis, the expression of monoglyceride lipase (MGLL) was significantly up-regulated and that of carboxylesterase 3 (CES3) was significantly down-regulated in 6- and 25-week-old CP compared with age-matched control (WKY and Lean rats). CONCLUSIONS: Our results suggest the possible involvement of proteins associated with adipocyte lipolysis in obesity related to the metabolic syndrome.
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Transactions of the Materials Research Society of Japan 2014年 査読有り
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CARDIOVASCULAR PATHOLOGY 23(1) 43-49 2014年1月 査読有りBackground: Cardiac dysfunction is reported in patients with the metabolic syndrome. We assessed the effects of high-phosphorus and zinc-free diet on cardiovascular system in spontaneously hypertensive rats (SHR)/NDmcr-cp (SHR/cp), a rat model of the metabolic syndrome. We also investigated the effects of N-acetyl-L-cysteine (NAC), an antioxidant, on the development of cardiac dysfunction under such conditions. Methods: Male SHR/cp and control [Wistar Kyoto (WKY)] rats were divided into three groups and fed control diet (P 0.3% w/w, Zn 0.2% w/w) or high-phosphorus and zinc-free (P 1.2% w/w, Zn 0.0% w/w) diet. The latter group was treated with either NAC (1.5 mg/g per day) or vehicle from 6 to 18 weeks of age (n=6 or 8 for each group). Results: High-phosphate and zinc-free diet increased systolic blood pressure in both WKY and SHR/cp. Echocardiography showed that high-phosphate and zinc-free diet markedly reduced left ventricular systolic and diastolic function in SHR/cp. Histopathologically, the same diet induced severe myocardial fibrosis in SHR/cp, and this effect was prevented by NAC. Whereas treatment with NAC prevented diastolic dysfunction induced by the same diet in WKY, it only improved systolic function but not diastolic function in SHR/cp. Conclusions: High-phosphate and zinc-free diet induced hypertension and cardiac dysfunction. These changes hamper the protective effects of NAC in the metabolic syndrome. Summary: The present study showed that consumption of high-phosphorus and zinc-free diet increased the myocardial expression of connective tissue growth factor and reduced the expression of metallothionein, which enhanced the development of severe cardiac dysfunction in rats with the metabolic syndrome. The results suggest that the metabolic syndrome seems to aggravate cardiac dysfunction and hamper the protective effects of antioxidant, NAC. (C) 2014 Published by Elsevier Inc.
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Industrial health 52(1) 54-65 2014年 査読有りNanomaterials tend to agglomerate in aqueous media, resulting in inaccurate safety assessment of the biological response to these substances. The present study searched for suitable dispersion methods for the preparation of nanomaterial suspensions. Titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles were dispersed in a biocompatible dispersion medium by direct probe-type sonicator and indirect cup-type sonicator. Size characterization was completed using dynamic light scattering and transmission electron microscopy. A series of dispersion time and output power, as well as two different particle concentrations were tested. Microscopic contamination of metal titanium that broke away from the tip of the probe into the suspension was found. Size of agglomerated nanoparticles decreased with increase in sonication time or output power. Particle concentration did not show obvious effect on size distribution of TiO2 nanoparticles, while significant reduction of secondary diameter of ZnO was observed at higher concentration. A practicable protocol was then adopted and sizes of well-dispersed nanoparticles increased by less than 10% at 7 d after sonication. Multi-walled carbon nanotubes were also well dispersed by the same protocol. The cup-type sonicator might be a useful alternative to the traditional bath-type sonicator or probe-type sonicator based on its effective energy delivery and assurance of suspension purity.
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CIRCULATION-CARDIOVASCULAR GENETICS 6(6) 569-578 2013年12月 査読有りBackground Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and offer the opportunity for disease prevention. Methods and Results We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alstrom syndrome 1 gene (ALMS1) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide polymorphisms of the ALMS1 promoter region were significantly associated with early-onset MI in both Japanese and Korean populations. Moreover, direct sequencing of the ALMS1 coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI. Conclusions The glutamic acid repeat polymorphism of ALMS1 identified in the present study may provide insight into the pathogenesis of early-onset MI.
