研究者業績
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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The Journal of Toxicological Sciences 51(3) 183-199 2026年
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Particle and Fibre Toxicology 2025年12月19日
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Toxicology research 14(6) tfaf179 2025年12月A previous study demonstrated that Nrf2, a transcription factor, unexpectedly promoted multi-walled carbon nanotube (MWCNT)-induced lung inflammation in mice. This finding contrasts with the well-established role of Nrf2 in suppressing inflammatory responses induced by environmental chemicals, highlighting a critical knowledge gap. The present study investigated the effect of sulforaphane, a known activator of Nrf2, on MWCNT-induced lung inflammation in mice, in order to better understand the underlying mechanisms of this response. Each of 48 C57BL/6 J male mouse was anesthetized and exposed once via pharyngeal aspiration to MWCNTs (Mitsui-7) at doses of 0, 10, or 20 μg in 40 μl of dispersion medium per mouse and treated thereafter with subcutaneous 25 mg/kg/day sulforaphane or vehicle for 14 days. Bronchoalveolar lavage fluid (BALF) was collected for differential cell counts. Lung tissues were processed for histopathological analysis and quantification of cytokine or chemokine mRNA expression and Nrf2 protein in nuclear extracts. MWCNTs exposure increased lung weight, BALF lymphocytes, and lung IL-6 expression. Sulforaphane attenuated MWCNTs-induced lung weight gain, lymphocytic infiltration, and upregulation of IL-6 expression, but paradoxically enhanced low-dose MWCNT-induced neutrophil infiltration in BALF, MIP-2 expression, and histopathological inflammation scores. These effects were accompanied by increased levels of active Nrf2 protein in nuclear extracts from lung tissue. Overall, the results indicate that sulforaphane suppresses lymphocyte infiltration while promoting neutrophil recruitment in response to low-dose MWCNTs, suggesting a dual effect of sulforaphane on MWCNT-induced lung inflammation mediated through Nrf2 activation.
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Toxicology Letters 413 111737-111737 2025年11月
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Journal of Hazardous Materials 496 139125-139125 2025年9月
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medRxiv : the preprint server for health sciences 2025年7月23日BACKGROUND: Polygenic risk scores (PRSs) improve type 2 diabetes (T2D) prediction beyond clinical risk factors but perform poorly in non-European populations, where T2D burden is often higher, undermining their global clinical utility. METHODS: We conducted the largest global effort to date to harmonize T2D genome-wide association study (GWAS) meta-analyses across five ancestries-European (EUR), African/African American (AFR), Admixed American (AMR), South Asian (SAS), and East Asian (EAS)-including 360,000 T2D cases and 1·8 million controls (41% non-EUR). We constructed ancestry-specific and multi-ancestry PRSs in training datasets including 11,000 T2D cases and 32,000 controls, and validated their performance in independent datasets including 39,000 T2D cases and 126,000 controls of diverse ancestries. In the All of Us Research Program, we compared these PRSs to those from the Polygenic Score Catalog and assessed their ability to predict diabetes micro- and macrovascular complications. FINDINGS: Ancestry-specific PRSs showed limited prediction power for T2D in AFR, AMR, and SAS compared to EUR and EAS. In contrast, multi-ancestry PRSs, built using GWAS data from five ancestries, substantially improved T2D prediction across all ancestries. Compared to those in the interquartile range, individuals at the 97·5th percentile of their PRSs had a 6-fold increased T2D risk in AMR, EAS, and EUR, and ≥3-fold in AFR and SAS. These PRSs were also associated with the development of microvascular complications and outperformed all previously reported PRSs for all ancestries. INTERPRETATION: We developed and extensively validated the most up-to-date T2D PRSs across diverse ancestry groups. These PRSs are publicly available to support further evaluation of their clinical utility in diverse ancestries.
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Annals of work exposures and health 69(1) 34-47 2025年1月8日Carbon fiber-reinforced plastics (CFRP) are leading functional materials with superior strength and low mass density compared to metal. Our previous factory site analyses found that CFRP processing generates fibrous debris and fine micro/nano-sized particles of various shapes. The present interventional study was conducted at a factory located in Japan and evaluated debris consisting of various-sized particles generated during the industrial processing of CFRP, such as cutting, grinding, and turning of CFRP pipes, using real-time particle monitoring devices of the following: PM4 Digital Dust Monitor (DDM), handled Optical Particle Counter (OPC), Condensation Particle Counter (CPC), and Scanning Mobility Particle Sizer (SMPS). In addition, personal exposure of workers was evaluated using a novel wearable PM2.5-compatible device (P-sensor). First, we confirmed the presence of micro/nano particles in the dust generated during industrial processing of CFRP. Finer CFRP-generated particles were detected by the nanoparticle-compatible devices; CPC and SMPS, but not by OPC or DDM. The dynamic detection pattern of the P-sensor resembled that recorded by the nanoparticle-compatible devices. The novel wearable P-sensor can be used to measure finer particles generated by CFRP processing in occupational settings. Second, the exposure assessment was conducted twice and the levels of the micro/nano particles in the second survey were significantly (less than half) lower than that in the first survey. By avoiding immediate power-off of the exhaust system after operations, the scattering of particles was effectively reduced. Our results indicate that effective use of local exhaust ventilation system improves the workplace environment for particle exposure.
