Updated on 2025/08/01

写真a

 
ONO Atsushi
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
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Degree

  • Ph.D ( 2000.7   Showa University )

Research Interests

  • 構造活性相関

  • トランスクリプトーム

  • Toxicogenimics

  • 情報毒性学

  • skin sensitization

  • endocrine disruptor

Research Areas

  • Life Science / Pharmaceutical hygiene and biochemistry  / Toxicology

Education

  • Hokkaido University   薬学研究科  

    1990 - 1992

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    Country： Japan

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  • Hokkaido University   薬学部  

    1987 - 1990

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Research History

  • Okayama University   Professor

    2016.8

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    Country：Japan

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  • National Institute of Health Sciences

    1993 - 2016

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Professional Memberships

  • Japanese Society for Clinical Toxicology

    2022.1

  • The Pharmaceutical Society of Japan

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  • The Japanese Society of Toxicological Sciences

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  • Japanese Society for The Study of Xenobiotics

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  • 日本中毒学会

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  • The Japanese Society for Alternatives to Animal Experiments

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Committee Memberships

  • 厚生労働省   薬事・食品衛生審議会専門委員  

    2021.1   

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    Committee type：Government

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  • 内閣府   食品安全委員会専門委員  

    2020.4   

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    Committee type：Government

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  • OECD   Advisory Group on Endocrine Disrupters Testing and Assessment  

    2020.3   

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    Committee type：Government

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  • 厚生労働省   労働安全衛生法GLP専門家  

    2020.2   

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    Committee type：Government

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  • OECD   Residue Definition Working Group  

    2019.4   

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    Committee type：Government

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  • 医薬品医療機器総合機構   専門委員  

    2019.4   

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    Committee type：Government

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  • OECD   QSAR Toolbox Management Group  

    2015.4   

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    Committee type：Government

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Papers

  • Borderline Range Determined Using Data From Validation Study of Alternative Methods for Skin Sensitization: ADRA, IL-8 Luc Assay, and EpiSensA. Reviewed International journal

    Toshihiko Kasahara, Yusuke Yamamoto, Natsumi Nakashima, Mika Imamura, Hideyuki Mizumachi, Sho Suzuki, Setsuya Aiba, Yutaka Kimura, Takao Ashikaga, Hajime Kojima, Atsushi Ono, Kazuhiko Matsumoto

    Journal of applied toxicology : JAT   2024.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    Most predictive models that use alternatives to animal experiments divide judgements into two classes with a cutoff value for each model. However, if the results of alternative methods are close to the cutoff values, the true result may be ambiguous because of variability in the data. Therefore, the OECD GL497 uses a judgement method that establishes a borderline range (BR) around a cutoff value using a statistical method. However, because there is no detailed description of how the BR is calculated, we clarified two specific points. The scale-constant correction method was used to calculate the median absolute deviation (MAD) around the median. In addition, the bottom-raised transformation method was used when the data were "0" because calculation of the BR requires that all data are logarithmic. Indeed, the BRs for the amino acid derivative reactivity assay (ADRA), interleukin-8 reporter gene assay (IL-8 Luc), and epidermal sensitization assay (EpiSensA) were calculated using data from each validation study. The results showed that the BR for ADRA and IL-8 Luc ranged from 4.1 to 5.9 and 1.25 to 1.57, respectively. Furthermore, the BRs of four genes (ATF3, GCLM, DNAJB4, and IL-8) evaluated using EpiSensA ranged from 10.71 to 21.02, 1.64 to 2.45, 1.61 to 2.52, and 3.11 to 5.16, respectively. The difference (deviation) between the lower and upper BR limits and cutoff value for each alternative method were comparable to those of the alternative methods listed in the guidelines (DPRA, KerarinoSens, and h-CLAT) and thus were considered as adequate.

    DOI： 10.1002/jat.4712

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  • Assessment of commercial polymers with and without reactive groups using amino acid derivative reactivity assay based on both molar concentration approach and gravimetric approach. Reviewed International journal

    Masaharu Fujita, Natsumi Nakashima, Sayaka Wanibuchi, Yusuke Yamamoto, Hajime Kojima, Atsushi Ono, Toshihiko Kasahara

    Journal of applied toxicology : JAT   43 ( 3 )   446 - 457   2023.3

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    Language：English   Publishing type：Research paper (scientific journal)  

    The amino acid derivative reactivity assay (ADRA), an alternative method for testing skin sensitization, has been established based on the molar concentration approach. However, the additional development of gravimetric concentration and fluorescence detection methods has expanded its range of application to mixtures, which cannot be evaluated using the conventional testing method, the direct peptide reactivity assay (DPRA). Although polymers are generally treated as mixtures, there have been no reports of actual polymer evaluations using alternative methods owing to their insolubility. Therefore, in this study, we evaluated skin sensitization potential of polymers, which is difficult to predict, using ADRA. As polymers have molecular weights ranging from several thousand to more than several tens of thousand Daltons, they are unlikely to cause skin sensitization due to their extremely low penetration into the skin, according to the 500-Da rule. However, if highly reactive functional groups remain at the ends or side chains of polymers, relatively low-molecular-weight polymer components may penetrate the skin to cause sensitization. Polymers can be roughly classified into three major types based on the features of their constituent monomers; we investigated the sensitization capacity of each type of polymer. Polymers with alert sensitization structures at their ends were classified as skin sensitizers, whereas those with no residual reactive groups were classified as nonsensitizers. Although polymers with a glycidyl group need to be evaluated carefully, we concluded that ADRA (0.5 mg/ml) is generally sufficient for polymer hazard assessment.