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INDUSTRIAL HEALTH 56(6) 965-994 2013年12月 査読有り
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Circulation. Cardiovascular genetics 6(6) 569-78 2013年12月 査読有りBACKGROUND: Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and offer the opportunity for disease prevention. METHODS AND RESULTS: We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alström syndrome 1 gene (ALMS1) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide polymorphisms of the ALMS1 promoter region were significantly associated with early-onset MI in both Japanese and Korean populations. Moreover, direct sequencing of the ALMS1 coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI. CONCLUSIONS: The glutamic acid repeat polymorphism of ALMS1 identified in the present study may provide insight into the pathogenesis of early-onset MI.
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Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 65(7-8) 1173-82 2013年11月 査読有りConsumption of relatively high amounts of processed food can result in abnormal nutritional status, such as zinc deficiency or phosphorus excess. Moreover, hyperphosphatemia and hypozincemia are found in some patients with diabetic nephropathy and metabolic syndrome. The present study investigated the effects of high-phosphorus/zinc-free diet on the reproductive function of spontaneously hypertensive rats/NDmcr-cp (SHR/cp), a model of the metabolic syndrome. We also investigated the effects of antioxidant, N-acetyl-l-cysteine (NAC), on testicular dysfunction under such conditions. Male SHR/cp and control rats (Wistar Kyoto rats, WKY) were divided into three groups; rats fed control diet (P 0.3%, w/w; Zn 0.2%, w/w), high-phosphorus and zinc-deficient diet (P 1.2%, w/w; Zn 0.0%, w/w) with vehicle, or high-phosphorus and zinc-deficient diet with NAC (1.5mg/g/day) for 12 weeks (n=6 or 8 rats/group). The weights of testis and epididymis were significantly reduced by high-phosphate/zinc-free diet in both SHR/cp and WKY. The same diet significantly reduced caudal epididymal sperm count and motility and induced histopathological changes in the testis in both strains. Treatment with NAC provided significant protection against the toxic effects of the diet on testicular function in WKY, but not in SHR/cp. The lack of the protective effects of NAC on impaired spermatogenesis in SHR/cp could be due to the more pronounced state of oxidative stress observed in these rats compared with WKY.
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Biomedical reports 1(6) 868-872 2013年11月 査読有り
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Clinical and experimental pharmacology & physiology 40(7) 443-8 2013年7月 査読有りObesity is associated with high chronic cardiac workload due to the need to supply more blood to peripheral tissue, and frequently leads to left ventricular (LV) dysfunction. The present study examined serial changes in cardiac function in the SHR/NDmcr-cp (SHR/cp) strain, an experimental model of obesity plus hypertension and metabolic syndrome. Transthoracic echocardiography was used to define cardiac dimensions and function in male spontaneously hypertensive rats (SHR/lean), SHR/cp and Wistar-Kyoto rats. We also assessed age-related changes in plasma and LV adipocytokine levels in this model. Although there were no significant differences in LV end-diastolic diameter and end-systolic diameter among the three rat strains until 24 weeks of age, these parameters were significantly higher and LV fractional shortening (%FS) was significantly lower in SHR/cp compared with SHR/lean at 32 weeks of age. At the same age, pronounced interstitial fibrosis and infiltration of macrophages and T lymphocytes into the LV was noted in SHR/cp relative to the other strains. In the myocardium, adiponectin levels were significantly lower and resistin levels and the expression of proinflammatory cytokines (tumour necrosis factor-α and interleukin-6) were significantly higher in SHR/cp than SHR/lean at 32 weeks of age. Using echocardiography, we demonstrated reduced systolic function in 32-week-old SHR/cp. Changes in myocardial cytokine concentrations could be involved in worsening of cardiac function in our animal model of metabolic syndrome.