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Annals of Work Exposures and Health 69(1) 34-47 2024年11月8日Abstract Carbon fiber-reinforced plastics (CFRP) are leading functional materials with superior strength and low mass density compared to metal. Our previous factory site analyses found that CFRP processing generates fibrous debris and fine micro/nano-sized particles of various shapes. The present interventional study was conducted at a factory located in Japan and evaluated debris consisting of various-sized particles generated during the industrial processing of CFRP, such as cutting, grinding, and turning of CFRP pipes, using real-time particle monitoring devices of the following: PM4 Digital Dust Monitor (DDM), handled Optical Particle Counter (OPC), Condensation Particle Counter (CPC), and Scanning Mobility Particle Sizer (SMPS). In addition, personal exposure of workers was evaluated using a novel wearable PM2.5-compatible device (P-sensor). First, we confirmed the presence of micro/nano particles in the dust generated during industrial processing of CFRP. Finer CFRP-generated particles were detected by the nanoparticle-compatible devices; CPC and SMPS, but not by OPC or DDM. The dynamic detection pattern of the P-sensor resembled that recorded by the nanoparticle-compatible devices. The novel wearable P-sensor can be used to measure finer particles generated by CFRP processing in occupational settings. Second, the exposure assessment was conducted twice and the levels of the micro/nano particles in the second survey were significantly (less than half) lower than that in the first survey. By avoiding immediate power-off of the exhaust system after operations, the scattering of particles was effectively reduced. Our results indicate that effective use of local exhaust ventilation system improves the workplace environment for particle exposure.
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Chemosphere 368 143745-143745 2024年11月
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Environment & health (Washington, D.C.) 2(7) 424-440 2024年7月19日Triclosan (TCS) has garnered significant attention due to its widespread use and associated endocrine-disrupting effects. However, its impact on the neuroendocrine system and underlying mechanisms remain poorly understood. Here, we established correlations between TCS exposure and serum sex hormone levels in participants of the National Health and Nutrition Examination Survey (NHANES). Additionally, we investigated TCS's influence on the neuroendocrine system using adult zebrafish exposed to environmentally relevant concentrations of TCS (0.361-48.2 μg/L) for 21 days. Assessment of reproductive and neurotoxicity included histopathological examination and behavioral tests. Transcriptomics, proteomics analyses, and biochemical detection were employed to elucidate mechanisms underlying TCS-induced neuroendocrine disruption. Significant correlations were found between TCS exposure and estradiol, testosterone, and sex hormone-binding globulin levels in NHANES participants. In addition, TCS exposure inhibited ovary development and spermatogenesis in zebrafish. Transcriptomics and proteomics analysis revealed gender-specific key signaling and metabolism-related pathways implicated in TCS-induced reproductive toxicity. Moreover, TCS exposure induced nervous system impairment, as evidenced by histological changes and altered motor behavior, possibly associated with oxidative damage. Correlation analysis further highlighted the potential connection between endocrine system disruption and nervous system impairment following TCS exposure. Overall, this study provided evidence supporting TCS-induced endocrine disruption and offered insights into its underlying mechanisms.
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Journal of hazardous materials 467 133679-133679 2024年4月5日Focusing on the relatively unexplored presence of micro- and nano-plastic aerosol particles, this study quantitatively assessed the emission of nano-plastic particles during the machining of carbon fiber reinforced plastic (CFRP) in the working environment. Measurements of aerosol particles smaller than 1 µm in size were performed by aerosol mass spectrometry. The findings revealed that concentrations of carbonous aerosol particles (organic aerosol and refractory black carbon (rBC)) were higher during working hours than during non-working hours. Positive matrix factorization identified CFRP particles as a significant source, contributing an average of approximately 30% of concentration of carbonous aerosol particles during working hours. This source apportionment was corroborated by the presence of bisphenol A and F fragments, principal components of the epoxy resins used in CFRP, and was corroborated by similarities to the carbon cluster ion distribution observed in rBC during CFRP pipe-cutting operations. Further, the particle size distribution suggested the existence of plastic aerosol particles smaller than 100 nm. This study established the method to quantitatively distinguish nano-plastic aerosol particles from other aerosol particles in high temporal resolution and these techniques are useful for accurately assessing exposure to nano-plastic aerosol particles in working environments.
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Fundamental Toxicological Sciences 11(3) 109-121 2024年
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Archives of toxicology 2023年11月16日Acrylamide is an environmental electrophile that has been produced in large amounts for many years. There is concern about the adverse health effects of acrylamide exposure due to its widespread industrial use and also presence in commonly consumed foods and others. IL-1β is a key cytokine that protects the brain from inflammatory insults, but its role in acrylamide-induced neurotoxicity remains unknown. We reported recently that deletion of IL-1β gene exacerbates ACR-induced neurotoxicity in mice. The aim of this study was to identify genes or signaling pathway(s) involved in enhancement of ACR-induced neurotoxicity by IL-1β gene deletion or ACR-induced neurotoxicity to generate a hypothesis mechanism explaining ACR-induced neurotoxicity. C57BL/6 J wild-type and IL-1β KO mice were exposed to ACR at 0, 12.5, 25 mg/kg by oral gavage for 7 days/week for 4 weeks, followed by extraction of mRNA from mice cerebral cortex for RNA sequence analysis. IL-1β deletion altered the expression of genes involved in extracellular region, including upregulation of PFN1 gene related to amyotrophic lateral sclerosis and increased the expression of the opposite strand of IL-1β. Acrylamide exposure enhanced mitochondria oxidative phosphorylation, synapse and ribosome pathways, and activated various pathways of different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, Huntington disease, and prion disease. Protein network analysis suggested the involvement of different proteins in related to learning and cognitive function, such as Egr1, Egr2, Fos, Nr4a1, and Btg2. Our results identified possible pathways involved in IL-1β deletion-potentiated and ACR-induced neurotoxicity in mice.