    DOI： 10.1002/jat.4395

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  • Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha. Reviewed International journal

    Susumu Kodama, Shuzo Matsumoto, Yuta Takamura, Michiko Fujihara, Masaki Watanabe, Atsushi Ono, Hiroki Kakuta

    Toxicology letters   373   76 - 83   2023.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXRα, but nevertheless cause significant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis-tert-butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXRα. In this study, we explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXRα activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXRα. Since 1,3-bis-tert-butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXRα ligands such as 9-cis-retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXRα-based toxicity to living organisms.

    DOI： 10.1016/j.toxlet.2022.11.003

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  • Applicability of amino acid derivative reactivity assay (4 mM) for the prediction of skin sensitization by combining multiple alternative methods to evaluate key events Reviewed International journal

    Mika Imamura, Yusuke Yamamoto, Masaharu Fujita, Sayaka Wanibuchi, Natsumi Nakashima, Hajime Kojima, Atsushi Ono, Toshihiko Kasahara

    Journal of Applied Toxicology   42 ( 7 )   1159 - 1167   2022.7

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    The amino acid derivative reactivity assay (ADRA) is an alternative method for evaluating key event 1 (KE-1) in the skin sensitization mechanism included in OECD TG442C (OECD, 2021). Recently, we found that ADRA with a 4-mM test chemical solution had a higher accuracy than the original ADRA (1 mM). However, ADRA (4 mM) has yet to be evaluated using integrated approaches to testing and assessment (IATA), a combination of alternative methods for evaluating KE. In this study, the sensitization potency of three defined approaches (DAs) using ADRA (4 mM) as KE-1 was predicted and compared with those of two additional ADRAs or direct peptide reactivity assay (DPRA): (i) "2 out of 3" approach, (ii) "3 out of 3" approach, and (iii) integrated testing strategy (ITS). In the hazard identification of chemical sensitizers, the accuracy of human data and local lymph node assay (LLNA) remained almost unchanged among the three approaches evaluated. Potency classifications for sensitization were predicted with the LLNA and human data sets using ITS. The potency classifications for the sensitization potency prediction accuracy of LLNA data using any alternative method were almost unchanged, at approximately 70%, and those with ITS were not significantly different. When ITS was performed using DPRA, the prediction accuracy was approximately 73% for human data, which was similar to that of the LLNA data; however, the accuracy tended to increase for all ADRA methods. In particular, when ITS was performed using ADRA (4 mM), the prediction accuracy was approximately 78%, which proved to be a practical level.

    DOI： 10.1002/jat.4283

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jat.4283

  • Within‐ and between‐laboratory reproducibility and predictive capacity of amino acid derivative reactivity assay (ADRA) using a 0.5 mg/mL test chemical solution: Results of the study for reproducibility confirmation implemented in five participating laboratories Reviewed International journal

    Yusuke Yamamoto, Masaharu Fujita, Shinichi Watanabe, Hiroaki Yamaga, Koji Wakabayashi, Yu Tahara, Nobuyuki Horie, Keiichi Fujimoto, Kazuya Takeuchi, Kohei Kamiya, Tsuyoshi Kawakami, Kohichi Kojima, Takashi Sozu, Hajime Kojima, Toshihiko Kasahara, Atsushi Ono

    Journal of Applied Toxicology   42 ( 6 )   1078 - 1090   2022.6

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    The amino acid derivative reactivity assay (ADRA) is an in chemico alternative assay for skin sensitization listed in OECD test guideline 442C. ADRA evaluates the reactivity of sensitizers to proteins, which is key event 1 in the skin sensitization adverse outcome pathway. Although the current key event 1 evaluation method is a simple assay that evaluates nucleophile and test chemical reactivity, mixtures of unknown molecular weights cannot be evaluated because a constant molar ratio between the nucleophile and test chemical is necessary. In addition, because the nucleophile is quantified by HPLC, the frequency of co-eluting the test chemical and nucleophile increases when measuring multi-component mixtures. To solve these issues, test conditions have been developed using a 0.5 mg/mL test chemical solution and fluorescence-based detection. Since the practicality of these methods has not been substantiated, a validation test to confirm reproducibility was conducted in this study. The 10 proficiency substances listed in the ADRA guidelines were tested three times at five different laboratories. The results of both within- and between-laboratory reproducibility were 100%, and the results of ultraviolet- and fluorescence-based measurements were also consistent. In addition to the proficiency substances, a new positive control, squaric acid diethyl ester, was tested three times at the five laboratories. The results showed high reproducibility with N-(2-(1-naphthyl)acetyl)-l-cysteine depletion of 37%-52% and α-N-(2-(1-naphthyl)acetyl)-l-lysine depletion of 99%-100%. Thus, high reproducibility was confirmed in both evaluations of the 0.5 mg/mL test chemical and the fluorescence-based measurements, validating the practicability of these methods.

    DOI： 10.1002/jat.4279

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jat.4279

  • Transforming Growth Factor Beta Promotes the Expansion of Cancer Stem Cells <i>via</i> S1PR3 by Ligand-Independent Notch Activation Reviewed

    Naoya Hirata, Shigeru Yamada, Shota Yanagida, Atsushi Ono, Yukuto Yasuhiko, Yasunari Kanda

    Biological and Pharmaceutical Bulletin   45 ( 5 )   649 - 658   2022.5

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    Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

    DOI： 10.1248/bpb.b22-00112

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  • Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer. Reviewed International journal

    Naoya Hirata, Shigeru Yamada, Shota Yanagida, Atsushi Ono, Yukuto Yasuhiko, Motohiro Nishida, Yasunari Kanda