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JOURNAL OF MEDICAL GENETICS 50(6) 410-418 2013年6月 査読有りBackground Although genome-wide association studies (GWASs) have implicated several genes in the predisposition to chronic kidney disease (CKD) in Caucasian or African American populations, the genes that confer susceptibility to CKD in Asian populations remain to be identified definitively. We performed a GWAS to identify genetic variants that confer susceptibility to CKD in Japanese individuals. Methods 3851 Japanese individuals from three independent subject panels were examined. Subject panels A, B, and C comprised 252, 910, and 190 individuals with CKD and 249, 838, and 1412 controls, respectively. A GWAS for CKD was performed in subject panel A. Results Five single nucleotide polymorphisms (SNPs) at chromosome 3q28, ALPK1, FAM78B, and UMODL1 were significantly (false discovery rate<0.05) associated with CKD by the GWAS. The relation of these five SNPs and of an additional 22 SNPs at these loci to CKD was examined in subject panel B, revealing that rs9846911 at 3q28 was significantly associated with CKD in all individuals and that rs2074381 and rs2074380 in ALPK1 were associated with CKD in individuals with diabetes mellitus. These three SNPs were further examined in subject panel C, revealing that rs2074381 and rs2074380 were significantly associated with CKD. For subject panels B and C combined, rs9846911 was significantly associated with CKD in all individuals and rs2074381 and rs2074380 were associated with CKD in diabetic individuals. Conclusions Chromosome 3q28 may be a susceptibility locus for CKD in Japanese individuals, and ALPK1 may be a susceptibility gene for CKD in such individuals with diabetes mellitus.
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ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE 18(3) 177-184 2013年5月 査読有りOxidative stress and inflammation are implicated in cardiovascular diseases such as atherosclerosis, reperfusion injury, hypertension, and heart failure. High levels of oxidative stress resulting from increased cardiac generation of reactive oxygen species (ROS) is thought to contribute to contractile and endothelial dysfunction, apoptosis and necrosis of myocytes, and extracellular matrix remodeling in the heart. ROS activate several transcription factors known as redox-regulated transcription factors, and these transcription factors play important roles in the pathophysiology of cardiovascular diseases. This review focuses on the pathological roles of environmental and redox stresses in cardiovascular diseases, especially severe cardiac dysfunction and the transition from compensated hypertrophy to heart failure. The aryl hydrocarbon receptor (AHR) and NF-E2 p45-related factor (Nrf2) are transcription factors involved in the regulation of drug-metabolizing enzymes. AHR has been studied as a receptor for environmental contaminants and as a mediator of chemical toxicity. However, other roles for AHR in cardiac and vascular development have recently been described. Moreover, Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes. The roles of these transcription factors, AHR and Nrf2 in angiogenesis are also discussed in this review.
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Toxicology 304 76-82 2013年2月8日 査読有りPURPOSE: 1-Bromopropane (1-BP) intoxication is associated with depression and cognitive and memory deficits. The present study tested the hypothesis that 1-BP suppresses neurogenesis in the dentate gyrus, which is involved in higher cerebral function, in adult rats. METHODS: Four groups of 12 male Wistar rats were exposed to 0, 400, 800, 1000 ppm 1-BP, 8 h/day for 7 days. Another four groups of six rats each were exposed to 0, 400, 800 and 1000 ppm 1-BP for 2 weeks followed by 0, 200, 400 and 800 ppm for another 2 weeks, respectively. Another four groups of six rats each were exposed to 0, 200, 400 and 800 ppm 1-BP for 4 weeks. Rats were injected with 5-bromo-2'-deoxy-uridine (BrdU) after 4-week exposure at 1000/800 ppm to examine neurogenesis in the dentate gyrus by immunostaining. We measured factors known to affect neurogenesis, including monoamine levels, and mRNA expression levels of brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor (GR), in different brain regions. RESULTS: BrdU-positive cells were significantly lower in the 800/1000 ppm-4-week group than the control. 1-Week exposure to 1-BP at 800 and 1000 ppm significantly reduced noradrenalin level in the striatum. Four-week exposure at 800 ppm significantly decreased noradrenalin levels in the hippocampus, prefrontal cortex and striatum. 1-BP also reduced hippocampal BDNF and GR mRNA levels. CONCLUSION: Long-term exposure to 1-BP decreased neurogenesis in the dentate gyrus. Downregulation of BDNF and GR mRNA expression and low hippocampal norepinephrine levels might contribute, at least in part, to the reduced neurogenesis.