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International journal of molecular sciences 24(12) 2023年6月8日Epidemiological studies showed the association between air pollution and dementia. A soluble fraction of particulate matters including polycyclic aromatic hydrocarbons (PAHs) is suspected to be involved with the adverse effects of air pollution on the central nervous system of humans. It is also reported that exposure to benzopyrene (B[a]P), which is one of the PAHs, caused deterioration of neurobehavioral performance in workers. The present study investigated the effect of B[a]P on noradrenergic and serotonergic axons in mouse brains. In total, 48 wild-type male mice (10 weeks of age) were allocated into 4 groups and exposed to B[a]P at 0, 2.88, 8.67 or 26.00 µg/mice, which is approximately equivalent to 0.12, 0.37 and 1.12 mg/kg bw, respectively, by pharyngeal aspiration once/week for 4 weeks. The density of noradrenergic and serotonergic axons was evaluated by immunohistochemistry in the hippocampal CA1 and CA3 areas. Exposure to B[a]P at 2.88 µg/mice or more decreased the density of noradrenergic or serotonergic axons in the CA1 area and the density of noradrenergic axons in the CA3 area in the hippocampus of mice. Furthermore, exposure to B[a]P dose-dependently upregulated Tnfα at 8.67 µg/mice or more, as well as upregulating Il-1β at 26 µg/mice, Il-18 at 2.88 and 26 µg/mice and Nlrp3 at 2.88 µg/mice. The results demonstrate that exposure to B[a]P induces degeneration of noradrenergic or serotonergic axons and suggest the involvement of proinflammatory or inflammation-related genes with B[a]P-induced neurodegeneration.
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medRxiv : the preprint server for health sciences 2023年3月31日Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.
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Antioxidants 12(4) 844-844 2023年3月31日Based on the known role of oxidative stress in the pathogenesis and progression of metabolic syndrome, we used two-dimensional gel electrophoresis with immunochemical detection of protein carbonyls (2D-Oxyblot) to characterize the carbonylated proteins induced by oxidative stress in spontaneously hypertensive rats/NDmcr-cp (CP), an animal model of metabolic syndrome. We also profiled the proteins that showed change of expression levels in their epididymal adipose tissue at the pre-symptomatic (6-week-old) and the symptomatic (25-week-old) stages of the metabolic syndrome. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS) was used to analyze proteins extracted from the epididymal adipose tissue. The up-regulated proteins identified at the pre-symptomatic stage were mainly associated with ATP production and redox reaction, while the down-regulated proteins found at the symptomatic stage were involved in antioxidant activity and the tricarboxylic acid (TCA) cycle. Further analysis using the 2D-Oxyblot showed significantly high carbonylation levels of gelsolin and glycerol-3-phosphate dehydrogenase [NAD+] at the symptomatic stage. These results suggest that reduced antioxidant capacity underlies the increased oxidative stress state in the metabolic syndrome. The identified carbonylated proteins, including gelsolin, are potential targets that may act as key regulators in the progression of the metabolic syndrome.
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Chemosphere 318 137911-137911 2023年3月
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BIOMEDICINES 11(2) 2023年2月
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日本毒性学会学術年会 50.1 P1-067S 2023年【目的】近年、ナノマテリアルは様々な分野で利用が拡大しているのに対し、その安全性は未だ研究途上である。非晶質シリカナノ粒子(OH-SiO2NPs)は、広範に使用されているナノマテリアルだが、アミノ基やカルボキシル基などで修飾を受けたSiO2NPsと比較して、in vivoで肺胞マクロファージを減少させるとともに、in vitroでマウスマクロファージ細胞株RAW264.7の細胞生存率を著しく低下させることが先行研究により明らかになっている。本研究は、in vitroでOH-SiO2NPsによるマクロファージ傷害メカニズムを検討した。 【方法】マウスマクロファージ細胞株RAW264.7をOH-SiO2NPsに曝露し、各種プログラム細胞死経路の阻害剤を処置することで、細胞傷害と各細胞死経路との関係を検討した。また、炎症性ケモカイン、サイトカインのmRNA発現量をRT-qPCRにより測定した。 【結果・考察】OH-SiO2NPsによって引き起こされた細胞生存率の低下は、各種阻害剤を単独で処置しても有意な改善は見られなかったが、非特異的カスパーゼ阻害剤とネクロトーシス阻害剤を同時に処置すると一定の改善傾向が見られた。このことから、OH-SiO2NPsによる細胞死にはアポトーシスまたはネクロトーシス経路の部分的関与が示唆された。また、RT-qPCRで測定したMIP-2, IL-1β, MCP-1, TNF-αのmRNA発現は、コントロール群と比較してOH-SiO2NPs曝露群で有意に上昇していた。この結果から、OH-SiO2NPsへの曝露がマクロファージの炎症性ケモカイン、サイトカインの発現を誘導することがわかったが、ケモカイン、サイトカインの細胞死における役割についてはさらなる研究が必要である。
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Toxicology Letters 370 24-34 2022年11月