    International journal of molecular sciences   23 ( 4 )   1967 - 1967   2022.2

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：{MDPI} {AG}  

    Triple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for new drug development. We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the CSC phenotype, which can be identified as the ALDH-positive cell population in several types of human cancer cell lines. In this study, we have investigated additional lipid receptors upregulated in BCSCs. We found that lysophosphatidic acid (LPA) receptor 3 was highly expressed in ALDH-positive TNBC cells. The LPAR3 antagonist inhibited the increase in ALDH-positive cells after LPA treatment. Mechanistically, the LPA-induced increase in ALDH-positive cells was dependent on intracellular calcium ion (Ca2+), and the increase in Ca2+ was suppressed by a selective inhibitor of transient receptor potential cation channel subfamily C member 3 (TRPC3). Moreover, IL-8 production was involved in the LPA response via the activation of the Ca2+-dependent transcriptional factor nuclear factor of activated T cells. Taken together, our findings provide new insights into the lipid-mediated regulation of BCSCs via the LPA-TRPC3 signaling axis and suggest several potential therapeutic targets for TNBC.

    DOI： 10.3390/ijms23041967

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  • The within‐ and between‐laboratories reproducibility and predictive capacity of Amino acid Derivative Reactivity Assay using 4 mM test chemical solution: Results of ring study implemented at five participating laboratories Reviewed International journal

    Masaharu Fujita, Yusuke Yamamoto, Sayaka Wanibuchi, Shinichi Watanabe, Hiroaki Yamaga, Koji Wakabayashi, Yu Tahara, Nobuyuki Horie, Keiichi Fujimoto, Kazuya Takeuchi, Kohei Kamiya, Tsuyoshi Kawakami, Kohichi Kojima, Takashi Sozu, Hajime Kojima, Toshihiko Kasahara, Atsushi Ono

    Journal of Applied Toxicology   42 ( 2 )   318 - 333   2022.2

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    Amino acid derivative reactivity assay (ADRA) for skin sensitization was adopted as an alternative method in the 2019 OECD Guideline for the Testing of Chemicals (OECD TG 442C). The molar ratio of the nucleophilic reagent to the test chemicals in the reaction solution was set to 1:50. Imamura et al. reported that changing this molar ratio from 1:50 to 1:200 reduced in false negatives and improved prediction accuracy. Hence, a ring study using ADRA with 4 mM of a test chemical solution (ADRA, 4 mM) was conducted at five different laboratories to verify within- and between-laboratory reproducibilities (WLR and BLR, respectively). In this study, we investigated the WLR and BLR using 14 test chemicals grouped into three classes: (1) eight proficiency substances, (2) four test chemicals that showed false negatives in the ADRA with 1 mM test chemical solution (ADRA, 1 mM), but correctly positive in ADRA (4 mM), and (3) current positive control (phenylacetaldehyde) and a new additional positive control (squaric acid diethyl ester). The results showed 100% reproducibility and 100% accuracy for skin sensitization. Hence, it is clear that the ADRA (4 mM) is an excellent test method in contrast to the currently used ADRA (1 mM). We plan to resubmit the ADRA (4 mM) test method to the OECD Test Guideline Group in the near future so that OECD TG 442C could be revised for the convenience and benefit of many ADRA users.

    DOI： 10.1002/jat.4268

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jat.4268

  • Contractility assessment of human iPSC-derived cardiomyocytes by using a motion vector system and measuring cell impedance. Reviewed International journal

    Ayano Satsuka, Sayo Hayashi, Shota Yanagida, Atsushi Ono, Yasunari Kanda

    Journal of pharmacological and toxicological methods   118   107227 - 107227   2022

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    Predicting drug-induced cardiotoxicity during the non-clinical stage is important to avoid severe consequences in the clinical trials of new drugs. Human iPSC-derived cardiomyocytes (hiPSC-CMs) hold great promise for cardiac safety assessments in drug development. To date, multi-electrode array system (MEA) has been a widely used as a tool for the assessment of proarrhythmic risk with hiPSC-CMs. Recently, new methodologies have been proposed to assess in vitro contractility, such as the force and velocity of cell contraction, using hiPSC-CMs. Herein, we focused on an imaging-based motion vector system (MV) and an electric cell-substrate impedance sensing system (IMP). We compared the output signals of hiPSC-CMs from MV and IMP in detail and observed a clear correlation between the parameters. In addition, we assessed the effects of isoproterenol and verapamil on hiPSC-CM contraction and identified a correlation in the contractile change of parameters obtained with MV and IMP. These results suggest that both assay systems could be used to monitor hiPSC-CM contraction dynamics.

    DOI： 10.1016/j.vascn.2022.107227

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  • Proarrhythmia Risk Assessment Using Electro-Mechanical Window in Human iPS Cell-Derived Cardiomyocytes. Reviewed

    Shota Yanagida, Ayano Satsuka, Sayo Hayashi, Atsushi Ono, Yasunari Kanda

    Biological & pharmaceutical bulletin   45 ( 7 )   940 - 947   2022

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    Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous studies have suggested that human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful platform for detecting drug-induced TdP risks. Comprehensive in vitro Proarrhythmia Assay (CiPA) validation study suggested that hiPSC-CMs can assess clinical TdP risk more accurately than the human ether-a-go-go-related assay and QT interval prolongation. However, there were still some outliers, such as bepridil, mexiletine, and ranolazine, among the CiPA 28 compounds in the CiPA international multi-site study using hiPSC-CMs. In this study, we assessed the effects of the positive compound dofetilide, the negative compound aspirin, and several CiPA compounds (bepridil, mexiletine, and ranolazine) on the electromechanical window (E-M window), which were evaluated using multi-electrode array assay and motion analysis, in hiPSC-CMs. Similar to previous in vivo studies, dofetilide, which has a high TdP risk, decreased the E-M window in hiPSC-CMs, whereas aspirin, which has a low TdP risk, had little effect. Bepridil, classified in the high TdP-risk group in CiPA, decreased the E-M window in hiPSC-CMs, whereas ranolazine and mexiletine, which are classified in the low TdP-risk group in CiPA, slightly decreased or had little effect on the E-M window of hiPSC-CMs. Thus, the E-M window in hiPSC-CMs can be used to classify drugs into high and low TdP risk.