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Journal of occupational health 55(1) 29-38 2013年 査読有りOBJECTIVES: Human cases of 1-bromopropane (1-BP) toxicity showed ataxic gait and cognitive dysfunction, whereas rat studies showed pyknotic shrinkage in cerebellar Purkinje cells and electrophysiological changes in the hippocampus. The present study investigated the effects of 1-BP on astrocytes and oligodendrocytes in the rat cerebellum and hippocampus to find sensitive markers of central nervous system toxicity. METHODS: Forty-eight F344 rats were divided into four equal groups and exposed to 1-BP at 0, 400, 800 and 1,000 ppm for 8 h/day; 7 days/week, for 4 weeks. Nine and three rats per group were used for biochemical and histopathological studies, respectively. RESULTS: Kluver-Barrera staining showed pyknotic shrinkage in the cytoplasm of Purkinje cells and nuclei of granular cells in the cerebellum at 1,000 ppm. Immunohistochemical analysis showed increased length of glial fibrillary acidic protein (GFAP)-positive processes of astrocytes in the cerebellum, hippocampus and dentate gyrus at 800 and 1,000 ppm. The myelin basic protein (MBP) level was lower at 1,000 ppm. The numbers of astrocytes and granular cells per tissue volume increased at 400 ppm or higher. CONCLUSION: The present study showed that elongation of processes of astrocytes accompanies degeneration of granular cells and Purkinje cells in the cerebellum of the rats exposed to 1-BP. The decrease in MBP and number of oligodendrocytes suggest adverse effects on myelination. The increase in astrocyte population per tissue volume in the cerebellum might be a sensitive marker of 1-BP neurotoxicity, but the underlying mechanism for this change remains elusive.
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Toxicology 302(1) 18-24 2012年12月8日 査読有り1-Bromopropane (1-BP), an alternative to ozone-depleting solvents, is reported to exhibit neurotoxicity and reproductive toxicity in animals and humans. However, the underlying mechanism of the toxicity remains elusive. This study was designed to identify the microglial changes and oxidative stress in the central nervous system (CNS) after 1-BP exposure. Four groups of Wistar-ST rats (n=12 each) were exposed to 0, 400, 800 and 1000ppm of 1-BP, 8h/day for 28 consecutive days. The cerebellum was dissected out in 9 rats of each group and subjected to biochemical analysis, while the brains of the remaining 3 rats were examined immunohistochemically. Exposure to 1-BP increased the levels of oxidative stress markers [thiobarbituric acid reactive substances (TBARS), protein carbonyl and reactive oxygen species (ROS)] in a dose-dependent manner. Likewise, there was also 1-BP dose-dependent increase in nitric oxide (NO) and dose-dependent decrease in protein concentrations in the cerebellum. Immunohistochemical studies showed 1-BP-induced increase in cd11b/c-positive microglia area in the white matter of the cerebellar hemispheres. The results showed that exposure to 1-BP induced morphological change in the microglia and oxidative stress, suggesting that these effects are part of the underlying neurotoxic mechanism of 1-BP in the CNS.
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Nutrition & metabolism 9(1) 87-87 2012年9月21日 査読有りUNLABELLED: BACKGROUND: It is difficult to study the mechanisms of the metabolic syndrome in humans due to the heterogeneous genetic background and lifestyle. The present study investigated changes in the gene and protein profiles in an animal model of the metabolic syndrome to identify the molecular targets associated with the pathogenesis and progression of obesity related to the metabolic syndrome. METHODS: We extracted mRNAs and proteins from the liver tissues of 6- and 25-week-old spontaneously hypertensive/NIH -corpulent rat SHR/NDmcr-cp (CP), SHR/Lean (Lean) and Wistar Kyoto rats (WKY) and performed microarray analysis and two-dimensional difference in gel electrophoresis (2D-DIGE) linked to a matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS). RESULTS: The microarray analysis identified 25 significantly up-regulated genes (P < 0.01; log10 > 1) and 31 significantly down-regulated genes (P < 0.01; log10 < -1) in 6- and 25-week-old CP compared with WKY and Lean. Several of these genes are known to be involved in important biological processes such as electron transporter activity, electron transport, lipid metabolism, ion transport, transferase, and ion channel activity. MALDI-TOF/TOF MS identified 31 proteins with ±1.2 fold change (P < 0.05) in 6- and 25-week-old CP, compared with age-matched WKY and Lean. The up-regulated proteins are involved in metabolic processes, biological regulation, catalytic activity, and binding, while the down-regulated proteins are involved in endoplasmic reticulum stress-related unfolded protein response. CONCLUSION: Genes with significant changes in their expression in transcriptomic analysis matched very few of the proteins identified in proteomics analysis. However, annotated functional classifications might provide an important reference resource to understand the pathogenesis of obesity associated with the metabolic syndrome.