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Scientific reports 12(1) 11222-11222 2022年7月2日1,2-Dichloropropane (1,2-DCP), a synthetic organic solvent, has been implicated in causality of cholangiocarcinoma (bile duct cancer). 1,2-DCP-induced occupational cholangiocarcinoma show a different carcinogenic process compared to common cholangiocarcinoma, but its mechanism remains elusive. We reported previously that exposure of MMNK-1 cholangiocytes co-cultured with THP-1 macrophages, but not monocultured MMNK-1 cholangiocytes, to 1,2-DCP induced activation-induced cytidine deaminase (AID) expression, DNA damage and ROS production. The aim of this study was to identify relevant biological processes or target genes expressed in response to 1,2-DCP, using an in vitro system where cholangiocytes are co-cultured with macrophages. The co-cultured cells were exposed to 1,2-DCP at 0, 0.1 or 0.4 mM for 24 h, and then the cell lysates were assessed by transcriptome analysis. 1,2-DCP upregulated the expression of base excision repair genes in MMNK-1 cholangiocytes in the co-cultures, whereas it upregulated the expression of cell cycle-related genes in THP-1 macrophages. Activation of the base excision repair pathway might result from the previously observed DNA damage in MMNK-1 cholangiocytes co-cultured with THP-1 macrophages, although involvement of other mechanisms such as DNA replication, cell death or other types of DNA repair was not disproved. Cross talk interactions between cholangiocytes and macrophages leading to DNA damage in the cholangiocytes should be explored.
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International archives of occupational and environmental health 2022年2月25日OBJECTIVES: Carbon fibers are used in a variety of industrial applications, based on their lightweight and high stiffness properties. There is little information on the characteristics and exposure levels of debris generated during the factory processing of carbon fibers or their composites. This study revisits the general assumption that carbon fibers or their debris released during composite processing are considered safe for human health. METHODS: The present interventional study was conducted at a factory located in Japan, and involved on-site collection of debris generated during the industrial processing of polyacrylonitrile (PAN)-based carbon-fiber-reinforced plastic (CFRP). The debris were collected before being exhausted locally from around different factory machines and examined morphologically and quantitatively by scanning electron microscopy. The levels of exposure to respirable carbon fibers at different areas of the factory were also quantified. RESULTS: The collected debris mainly contained the original carbon fibers broken transversely at the fiber's major axis. However, carbon fiber fragments morphologically compatible with the WHO definition of respirable fibers (length: > 5 μm, width: < 3 μm, length/width ratio: > 3:1) were also found. The concentrations of respirable fibers at the six examined factory areas under standard working conditions in the same factory were below the standard limit of 10 fibers/L, specified for asbestos dust-generating facilities under the Air Pollution Control Law in Japan. CONCLUSIONS: Our study identified potentially dangerous respirable fibers with high aspect ratio, which was generated during the processing of PAN-based CFRP. Regular risk assessment of carbon fiber debris is necessary to ensure work environment safety.
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Toxicology letters 349 134-144 2021年10月1日Recent epidemiological studies reported cases of cholangiocarcinoma in workers exposed to 1,2-dichloropropane (1,2-DCP) in an offset proof printing factory in Japan. The present study investigated the effects of 1,2-DCP on the expression of histone family member X (H2AX) phosphorylated on Ser 139 (γ-H2AX), a marker of DNA double strand break, in human immortalized cholangiocytes MMNK-1 cells. Mono-cultures of MMNK-1 cells and co-cultures of MMNK-1 cells with THP-1 macrophages were exposed to 1,2-DCP at concentrations of 100 and 500 μM for 24 h. Expression of γ-H2AX was visualized by immunofluorescence staining. Exposure to 1,2-DCP had no effect on the expression of γ-H2AX in mono-cultured MMNK-1 cells, but significantly increased the number of nuclear foci stained by γ-H2AX in MMNK-1 cells co-cultured with THP-1 macrophages. Exposure to 1,2-DCP also significantly increased the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in co-cultured MMNK-1 cells. The results suggest that macrophages play a critical role by producing cytokines in 1,2-DCP-induced DNA double strand break in MMNK-1 cells.