    DOI： 10.1248/bpb.b22-00268

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  • Comprehensive Cardiotoxicity Assessment of COVID-19 Treatments Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Reviewed International journal

    Shota Yanagida, Ayano Satsuka, Sayo Hayashi, Atsushi Ono, Yasunari Kanda

    Toxicological sciences : an official journal of the Society of Toxicology   183 ( 1 )   227 - 239   2021.8

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press ({OUP})  

    Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment. However, the cardiotoxicity of COVID-19 treatments has not been fully assessed using hiPSC-CMs. In this study, we focused on drug repurposing with various modes of actions and examined the TdP risk associated with COVID-19 treatments using field potential using multi-electrode array system and motion analysis with hiPSC-CMs. Hydroxychloroquine induced early after depolarization, while remdesivir, favipiravir, camostat, and ivermectin had little effect on field potentials. We then analyzed electromechanical window, which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased electromechanical window of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs had little effect. Our data suggest that hydroxychloroquine has proarrhythmic risk and other drugs have low proarrhythmic risk. Thus, hiPSC-CMs represent a useful tool for assessing the comprehensive cardiotoxicity caused by COVID-19 treatments in nonclinical settings.

    DOI： 10.1093/toxsci/kfab079

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  • Refinement of decision tree to assess the consequences of increased serum ALP in dogs: Additional analysis on toxicity studies of pesticides evaluated recently in Japan Reviewed

    Yoko Yokoyama, Atsushi Ono, Midori Yoshida, Kiyoshi Matsumoto, Mikako Saito

    Regulatory Toxicology and Pharmacology   124   104963 - 104963   2021.8

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.yrtph.2021.104963

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  • FTY720 Inhibits Expansion of Breast Cancer Stem Cells via PP2A Activation. Reviewed International journal

    Naoya Hirata, Shigeru Yamada, Shota Yanagida, Atsushi Ono, Yasunari Kanda

    International journal of molecular sciences   22 ( 14 )   2021.7

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    Growing evidence suggests that breast cancer originates from a minor population of cancer cells termed cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry analysis. However, novel therapeutic drugs for the eradication of CSCs have not been discovered yet. Recently, drug repositioning, which finds new medical uses from existing drugs, has been expected to facilitate drug discovery. We have previously reported that sphingosine kinase 1 (SphK1) induced proliferation of breast CSCs. In the present study, we focused on the immunosuppressive agent FTY720 (also known as fingolimod or Gilenya), since FTY720 is known to be an inhibitor of SphK1. We found that FTY720 blocked both proliferation of ALDH-positive cells and formation of mammospheres. In addition, we showed that FTY720 reduced the expression of stem cell markers such as Oct3/4, Sox2 and Nanog via upregulation of protein phosphatase 2A (PP2A). These results suggest that FTY720 is an effective drug for breast CSCs in vitro.

    DOI： 10.3390/ijms22147259

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  • Characterisation and validation of an in vitro transactivation assay based on the 22Rv1/MMTV_GR-KO cell line to detect human androgen receptor agonists and antagonists Reviewed

    Yooheon Park, Da-Woon Jung, Anne Milcamps, Masahiro Takeyoshi, Miriam N. Jacobs, Keith A. Houck, Atsushi Ono, Toine F.H. Bovee, Patience Browne, Nathalie Delrue, YunSook Kang, Hee-Seok Lee

    Food and Chemical Toxicology   152   112206 - 112206   2021.6

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.fct.2021.112206

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  • Improving predictive capacity of the Amino acid Derivative Reactivity Assay test method for skin sensitization potential with an optimal molar concentration of test chemical solution Reviewed International journal

    Mika Imamura, Sayaka Wanibuchi, Yusuke Yamamoto, Hajime Kojima, Atsushi Ono, Toshihiko Kasahara, Masaharu Fujita

    Journal of Applied Toxicology   41 ( 2 )   303 - 329   2021.2

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    The Amino acid Derivative Reactivity Assay (ADRA) is a convenient and effective in chemico test method for assessing covalent binding of test chemicals with protein-derived nucleophilic reagents as a means of predicting skin sensitization potential. Although the original molar-concentration approach to ADRA testing was not suitable for testing multiconstituent substances of an unknown composition, a weight-concentration approach that is suitable for such substances was developed, which also led to the realization that test chemical solutions prepared to molar concentrations higher than the original 1 mM would reduce false negative results as well as enhance predictive capacity. The present study determined an optimal molar-concentration that achieves even higher predictive capacity than the original ADRA. Eight chemicals that were false negatives when tested with 1 mM test chemical solutions were retested with test chemical solutions between 2 and 5 mM, which showed 4 mM to be the optimal molar-concentration for ADRA testing. When 82 chemicals used in the original development were retested with 4 mM test chemical solutions, false negative results were reduced by four. When an additional 85 chemicals used to evaluate the weight-concentration approach to ADRA were retested, the results essentially replicated those obtained with 0.5 mg/ml test chemical solutions and gave 10 fewer false negatives than original ADRA with 1 mM solutions. A comparison of these results for 136 chemicals showed that ADRA testing with 4 mM solutions achieved a four percentage point improvement in accuracy over original ADRA and a two percentage point improvement over DPRA testing.