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Toxicology and applied pharmacology 263(1) 44-52 2012年8月15日 査読有り1-Bromopropane (1-BP) is neurotoxic in both experimental animals and humans. Previous proteomic analysis of rat hippocampus implicated alteration of protein expression in oxidative stress, suggesting that oxidative stress plays a role in 1-BP-induced neurotoxicity. To understand this role at the protein level, we exposed male F344 rats to 1-BP at 0, 400, or 1000 ppm for 8h/day for 1 week or 4 weeks by inhalation and quantitated changes in hippocampal protein carbonyl using a protein carbonyl assay, two-dimensional gel electrophoresis (2-DE), immunoblotting, and matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF-TOF/MS). Hippocampal reactive oxygen species and protein carbonyl were significantly increased, demonstrating 1-BP-associated induction of oxidative stress and protein damage. MALDI-TOF-TOF/MS identified 10 individual proteins with increased carbonyl modification (p < 0.05; fold-change ≥ 1.5). The identified proteins were involved in diverse biological processes including glycolysis, ATP production, tyrosine catabolism, GTP binding, guanine degradation, and neuronal metabolism of dopamine. Hippocampal triosephosphate isomerase (TPI) activity was significantly reduced and negatively correlated with TPI carbonylation (p < 0.001; r = 0.83). Advanced glycation end-product (AGE) levels were significantly elevated both in the hippocampus and plasma, and hippocampal AGEs correlated negatively with TPI activity (p < 0.001; r = 0.71). In conclusion, 1-BP-induced neurotoxicity in the rat hippocampus seems to involve oxidative damage of cellular proteins, decreased TPI activity, and elevated AGEs.
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Toxicology and applied pharmacology 257(1) 93-101 2011年11月15日 査読有り1-Bromopropane (1-BP) is a compound used as an alternative to ozone-depleting solvents and is neurotoxic both in experimental animals and human. However, the molecular mechanisms of the neurotoxic effects of 1-BP are not well known. To identify the molecular mechanisms of 1-BP-induced neurotoxicity, we analyzed quantitatively changes in protein expression in the hippocampus of rats exposed to 1-BP. Male F344 rats were exposed to 1-BP at 0, 400, or 1000 ppm for 8h/day for 1 or 4 weeks by inhalation. Two-dimensional difference in gel electrophoresis (2D-DIGE) combined with matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) were conducted to detect and identify protein modification. Changes in selected proteins were further confirmed by western blot. 2D-DIGE identified 26 proteins with consistently altered model (increase or decrease after both 1- and 4-week 1-BP exposures) and significant changes in their levels (p<0.05; fold change ≥ ± 1.2) at least at one exposure level or more compared with the corresponding controls. Of these proteins, 19 were identified by MALDI-TOF-TOF/MS. Linear regression analysis of 1-BP exposure level identified 8 differentially expressed proteins altered in a dose-dependent manner both in 1- and 4-week exposure experiments. The identified proteins could be categorized into diverse functional classes such as nucleocytoplasmic transport, immunity and defense, energy metabolism, ubiquitination-proteasome pathway, neurotransmitter and purine metabolism. Overall, the results suggest that 1-BP-induced hippocampal damage involves oxidative stress, loss of ATP production, neurotransmitter dysfunction and inhibition of ubiquitination-proteasome system.
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The AH Receptor in Biology and Toxicology 413-421 2011年11月10日 査読有り
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Journal of occupational and environmental medicine 53(10) 1095-8 2011年10月 査読有り
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Toxicology 285(1-2) 67-71 2011年7月11日 査読有り1-Bromopropane (1-BP) has been used as an alternative to ozone-depleting solvents. Previous studies showed that 1-BP is neurotoxic in animals and humans. In humans, exposure to 1-BP caused various neurological and neurobehavioral symptoms or signs including depressive or irritated mood. However, the neurobiological changes underlying the depressive symptoms induced by 1-BP remain to be determined. The depressive symptoms are thought to be associated with degeneration of axons containing noradrenaline and serotonin. Based on this hypothesis, the present study examined the effects of repeated exposure to 1-BP on serotonergic and noradrenergic axons. Exposure to 1-BP induced dose-dependent decreases in the density of noradrenergic axons in the rat prefrontal cortex, but no apparent change in the density of serotonergic axons. The results suggest that depressive symptoms in workers exposed to 1-BP are due, at least in part, to the degeneration of noradrenergic axons in the brain.