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Environmental pollution (Barking, Essex : 1987) 289 117940-117940 2021年8月10日Arsenic is a well-recognized environmental contaminant that occurs naturally through geogenic processes in the aquifer. More than 200 million people around the world are potentially exposed to the elevated level of arsenic mostly from Asia and Latin America. Many adverse health effects including skin diseases (i.e., arsenicosis, hyperkeratosis, pigmentation changes), carcinogenesis, and neurological diseases have been reported due to arsenic exposure. In addition, arsenic has recently been shown to contribute to the onset of non-communicable diseases, such as diabetes mellitus and cardiovascular diseases. The mechanisms involved in arsenic-induced diabetes are pancreatic β-cell dysfunction and death, impaired insulin secretion, insulin resistance and reduced cellular glucose transport. Whereas, the most proposed mechanisms of arsenic-induced hypertension are oxidative stress, disruption of nitric oxide signaling, altered vascular response to neurotransmitters and impaired vascular muscle calcium (Ca2+) signaling, damage of renal, and interference with the renin-angiotensin system (RAS). However, the contributions of arsenic exposure to non-communicable diseases are complex and multifaceted, and little information is available about the molecular mechanisms involved in arsenic-induced non-communicable diseases and also no suitable therapeutic target identified yet. Therefore, in the future, more basic research is necessary to identify the appropriate therapeutic target for the treatment and management of arsenic-induced non-communicable diseases. Several reports demonstrated that a daily balanced diet with proper nutrient supplements (vitamins, micronutrients, natural antioxidants) has shown effective to reduce the damages caused by arsenic exposure. Arsenic detoxication through natural compounds or nutraceuticals is considered a cost-effective treatment/management and researchers should focus on these alternative options. This review paper explores the scenarios of arsenic contamination in groundwater with an emphasis on public health concerns. It also demonstrated arsenic sources, biogeochemistry, toxicity mechanisms with therapeutic targets, arsenic exposure-related human diseases, and onsets of cardiovascular diseases as well as feasible management options for arsenic toxicity.
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Toxics 9(6) 2021年6月1日1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated organic compound, was extensively used in the past in offset color proof-printing. In 2014, the International Agency for Research on Cancer (IARC) reclassified 1,2-DCP from its initial Group 3 to Group 1. Prior to the reclassification, cholangiocarcinoma was diagnosed in a group of workers exposed to 1,2 -DCP in an offset color proof-printing company in Japan. In comparison with other forms of cholangiocarcinoma, 1,2-DCP-induced cholangiocarcinoma was of early onset and accompanied by extensive pre-cancerous lesions in large bile ducts. However, the mechanism of 1,2-DCP-induced cholangiocarcinoma is poorly understood. Inflammatory cell proliferation was observed in various sites of the bile duct in the noncancerous hepatic tissues of the 1,2-DCP-induced cholangiocarcinoma. The aim of this study was to enhance our understanding of the mechanism of 1,2-DCP-related cholangiocarcinogenesis. We applied an in vitro system to investigate the effects of 1,2-DCP, using MMNK-1 cholangiocytes cultured alone or with THP-1 macrophages. The cultured cells were exposed to 1,2-DCP at 0, 0.1, 0.2, 0.4, and 0.8 mM for 24 h, and then assessed for cell proliferation, cell cytotoxicity, DNA damage, and ROS production. Exposure to 1,2-DCP increased proliferation of MMNK-1 cholangiocytes cultured alone, but not those cultured with macrophages. 1,2-DCP also increased LDH cytotoxicity, DNA damage, and ROS production in MMNK-1 cholangiocytes co-cultured with macrophages but not those cultured alone. 1,2-DCP increased TNFα and IL-1β protein expression in macrophages. The results highlight the role of macrophages in enhancing the effects of 1,2-DCP on cytotoxicity, ROS production, and DNA damage in cholangiocytes.
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Toxicology 456 152785-152785 2021年5月30日Acrylamide (ACR), a recognized neurotoxicant in humans and experimental animals, is widely used in industry and in food generated through Maillard reaction. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular defense system and activates antioxidants and cytoprotective genes. The exact roles of Nrf2 in environmental electrophile-induced neurotoxicity is poorly understood. The aim of this study was to determine the roles of Nrf2 in ACR-induced neurotoxicity including degeneration of monoaminergic axons and sensorimotor dysfunction. Male 10-week-old C57BL/6JJcl Nrf2-knockout mice and wild type (WT) counterparts were each divided into four groups of 12 and provided with drinking water containing acrylamide at 0, 67, 110 or 200 ppm for four weeks. The effects of acrylamide were examined by landing foot spread test, immunohistochemistry for noradrenaline (NA) and serotonin (5-HT)-containing axons and Iba1-positive microglia in the prefrontal cortex as well as quantitative real-time polymerase chain reaction (qRT-PCR) on antioxidant, proinflammatory and anti-inflammatory genes in the prefrontal cortex. Relative to the wild type, exposure of Nrf2-knockout mice to acrylamide increased hindlimb splay length, microglial area and process length as well as decreasing the density of NA and 5-HT-immunoreactive axons to a greater extent. Moreover, deletion of Nrf2 gene suppressed acrylamide-induced mRNA upregulation of Nrf2-antioxidants, NAD(P): quinone oxidoreductase 1 (NQO1), superoxide dismutase-1 (SOD-1) and heme oxygenase-1 (HO-1) as well as anti-inflammatory markers such as, arginase-1 (Arg1), found in the inflammatory zone-1 (Fizz1), chitinase-like 3 (Chi3l3), interleukin-4 receptor alpha (IL-4Rα), cluster of differentiation 206 (CD206) and transforming growth factor beta-1 (TGFβ1) while enhancing acrylamide-induced upregulation of pro-inflammatory cytokines, interleukin-1 beta (IL-1β), tumor necrosis-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the prefrontal cortex. The results demonstrate susceptibility of mice lacking the Nrf2 gene to acrylamide-induced neurotoxicity and neuroinflammation with the activation of microglia. Moreover, the results suggest the role of Nrf2 not only in induction of antioxidant gene expression, but also in suppression of proinflammatory cytokine gene expression.