    DOI： 10.1002/jat.4082

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jat.4082

  • Chronic cardiotoxicity assessment of BMS-986094, a guanosine nucleotide analogue, using human iPS cell-derived cardiomyocytes Reviewed

    Shota Yanagida, Ayano Satsuka, Sayo Hayashi, Atsushi Ono, Yasunari Kanda

    The Journal of Toxicological Sciences   46 ( 8 )   359 - 369   2021

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Toxicology  

    Predicting drug-induced side effects in the cardiovascular system is very important because it can lead to the discontinuation of new drugs/candidates or the withdrawal of marketed drugs. Although chronic assessment of cardiac contractility is an important issue in safety pharmacology, an in vitro evaluation system has not been fully developed. We previously developed an imaging-based contractility assay system to detect acute cardiotoxicity using human iPS cell-derived cardiomyocytes (hiPSC-CMs). To extend the system to chronic toxicity assessment, we examined the effects of the anti-hepatitis C virus (HCV) drug candidate BMS-986094, a guanosine nucleotide analogue, which was withdrawn from phase 2 clinical trials because of unexpected contractility toxicities. Additionally, we examined sofosbuvir, another nucleotide analogue inhibitor of HCV that has been approved as an anti-HCV drug. Motion imaging analysis revealed the difference in cardiotoxicity between the cardiotoxic BMS-986094 and the less toxic sofosbuvir in hiPSC-CMs, with a minimum of 4 days of treatment. In addition, we found that BMS-986094-induced contractility impairment was mediated by a decrease in calcium transient. These data suggest that chronic treatment improves the predictive power for the cardiotoxicity of anti-HCV drugs. Thus, hiPSC-CMs can be a useful tool to assess drug-induced chronic cardiotoxicity in non-clinical settings.

    DOI： 10.2131/jts.46.359

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  • Association between in vitro nuclear receptor-activating profiles of chemical compounds and their in vivo hepatotoxicity in rats Reviewed

    Susumu Kodama, Nao Yoshii, Akihiro Ota, Jun-ichi Takeshita, Kouichi Yoshinari, Atsushi Ono

    The Journal of Toxicological Sciences   46 ( 12 )   569 - 587   2021

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    Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Toxicology  

    DOI： 10.2131/jts.46.569

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  • Oxidation of a cysteine‐derived nucleophilic reagent by dimethyl sulfoxide in the amino acid derivative reactivity assay Reviewed International journal

    Miyuki Akimoto, Yusuke Yamamoto, Shinichi Watanabe, Hiroaki Yamaga, Kousuke Yoshida, Koji Wakabayashi, Yu Tahara, Nobuyuki Horie, Keiichi Fujimoto, Kei Kusakari, Kohei Kamiya, Kohichi Kojima, Tsuyoshi Kawakami, Hajime Kojima, Atsushi Ono, Toshihiko Kasahara, Masaharu Fujita

    Journal of Applied Toxicology   40 ( 6 )   843 - 854   2020.6

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    The amino acid derivative reactivity assay (ADRA), which is an in chemico alternative to the use of animals in testing for skin sensitization potential, offers significant advantages over the direct peptide reactivity assay (DPRA) in that it utilizes nucleophilic reagents that are sensitive enough to be used with test chemical solutions prepared to concentrations of 1 mm, which is one-hundredth that of DPRA. ADRA testing of hydrophobic or other poorly soluble compounds requires that they be dissolved in a solvent consisting of dimethyl sulfoxide (DMSO) and acetonitrile. DMSO is known to promote dimerization by oxidizing thiols, which then form disulfide bonds. We investigated the extent to which DMSO oxidizes the cysteine-derived nucleophilic reagents used in both DPRA and ADRA and found that oxidation of both N-(2-(1-naphthyl)acetyl)-l-cysteine (NAC) and cysteine peptide increases as the concentration of DMSO increases, thereby lowering the concentration of the nucleophilic reagent. We also found that use of a solvent consisting of 5% DMSO in acetonitrile consistently lowered NAC concentrations by about 0.4 μm relative to the use of solvents containing no DMSO. We also tested nine sensitizers and four nonsensitizers having different sensitization potencies to compare NAC depletion with and without 5% DMSO and found that reactivity was about the same with either solvent. Based on the above, we conclude that the use of a solvent containing 5% DMSO has no effect on the accuracy of ADRA test results. We plan to review and propose revisions to OECD Test Guideline 442C based on the above investigation.

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  • Toxicological significance of increased serum alkaline phosphatase activity in dog studies of pesticides: Analysis of toxicological data evaluated in Japan Reviewed

    Yoko Yokoyama, Atsushi Ono, Midori Yoshida, Kiyoshi Matsumoto, Mikako Saito

    Regulatory Toxicology and Pharmacology   109   104482 - 104482   2019.12

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  • The within- and between-laboratory reproducibility and predictive capacity of the in chemico amino acid derivative reactivity assay: Results of validation study implemented in four participating laboratories. Reviewed International journal

    Masaharu Fujita, Yusuke Yamamoto, Shinichi Watanabe, Tsunetsugu Sugawara, Koji Wakabayashi, Yu Tahara, Nobuyuki Horie, Keiichi Fujimoto, Kei Kusakari, Yoshihiko Kurokawa, Tsuyoshi Kawakami, Kohichi Kojima, Takashi Sozu, Takuto Nakayama, Takeru Kusao, Jon Richmond, Kleinstreuer Nicole, Bae-Hwa Kim, Hajime Kojima, Toshihiko Kasahara, Atsushi Ono