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DIABETES RESEARCH AND CLINICAL PRACTICE 92(3) E61-E65 2011年6月 査読有りWe evaluated the ratio of adiponectin level to homeostasis model assessment of insulin resistance (A/H ratio) as a risk marker for metabolic syndrome (MetS) and each of its components. The A/H ratio may prove to be a powerful index for evaluation of risk for MetS and each of its components. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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EUROPEAN JOURNAL OF HUMAN GENETICS 19(3) 262-269 2011年3月 査読有りAdiponectin is an adipocyte-derived protein that is down-regulated in obesity-linked disorders. Variants of the adiponectin gene (ADIPOQ) have been shown to affect adiponectin level. We have now examined the relation of polymorphisms of ADIPOQ to adiponectin concentration and to metabolic disorders in the Kita-Nagoya Genomic Epidemiology study, a population-based study of elderly Japanese. The genomic region including ADIPOQ was genotyped for 30 single nucleotide polymorphisms in 500 subjects of a screening population with the use of a fluorescence-or colorimetry-based allele-specific DNA primer-probe assay system. Four polymorphisms were then selected for genotyping in an additional 2797 subjects. Serum adiponectin level was negatively associated with metabolic abnormalities after adjustment for age and sex. The minor alleles of the rs1656930, Ile164Thr, and rs9882205 polymorphisms were associated with a low serum adiponectin level. Whereas the minor alleles of rs1656930 and rs9882205 were common (minor allele frequency of 6.2 and 38.5%, respectively), that of Ile164Thr was rare (0.9%). The minor allele of rs1656930 was positively associated with systolic blood pressure and the prevalence of hypertension. The association of rs1656930 with adiponectin level was replicated in an independent population. A subject with the 164Thr/Thr genotype had an extremely low serum adiponectin level (0.6 mu g/ml) and the phenotype of metabolic syndrome. Our results suggest that a common variant of ADIPOQ, the minor allele of rs1656930, is associated with hypoadiponectinemia and hypertension. Screening for a common genetic background underlying low adiponectin levels might provide important information for assessment and management of metabolic disorders. European Journal of Human Genetics (2011) 19, 262-269; doi:10.1038/ejhg.2010.201; published online 8 December 2010
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ATHEROSCLEROSIS 215(1) 145-152 2011年3月 査読有りObjective: We have performed a genome-wide association study (GWAS) to identify genetic variants that confer susceptibility to myocardial infarction (MI) in Japanese and Korean populations. Methods: A total of 17,447 Japanese or Korean individuals from four independent subject panels was examined. Japanese subject panels A, B, and C comprised 134 individuals with MI and 137 controls, 1431 individuals with MI and 3161 controls, and 643 individuals with MI and 1347 controls, respectively, whereas the Korean population comprised 1880 individuals with MI and 8714 controls. A GWAS for MI was performed in Japanese subject panel A with the use of the Affymetrix GeneChip Human Mapping 500K Array Set. Results: Seventy single nucleotide polymorphisms (SNPs) significantly (P < 1.0 x 10(-7)) associated with MI by the GWAS were examined further in Japanese subject panel B, revealing two SNPs (rs6929846 of BTN2A1, rs2569512 of ILF3) to be significantly (P < 0.0007) associated with MI. The rs6929846 SNP of BTN2A1, but not rs2569512 of ILF3, was also significantly associated with MI in Japanese subject panel C. However, the association of neither rs6929846 nor rs2569512 with MI was replicated in the Korean population. Conclusion: BTN2A1 may be a susceptibility gene for MI in Japanese individuals. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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Industrial health 49(5) 626-33 2011年 査読有りPleural plaques are asymptomatic focal thickenings of the pleura and considered the hallmark of asbestos exposure. However, it is often difficult to detect pleural plaques on chest x-rays (CXR). In a retrospective study, using chest CT scans of 140 Japanese asbestos-exposed construction workers who have probable or definite findings of pleural plaque on CXR; firstly, we proposed plaque morphology-based classification for CXR findings, and then we examined if those classified findings could be confirmed as pleural plaques on CT scans. Our morphology-based classification of pleural plaque findings included nine types. The percentages of confirmed pleural plaques on CT scans by type (number of confirmed pleural plaque on CT/number of observed on CXR) were 93% (40/43) for straight, 89% (56/63) for diamond, 88% (7/8) for double, 83% (19/23) for tapered medially, 80% (20/25) for parallel, 77% (23/30) for crescent, 79% (11/14) for tenting, 72% (18/25) for tapered-laterally (long type), and 0% (0/9) for tapered-laterally (short type). When added to the ILO classification, morphology-based classification of CXR pleural plaque findings makes its detection easier and hence chest radiograph continues to be a suitable tool for screening asbestos-related pleural plaques based on its simplicity, low radiation exposure, wide availability and cost-effectiveness.