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Rheumatology (Oxford, England) 60(9) 4430-4432 2021年5月4日
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Scientific Reports 10(1) 2020年12月<title>Abstract</title> Smoking increases the risk of cardiovascular diseases. The present study was designed to determine the effects of 2-month exposure to cigarette smoke (CS) on proteins in the left ventricles of spontaneously hypertensive rats (SHR) and to identify the molecular targets associated with the pathogenesis/progression of CS-induced cardiac hypertrophy. SHR and Wistar Kyoto rats (WKY) were exposed to CS at low (2 puffs/min for 40 min) or high dose (2 puffs/min for 120 min), 5 days a week for 2 months. Using the two-dimensional fluorescence difference gel electrophoresis combined with MALDI-TOF/TOF tandem mass spectrometry, we compared differences in the expression levels of proteins in the whole left ventricles induced by long-term smoking. High-dose CS mainly caused cardiac hypertrophy in SHR, but not WKY, but no change in blood pressure. Proteomic analysis identified 30 protein spots with significant alterations, with 14 up-regulated and 16 down-regulated proteins in the left ventricles of CS-exposed SHR, compared with control SHR. Among these proteins, two members of the heat shock proteins (HSP70 and HSP20) showed significant up-regulation in the left ventricles of CS high-dose SHR, and the results were confirmed by western blot analysis. Our findings suggested that HSPs play an important role in regulation of CS-induced cardiac hypertrophy.
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Present Environment and Sustainable Development 14(2) 151-162 2020年10月14日Untreated wastewater disposal from industries has been a crucial environmental issue for developing countries like Bangladesh. The current study aims to investigate the status of Effluent Treatment Plant (ETP) and the quality of effluents in the Noakhali industrial area, Bangladesh. Total 10 industries were surveyed and the ETP status showed that about 30% of industries do not have ETP facilities and only 30% of industries use their ETP for the treatment of the effluents where the rest of the industry’s ETPs were under construction or exit but not used. Effluent samples were collected from seven locations near the discharge points of various industries. All the physicochemical parameters were determined using standard analytical procedures and analyzed the values comparing with the guideline standard by the Department of Environment (DoE), Bangladesh. The average values of electric conductivity (EC) have exceeded the tolerable limit in maximum effluent samples. On the contrary, the temperature, pH, and total dissolved solids (TDS) values were within the standard limit for all of the collected effluent samples. The chloride concentration of the three effluent samples surpassed the limit. The biological oxygen demand (BOD) and chemical oxygen demand (COD) limit were exceeded for the effluent sampling sites S-6 and S-7 collected near the food and beverage industry. Besides, the maximum dissolved oxygen (DO) values of the effluents were below the standard which indicates poor water quality. Environmental nuisance is producing in Noakhali industrial area as maximum industries have not enough wastewater treatment facilities. Present study demonstrated that it is obvious to operate the ETP regularly for improving the quality of effluents to save our native environment from the harmful effects of wastewater.
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NanoImpact 20 100257-100257 2020年10月
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Nature 582(7811) 240-245 2020年6月
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Chemical research in toxicology 2020年5月8日 査読有りNanoparticles (NPs) are widely used in food, and analysis of their potential gastrointestinal toxicity is necessary. The present study was designed to determine the effects of silica dioxide (SiO2), titanium dioxide (TiO2), and zinc oxide (ZnO) NPs on cultured THP-1 monocyte-derived macrophages and human epithelial colorectal adenocarcinoma (Caco-2) cells. Exposure to ZnO NPs for 24 h increased the production of redox response species (ROS) and reduced cell viability in a dose-dependent manner in THP-1 macrophages and Caco-2 cells. Although TiO2 and SiO2 NPs induced oxidative stress, they showed no apparent cytotoxicity against both cell types. The effects of functionalized SiO2 NPs on undifferentiated and differentiated Caco-2 cells were investigated using fluorescently labeled SiO2 NPs with neutral, positive, or negative surface charge. Exposure of both types of cells to the three kinds of SiO2 NPs significantly increased their interaction in a dose-dependent manner. The largest interaction with both types of cells was noted with exposure to more negatively surface-charged SiO2 NPs. Exposure to either positively or negatively, but not neutrally, surface-charged SiO2 NPs increased NO levels in differentiated Caco-2 cells. Exposure of differentiated Caco-2 cells to positively or negatively surface-charged SiO2 NPs also upregulated interleukin-8 expression. We conclude that functionalized surface-charged SiO2 NPs can induce pro-inflammatory responses but are noncytotoxic.
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Neurotoxicology 2020年3月5日 査読有りPURPOSE: Acrylamide is known to induce disorders in the central nervous system in humans and experimental animals. The present study investigated effects of exposure to acrylamide on adult neurogenesis, noradrenergic axons and the level of norepinephrine in the brain of male rats. METHOD: Four groups of 12 male Wistar rats each were exposed to acrylamide at 0, 0.2, 2 and 20 mg/kg body weight by gavage for 5 weeks. Six rats of each groups were injected with 5-bromo-2'-deoxy-uridine (BrdU) after five-week exposure to acrylamide to examine proliferative cells in the dentate gyrus using immunostaining. Density of noradrenergic and serotonergic axons in the prefrontal cortex, hippocampus and cortex behind the bregma was quantified. Remaining 6 rats were decapitated after the last exposure and brains were dissected out to measure monoamine level in the hippocampus and prefrontal cortex using high performance liquid chromatography. RESULT: Exposure to acrylamide dose-dependently decreased the density of noradrenergic axons in the prefrontal cortex with a significant change at 20 mg/kg. Norepinephrine level decreased in the hippocampus at 20 mg/kg. Exposure to acrylamide at 20 mg/kg or less did not change the number of BrdU positive cells, but the result should be considered preliminary. CONCLUSION: The results show that oral exposure to acrylamide induces decrease in noradrenergic axons and norepinephrine level in the brain of rats. Given the similar effects are observed in 1-bromopropane-exposed rats, there may be the common mechanism in the toxicity of soft electrophiles to the central nervous system.