    Journal of applied toxicology : JAT   39 ( 11 )   1492 - 1505   2019.11

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    The amino acid derivative reactivity assay (ADRA) is an in chemico alternative method that focuses on protein binding as the molecular initiating event for skin sensitization. It is a simple and versatile method that has successfully solved some of the problems of the direct peptide reactivity assay (DPRA). The transferability and within- and between-laboratory reproducibility of ADRA were evaluated and confirmed as part of a validation study conducted at four participating laboratories. The transfer of ADRA technology from the lead laboratory to the four participating laboratories was completed successfully during a two-step training program, after which the skin sensitization potentials of 40 coded chemicals were predicted based on the results of ADRA testing. Within-laboratories reproducibility was 100% (10 of 10), 100% (10 of 10), 100% (7 of 7) and 90% (9 of 10), or an average of 97.3% (36 of 37); between-laboratory reproducibility as calculated on the results of three laboratories at the time was 91.9%. The overall predictive capacity comprised an accuracy of 86.9%, sensitivity of 81.5% and specificity of 98.1%. These results satisfied the targets set by the validation management team for demonstrating transferability, within- and between-laboratory reproducibility, and predictive capacity as well as gave a clear indication that ADRA is easily transferable and sufficiently robust to be used in place of DPRA.

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  • The within‐ and between‐laboratory reproducibility and predictive capacity of the in chemico amino acid derivative reactivity assay: Results of validation study implemented in four participating laboratories Reviewed International journal

    Masaharu Fujita, Yusuke Yamamoto, Shinichi Watanabe, Tsunetsugu Sugawara, Koji Wakabayashi, Yu Tahara, Nobuyuki Horie, Keiichi Fujimoto, Kei Kusakari, Yoshihiko Kurokawa, Tsuyoshi Kawakami, Kohichi Kojima, Takashi Sozu, Takuto Nakayama, Takeru Kusao, Jon Richmond, Kleinstreuer Nicole, Bae‐Hwa Kim, Hajime Kojima, Toshihiko Kasahara, Atsushi Ono

    Journal of Applied Toxicology   42 ( 6 )   1078 - 1090   2019.7

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    The amino acid derivative reactivity assay (ADRA) is an in chemico alternative assay for skin sensitization listed in OECD test guideline 442C. ADRA evaluates the reactivity of sensitizers to proteins, which is key event 1 in the skin sensitization adverse outcome pathway. Although the current key event 1 evaluation method is a simple assay that evaluates nucleophile and test chemical reactivity, mixtures of unknown molecular weights cannot be evaluated because a constant molar ratio between the nucleophile and test chemical is necessary. In addition, because the nucleophile is quantified by HPLC, the frequency of co-eluting the test chemical and nucleophile increases when measuring multi-component mixtures. To solve these issues, test conditions have been developed using a 0.5 mg/mL test chemical solution and fluorescence-based detection. Since the practicality of these methods has not been substantiated, a validation test to confirm reproducibility was conducted in this study. The 10 proficiency substances listed in the ADRA guidelines were tested three times at five different laboratories. The results of both within- and between-laboratory reproducibility were 100%, and the results of ultraviolet- and fluorescence-based measurements were also consistent. In addition to the proficiency substances, a new positive control, squaric acid diethyl ester, was tested three times at the five laboratories. The results showed high reproducibility with N-(2-(1-naphthyl)acetyl)-l-cysteine depletion of 37%-52% and α-N-(2-(1-naphthyl)acetyl)-l-lysine depletion of 99%-100%. Thus, high reproducibility was confirmed in both evaluations of the 0.5 mg/mL test chemical and the fluorescence-based measurements, validating the practicability of these methods.

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  • Expanding the applicability of the amino acid derivative reactivity assay: Determining a weight for preparation of test chemical solutions that yield a predictive capacity identical to the conventional method using molar concentration and demonstrating the capacity to detect sensitizers in liquid mixtures Reviewed

    Yusuke Yamamoto, Masaru Fujita, Sayaka Wanibuchi, Yasuhiro Katsuoka, Atsushi Ono, Toshihiko Kasahara

    Journal of Pharmacological and Toxicological Methods   97   67 - 79   2019.5

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  • Cause of and countermeasures for oxidation of the cysteine-derived reagent used in the amino acid derivative reactivity assay Reviewed International journal

    Masaharu Fujita, Yusuke Yamamoto, Shinichi Watanabe, Tsunetsugu Sugawara, Koji Wakabayashi, Yu Tahara, Nobuyuki Horie, Keiichi Fujimoto, Kei Kusakari, Yoshihiko Kurokawa, Tsuyoshi Kawakami, Kohichi Kojima, Hajime Kojima, Atsushi Ono, Yasuhiro Katsuoka, Hideto Tanabe, Hiroshi Yokoyama, Toshihiko Kasahara

    Journal of Applied Toxicology   39 ( 2 )   191 - 208   2019.2

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    DOI： 10.1002/jat.3707

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  • Applicability of amino acid derivative reactivity assay for prediction of skin sensitization by combining multiple alternative methods to evaluate key events Reviewed

    Yusuke Yamamoto, Masaharu Fujita, Sayaka Wanibuchi, Ayako Sato, Miyuki Akimoto, Yasuhiro Katsuoka, Atsushi Ono, Toshihiko Kasahara