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Arteriosclerosis, thrombosis, and vascular biology 30(8) 1553-61 2010年8月 査読有りOBJECTIVE: To investigate the potential role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in neovascularization with a murine surgical model of ischemia. METHODS AND RESULTS: The transcription factor Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes that contain an antioxidant response element. Ischemia was induced by femoral artery ligation in Nrf2-deficient (Nrf2(-/-)) and wild-type mice. Ischemia-induced neovascularization was enhanced in Nrf2(-/-) mice compared with that in wild-type mice. The expression of Nrf2 target genes for heme oxygenase 1 and thioredoxin 1 and the concentration of total glutathione in the ischemic hindlimb were reduced for Nrf2(-/-) mice compared with wild-type mice. The infiltration of inflammatory cells and the abundance of adhesion molecule mRNA were greater in the ischemic hindlimb of Nrf2(-/-) mice than in wild-type mice. The expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha, cyclooxygenase 2, and angiogenic factors in the ischemic hindlimb was also greater for Nrf2(-/-) mice than for wild-type mice. CONCLUSIONS: The ablation of Nrf2 promoted ischemia-induced neovascularization. This effect likely resulted from impaired antioxidant defense and increased accumulation of reactive oxygen species in endothelial cells; consequently, there was an enhanced inflammatory response.
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Journal of occupational and environmental medicine 52(8) 769-77 2010年8月 査読有りOBJECTIVES: To investigate the health effects of 1-bromopropane (1-BP) and its dose-dependency in 1-BP production factories in China. METHODS: Data of 60 female and 26 male workers in three 1-BP factories and the same number of age-, sex-, and region-matched controls were interviewed and examined. The time-weighed average exposure levels of individual workers were estimated. RESULTS: Regression analysis on exposure level showed dose-dependent increase in the distal latency of tibial nerve, threshold for vibration sense in toes, lactate dehydrogenase, thyroid stimulating hormone, and follicle stimulating hormone in female workers. The analysis also showed dose-dependent decrease in sensory nerve conduction velocity of the sural nerve, red blood cell, and hematocrit in female workers. CONCLUSIONS: The results indicate that exposure to 1-BP induces dose-dependent neurotoxicity in female workers.
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Toxicological sciences : an official journal of the Society of Toxicology 115(2) 596-606 2010年6月 査読有り1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity, and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Groups of 24 male Nrf2-null mice and 24 male wild-type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at 0, 100, or 300 ppm for 8 h/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of oxidized glutathione/reduced form of glutathione, and lower total glutathione content. The constitutive level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the messenger RNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate-cysteine synthetase (GcLc), glutathione reductase, and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.