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日本毒性学会学術年会 47.1 P-28E 2020年Acrylamide (ACR) is an electrophile which has been used extensively in industry and is also formed unintentionally in food substances cooked or processed at high temperatures, such as potato chips or coffee through Maillard reaction. Acrylamide has been recognized as a potent neurotoxin which is known to cause neuropathy or encephalopathy in humans and experimental animals. As a measure of protection against neurotoxicity, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified to be a master regulator of the cellular defense system which activates antioxidant and cytoprotective genes. However, knowledge about mechanistic roles of Nrf2 in acrylamide-induced neurotoxicity remains poorly understood. This study therefore sought to investigate and clarify the roles of Nrf2 in ACR-induced neurotoxicity. Forty-eight male Nrf2-knockout (Nrf2-KO) mice from the C57BL/6JJcl background, aged 10-weeks together with their age and sex-matched wild-type (WT) counterparts were each divided into four groups of twelve and daily exposed to ACR at 0, 67, 110 or 200 ppm in drinking water for 28 days. Following exposure of mice to ACR, Landing Foot spread test, an assessment of motor function and a major endpoint marker of neurotoxicity as well as immunohistochemistry for noradrenaline transporter (NAT) and serotonin transporter (SERT) antibody in the dorsal and ventral medial prefrontal cortex were performed. Nrf2-KO mice showed exacerbated impairment of motor functions evidenced by the increased hindlimb splay relative to WT mice at the same exposure levels. Immunohistochemistry results showed severe degeneration of both noradrenergic and serotonergic axons characterized by a dose-dependent decrease in the density of immunoreactive axons in Nrf2-KO mice relative to WT mice. Moreover, body weight, whole brain weight and cerebellum weight were significantly reduced in Nrf2-KO mice compared to the WT mice. The results suggest increased susceptibility to ACR-induced neurotoxicity in mice lacking the Nrf2 gene. In conclusion, Nrf2 is able to attenuate the effects of ACR-induced neurotoxicity in mice and thus remains a crucial target for the preventive modulation of neurotoxicity.
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Particle and fibre toxicology 16(1) 47-47 2019年12月16日 査読有り
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Annals of the rheumatic diseases 78(10) 1430-1437 2019年10月 査読有りOBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.
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APPL SURF SCI 490 70-80 2019年10月1日 査読有り
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Applied Surface Science 484 568-577 2019年8月1日 査読有り
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Archives of toxicology 93(7) 1993-2006 2019年7月 査読有りAcrylamide has been used industrially and also found in certain foods cooked at high temperatures. Previous reports described acrylamide-related human intoxication who presented with ataxia, memory impairment, and/or illusion. The aim of this study was to characterize the molecular mechanisms of neurotoxicity of acrylamide by analyzing the expression levels of various proteins in the hippocampus of rats exposed to acrylamide. Male Wistar rats were administered acrylamide by gavage at 0, 2, and 20 mg/kg for 1 week or 0, 0.2, 2, and 20 mg/kg for 5 weeks. At the end of the experiment, the hippocampus was dissected out and proteins were extracted for two-dimensional difference gel electrophoresis combined with matrix-assisted laser-desorption ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF/TOF/MS). MALDI-TOF/TOF/MS identified significant changes in two proteins in the 1-week and 22 proteins in the 5-week exposure groups. These changes were up-regulation in 9 and down-regulation in 13 proteins in the hippocampus of rats exposed to acrylamide at 20 mg/kg for 5 weeks. PANTHER overrepresentation test based on the GO of biological process showed significant overrepresentation in proteins annotated to nicotinamide nucleotide metabolic process, coenzyme biosynthetic process, pyruvate metabolic process, and carbohydrate metabolic process. The test also showed significant overrepresentation in proteins annotated to creatinine kinase activity for the GO of molecular function as well as myelin sheath, cytoplasmic part, and cell body for the GO of cellular component. Comparison with a previous proteomic study on hippocampal proteins in rats exposed to 1-bromopropane identified triosephosphate isomerase, mitochondrial creatine kinase U-type, creatine kinase β-type and proteasome subunit α type-1 as proteins affected by exposure to acrylamide and 1-bromopropane, suggesting a common mechanism of neurotoxicity for soft electrophiles.