    The Journal of Toxicological Sciences   44 ( 9 )   585 - 600   2019

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    Amino acid derivative reactivity assay (ADRA) has previously been developed as an alternative method to direct peptide reactivity assay (DPRA) to evaluate key event 1 in skin sensitization mechanisms. However, when using alternative methods for skin sensitization, integrated approaches to testing and assessment (IATA) that combine the results of multiple tests evaluating different key events are generally required. To verify whether ADRA can be used in IATA, we replaced DPRA with ADRA in five IATA methods combining DPRA, KeratinoSens, and h-CLAT: (i) the “2 out of 3” approach, (ii) the “3 out of 3” approach, (iii) sequential testing strategy (STS), (iv) integrated testing strategy by scoring approach (ITS-SA), and (v) the “ITS by two methods approach” (ITS-2MA). The prediction accuracy of the “2 out of 3” approach using ADRA (1 mM) and ADRA (0.5 mg/mL) was 90.0% and 91.1%, respectively, for human data, and was very similar to that obtained using DPRA (91.1%). The “3 out of 3” approach also showed good predictability (83.2%) using either ADRA (1 mM) or ADRA (0.5 mg/mL) compared to DPRA. Regarding the accuracy of the prediction of sensitization intensity for the human data by the third classification, prediction accuracy using ADRA was almost the same as STS, ITS-SA, or ITS-2MA using DPRA. As a result, this study showed that ADRA can be used as a test method for key event 1 in the evaluation of skin sensitization by combining multiple alternative methods.

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  • A Summary Report of FSCJ Workshop “Future Challenges and Opportunities in Developing Methodologies for Improved Human Risk Assessments” Reviewed

    Kaoruko Tachibana, George E.N. Kass, Atsushi Ono, Takashi Yamada, Weida Tong, Daniel R. Doerge, Yasushi Yamazoe

    Food Safety   7 ( 4 )   83 - 89   2019

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    DOI： 10.14252/foodsafetyfscj.2018017

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  • Initial hazard assessment of 4-benzylphenol, a structural analog of bisphenol F: Genotoxicity tests in vitro and a 28-day repeated-dose toxicity study in rats Reviewed

    Toshime Igarashi, Hideki Serizawa, Katsumi Kobayashi, Hiroshi Suzuki, Mariko Matsumoto, Takako Iso, Tomoko Kawamura, Kaoru Inoue, Atsushi Ono, Takashi Yamada, Akihiko Hirose

    Regulatory Toxicology and Pharmacology   96   64 - 75   2018.7

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    DOI： 10.1016/j.yrtph.2018.04.017

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  • Evaluation of Necessity of 1-year Toxicity Study in Dogs - development of the New Tiered Approach for Toxicity Studies of Pesticide Considering Species Difference in “toxicity profile” and “toxicity dose-response” Reviewed

    Atsushi Ono, Takahiro Yoshizawa, Kiyoshi Matsumoto

    Food Safety   6 ( 3 )   109 - 117   2018

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  • Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor a (PPARa) activity of an ultraviolet absorber, 2-(2 '-hydroxy-3 ',5 '-di-tert-butylphenyl) benzotriazole, as possible mechanism of their toxicity and the gender differences Reviewed

    Mutsuko Hirata-Koizumi, Ryota Ise, Hirohito Kato, Takashi Matsuyama, Tomoko Nishimaki-Mogami, Mika Takahashi, Atsushi Ono, Makoto Ema, Akihiko Hirose

    JOURNAL OF TOXICOLOGICAL SCIENCES   41 ( 5 )   693 - 700   2016.10

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  • Analysis of toxicity studies that has been used as basis of the ADI setting of pesticide in Japan

    ONO Atsushi

    Annual Meeting of the Japanese Society of Toxicology   43   S7 - 2   2016

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    DOI： 10.14869/toxpt.43.1.0_S7-2

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  • Screening for repeated dose and reproductive/developmental toxicity of 1,4-dichlorobutane in rats

    IGARASHI Toshime, KOBAYASHI Katsumi, KAWAMURA Tomoko, MATSUMOTO Mariko, NAGASE Takahiko, KATSUMATA Yoshihiro, ONO Atsushi, YAMADA Takashi, HIROSE Akihiko

    Annual Meeting of the Japanese Society of Toxicology   43   P - 204   2016

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  • A repeated dose 28-day oral toxicity study of β-bromostyrene in rats Reviewed

    Ono, A, Kobayashi, K, Serizawa, H, Kawamura, T, Kato, H, Matsumoto, M, Takahashi, M, Hirata-Koizumi, M, Matsushima, Y, Hirose, A

    Fundam. Toxicol. Sci.   2 ( 4 )   191 - 200   2015

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    To obtain information on the possible repeated-dose oral toxicity of β-bromostyrene and its reversibility, Crl: CD (SD) rats were administered β-bromostyrene through gavage at 0, 30, 125, and 500 mg/kg/day once for 28 days, followed by a 14-day recovery period. In the 500 mg/kg group, decrease in spontaneous movement was observed in all males and females on the first dosing day, and one female rat died on Day 3. There were no significant changes in body weight or food consumption. An increase in urine volume and decrease in urine osmolality were observed in males receiving 125 mg/kg and above, and an increase in urine volume was observed in females receiving 500 mg/kg. On blood biochemical examination, increases in total cholesterol, phospholipids, triglycerides, total protein, albumin, inorganic phosphorus, and/or chlorine were observed in the 125 and/or 500 mg/kg groups. Histopathologically, eosinophilic bodies of tubular cells and/or renal tubular degeneration were observed in the kidneys of males in the 125 and 500 mg/kg groups. In the thyroid, hypertrophy of follicular cells was observed in females receiving 125 mg/kg and above and males receiving 500 mg/kg. Furthermore, centrilobular hepatocellular hypertrophy was observed in both sexes receiving 500 mg/kg. These changes observed at the end of the dosing period disappeared or were reduced after the recovery period. Based on these results, the no-observed-adverse-effect-level of β-bromostyrene was judged to be 30 mg/kg/day for both sexes.