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CIRCULATION JOURNAL 74(1) 163-170 2010年1月 査読有りBackground: Growth hormone-releasing peptide (GHRP) may act directly on the myocardium and improve left ventricular (LV) function, suggesting a potential new approach to the treatment of cardiomyopathic hearts. The present study tested the hypothesis that the beneficial cardiac effects of GHRP might include attenuation of myocardial oxidative stress. Methods and Results: Dilated cardiomyopathic TO-2 hamsters were injected with GHRP-2 (1 mg/kg) or saline from 6 to 12 weeks of age. F1B hamsters served as controls. Untreated TO-2 hamsters progressively developed LV dilation, wall thinning, and systolic dysfunction between 6 and 12 weeks of age. Marked myocardial fibrosis was apparent in untreated hamsters at 12 weeks of age in comparison with F1B controls. The ratio of reduced to oxidized glutathione (GSH/GSSG) was decreased and the concentration of 4-hydroxynonenal (4-HNE) was increased in the hearts of untreated TO-2 hamsters. Treatment with GHRP-2 attenuated the progression of LV remodeling and dysfunction, as well as myocardial fibrosis, in TO-2 hamsters. GHRP-2 also inhibited both the decrease in the GSH/GSSG ratio and the increase in the concentration of 4-HNE in the hearts of TO-2 hamsters. Conclusions: GHRP-2 can suppress the increase in the level of myocardial oxidative stress, leading to attenuation of progressive LV remodeling and dysfunction in dilated cardiomyopathic hamsters. (Circ J 2010; 74: 163-170)
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Neurotoxicology 30(6) 1078-83 2009年11月 査読有り1-Bromopropane (1-BP), an alternative to ozone-depleting solvents, exhibits neurotoxicity and reproductive toxicity in animals and humans. The present study investigated the effects of exposure to 1-BP on expression of neurotransmitter receptor genes in the rat brain to explore possible biomarkers for central neurotoxicity and find brain regions sensitive for microarray analysis. Thirty-six F344 rats were divided at random into four equal groups of nine and exposed to 1-BP at 0, 400, 800 and 1000 ppm for 8 h/day; 7 days/week for 4 weeks. Total RNA from different brain regions was extracted and real-time PCR was conducted to quantify the mRNA levels of serotonin, dopamine and GABA receptors. Western blot analysis for specific regions of interest was also carried out to determine the protein levels. The mRNAs of 5HTr2a, D2R and GABAa1 were down regulated in a 1-BP dose-dependent manner in the hippocampus. The mRNA levels of 5HTr1a, 5HTr2a, D1R and GABAa1 were significantly decreased in the cortex of rats exposed to 800 ppm, but not to 1000 ppm. The mRNAs of 5HTr1a and 5HTr3a in the pons-medulla were decreased in rats exposed to 400 ppm or higher concentrations. The mRNA expression of D2R in the hippocampus and 5HTr1a and 5HTr3a in the pons-medulla oblongata were the most sensitive indicators of 1-BP neurotoxicity. The results suggest that mRNA expression analysis is useful in identifying brain regions susceptible to 1-BP, as well as providing potential biomarkers for central nervous system toxicity.
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Toxicological sciences : an official journal of the Society of Toxicology 112(1) 100-10 2009年11月 査読有りPrevious studies indicate that 1-bromopropane (1BP) has neurotoxicity and reproductive toxicity both in humans and animals. The present study investigated strain differences in susceptibility to 1BP and identified possible biological factors that determine such susceptibility. Twenty-four male mice of each of the three strains (C57BL/6J, DBA/2J, and BALB/cA) were divided into four groups of six each and exposed to 1BP at 0, 50, 110, and 250 ppm for 8 h/day for 28 days by inhalation. At the end of exposure period, the relative susceptibilities of each strain to 1BP-mediated hepatotoxicity and male reproductive toxicity were evaluated. The contributing factors to strain-dependent susceptibility were assessed by determination of hepatic CYP2E1 levels, glutathione-S-transferase (GST) activity, glutathione (GSH) status, and NAD(P)H:quinone oxidoreductase and heme oxygenase-1 mRNA levels. Liver histopathology showed significantly larger area of liver necrosis and more degenerative lobules in BALB/cA in the order of BALB/cA > C57BL/6J > DBA/2J. BALB/cA showed higher CYP2E1 protein level and lower total GSH content and GST activity in the liver than DBA/2J. These results indicate that BALB/cA mice are the most susceptible to hepatotoxicity of 1BP among the three strains tested, and that CYP2E1, GSH level/GST activity may contribute to the susceptibility to 1BP hepatotoxicity. Exposure to > or = 50 ppm of 1BP also decreased sperm count and sperm motility and increased sperms with abnormal heads in all three strains mice in a dose-dependent manner. Comparison with previous studies in rats indicates that mice are far more susceptible than rats to 1BP regarding hepatotoxicity and reproductive toxicity.
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SAFETY AND HEALTH AT WORK 13 S224-S224 2022年1月
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Society of Toxicology 58th Annual Meeting (SOT2018) 2019年3月
共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2023年9月 - 2027年3月
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日本学術振興会 科学研究費助成事業 2022年4月 - 2025年3月
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日本学術振興会 科学研究費助成事業 2021年4月 - 2024年3月
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日本学術振興会 科学研究費助成事業 2022年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2020年7月 - 2023年3月