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Archives of toxicology 93(7) 2007-2019 2019年7月 査読有りAcrylamide, a soft electrophile, is widely used in the industry and laboratories, and also contaminates certain foods. Neurotoxicity and neurodegenerative effects of acrylamide have been reported in humans and experimental animals, although the underlying mechanism remains obscure. Activation of microglia and neuroinflammation has been demonstrated in various neurodegenerative diseases as well as other pathologies of the brain. The present study aimed to investigate the role of microglial activation and neuroinflammation in acrylamide neurotoxicity. Male 10-week-old Wistar rats were exposed to acrylamide by gavage at 0, 0.2, 2, or 20 mg/kg BW, once per day for 5 weeks. The results showed that 5-week exposure to acrylamide induced inflammatory responses in the cerebral cortex, evident by upregulated mRNA and protein expression of pro-inflammatory cytokines IL-1β, IL-6, and IL-18. Acrylamide also induced activation of microglia, indicated by increased expression of microglial markers, CD11b and CD40, and increased CD11b/c-positive microglial area and microglial process length. In vitro studies using BV-2 microglial cells confirmed microglial inflammatory response, as evident by time- (0-36 h; 50 μM) and dose- (0-500 μM; 24 h) dependent increase in mRNA expression of IL-1β and IL-18, as well as the inflammatory marker iNOS. Furthermore, acrylamide-induced upregulation of pro-inflammatory cytokines was mediated through the NLRP3 inflammasome pathway, as evident by increased expression of NLRP3, caspase 1, and ASC in the rat cerebral cortex, and by the inhibitory effects of NLRP3 inflammasome inhibitor on the acrylamide-induced upregulation of NLRP3, caspase 1, IL-1β, and IL-18 in BV-2 microglia.
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Particle and fibre toxicology 16(1) 26-26 2019年6月27日 査読有り
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The Journal of Toxicological Sciences 44(Suppl.) S223-S223 2019年6月
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ARCH TOXICOL 93(6) 1543-1553 2019年6月 査読有り
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Particle and fibre toxicology 16(1) 19-19 2019年4月23日 査読有りBACKGROUND: Particles and fibres affect human health as a function of their properties such as chemical composition, size and shape but also depending on complex interactions in an organism that occur at various levels between particle uptake and target organ responses. While particulate pollution is one of the leading contributors to the global burden of disease, particles are also increasingly used for medical purposes. Over the past decades we have gained considerable experience in how particle properties and particle-bio interactions are linked to human health. This insight is useful for improved risk management in the case of unwanted health effects but also for developing novel medical therapies. The concepts that help us better understand particles' and fibres' risks include the fate of particles in the body; exposure, dosimetry and dose-metrics and the 5 Bs: bioavailability, biopersistence, bioprocessing, biomodification and bioclearance of (nano)particles. This includes the role of the biomolecule corona, immunity and systemic responses, non-specific effects in the lungs and other body parts, particle effects and the developing body, and the link from the natural environment to human health. The importance of these different concepts for the human health risk depends not only on the properties of the particles and fibres, but is also strongly influenced by production, use and disposal scenarios. CONCLUSIONS: Lessons learned from the past can prove helpful for the future of the field, notably for understanding novel particles and fibres and for defining appropriate risk management and governance approaches.
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Communications Biology 2019年4月8日 査読有り<5 × 10
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International journal of molecular sciences 20(4) 2019年2月18日 査読有り
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日本毒性学会学術年会 46.1 P-1E 2019年[Background] Acrylamide exhibits neurotoxicity in humans and experimental animals. Our previous study revealed that exposure to acrylamide induced specific decrease in norepinephrine level and density of noradrenergic axons in rat brain, although the underling mechanism remains obscure. This study aims to investigate role of microglia and autophagy pathway in neurotoxicity of acrylamide. [Methods] In vivo: Six groups (n=3) of C57BL/6J mice were exposed to single dose of acrylamide by oral gavage at 20 mg/kg BW or vehicle, and were perfused through ascending aorta 1, 3, or 6 h after exposure. Induction of autophagy was investigated by immunostaining of LC3B. In vitro: CATH.a catecholaminergic neuronal cells or BV-2 microglial cells were mono-cultured or co-cultured through directly mixing or using insert, and then exposed to acrylamide (0, 0.1, 0.5, 1, 2 mM; 24 h). Cell viability, cytotoxicity, ATP production, caspase-3/7 activity, apoptosis, and expression of autophagy marker LC3B were measured. [Results] LC3B positive neuronal cell bodies were observed in the cerebellum of mice brain, at 1 or 3 hrs after acrylamide exposure. Exposure to acrylamide at 2mM significantly decreased cell viability and ATP production in CATH.a neuronal cells, although LDH release was not changed. Exposure to acrylamide at 1 or 2 mM significantly decreased caspase-3/7 activity in CATH.a cells. Caspase-3/7 activity was dose-dependently increased in CATH.a cells by autophagy inhibitor chloroquine. However, the ratio of LC3-II/LC3-I showed no change in CATH.a cells after acrylamide exposure. Exposure to acrylamide at 2 mM also decreased cell viability, and increased LDH release and caspase-3/7 activity, in BV-2 microglial cells. Moreover, acrylamide exposure at 1 mM, significantly decreased cell viability, and increased LDH release. [Conclusion] Compared to mono-culture, co-culture of CATH.a neuronal cells with BV-2 microglial cells may exacerbate the cytotoxicity of acrylamide. The in vivo results also suggested involvement of autophagy in neurotoxicity of acrylamide, but further studies are needed to reveal it.
MISC
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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 2025年4月 - 2028年3月
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日本学術振興会 科学研究費助成事業 2024年6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 2024年4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 2023年9月 - 2027年3月