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  • Repeated dose and reproductive/developmental toxicity of long-chain perfluoroalkyl carboxylic acids in rats: perfluorohexadecanoic acid and perfluorotetradecanoic acid Reviewed

    Hirata-Koizumi, M, Fujii, S, Kato, H, Matsumoto, M, Takahashi, M, Ono, A, Hirose, A

    Fundam. Toxicol. Sci.   2 ( 4 )   177 - 190   2015

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    Perfluoroalkyl carboxylic acids (PFCAs) are global environmental contaminants that are the cause of concern due to their possible effects on wildlife and human health. Since few studies have investigated the toxicity of long-chain PFCAs, we have performed combined repeated dose toxicity studies with the reproduction/developmental toxicity screening tests. We previously examined perfluoroundecanoic acid (C11), perfluorododecanoic acid (C12), and perfluorooctadecanoic acid (C18). We herein reported our results for perfluorotetradecanoic acid (PFTeDA; C14) and perfluorohexadecanoic acid (PFHxDA: C16). Male and female rats were administered PFTeDA at 1, 3 or 10 mg/kg/day or PFHxDA at 4, 20 or 100 mg/kg/day by gavage, and each female was then mated with a male in the same dose group after 14 days. Males were dosed for a total of 42 days and females were dosed throughout the gestation period until day 5 after parturition. PFTeDA and PFHxDA caused hepatocyte hypertrophy and/or fatty changes in the liver at the middle and high doses. PFTeDA also induced follicular cell hypertrophy in the thyroid at the middle and high doses. The only reproductive/developmental effect observed was an inhibited postnatal body weight gain in pups in the 10 mg/kg/day PFTeDA group. Based on these results, the NOAELs for the repeated dose and reproductive/developmental toxicity were concluded to be 1 and 3 mg/kg/day for PFTeDA and 4 and 100 mg/kg/day for PFHxDA, respectively. Our current and previous results indicate that the toxicity of PFCAs decreases with increases in the carbon chain length from 12 to 18.

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  • Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model Reviewed

    Ko Omura, Takeki Uehara, Yuji Morikawa, Hitomi Hayashi, Kunitoshi Mitsumori, Keiichi Minami, Masayuki Kanki, Hiroshi Yamada, Atsushi Ono, Tetsuro Urushidani

    JOURNAL OF TOXICOLOGICAL SCIENCES   39 ( 6 )   837 - 848   2014.12

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  • Detection of initiating potential of non-genotoxic carcinogens in a two-stage hepatocarcinogenesis study in rats Reviewed

    Ko Omura, Takeki Uehara, Yuji Morikawa, Hitomi Hayashi, Kunitoshi Mitsumori, Keiichi Minami, Masayuki Kanki, Hiroshi Yamada, Atsushi Ono, Tetsuro Urushidani

    JOURNAL OF TOXICOLOGICAL SCIENCES   39 ( 5 )   785 - 794   2014.10

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  • Repeated dose and reproductive/developmental toxicity of perfluoroundecanoic acid in rats Reviewed

    Mika Takahashi, Shigeru Ishida, Mutsuko Hirata-Koizumi, Atsushi Ono, Akihiko Hirose

    JOURNAL OF TOXICOLOGICAL SCIENCES   39 ( 1 )   97 - 108   2014.2

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  • A new parameter that supports speculation on the possible mechanism of hypothyroidism induced by chemical substances in repeated-dose toxicity studies Reviewed

    Takashi Yamada, Ryuichi Hasegawa, Satoshi Nishikawa, Yuki Sakuratani, Jun Yamada, Tatsuhiro Yamashita, Koichi Yoshinari, Yasushi Yamazoe, Eiichi Kamata, Atsushi Ono, Akihiko Hirose, Makoto Hayashi

    JOURNAL OF TOXICOLOGICAL SCIENCES   38 ( 2 )   291 - 299   2013.4

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  • Simulation of acute reference dose (ARfD) settings for pesticides in Japan Reviewed

    Midori Yoshida, Daisetsu Suzuki, Kiyoshi Matsumoto, Mariko Shirota, Kaoru Inoue, Miwa Takahashi, Takeshi Morita, Atsushi Ono

    JOURNAL OF TOXICOLOGICAL SCIENCES   38 ( 2 )   205 - 214   2013.4

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  • Ovariectomized mouse uterotrophic assay of 36 chemicals Reviewed

    Ryo Ohta, Atsuya Takagi, Hideo Ohmukai, Hideki Marumo, Atsushi Ono, Yuko Matsushima, Tohru Inoue, Hiroshi Ono, Jun Kanno

    JOURNAL OF TOXICOLOGICAL SCIENCES   37 ( 5 )   879 - 889   2012.10

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  • Evaluation of DNA microarray results in the Toxicogenomics Project (TGP) consortium in Japan Reviewed

    Nakatsu Noriyuki, Yoshinobu Igarashi, Atsushi Ono, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani

    JOURNAL OF TOXICOLOGICAL SCIENCES   37 ( 4 )   791 - 801   2012.8

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  • No toxicological effects on acute and repeated oral gavage doses of single-wall or multi-wall carbon nanotube in rats Reviewed

    Mariko Matsumoto, Hideki Serizawa, Masao Sunaga, Hina Kato, Mika Takahashi, Mutsuko Hirata-Koizumi, Atsushi Ono, Eiichi Kamata, Akihiko Hirose

    JOURNAL OF TOXICOLOGICAL SCIENCES   37 ( 3 )   463 - 474   2012.6

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  • Validation of the (Q)SAR combination approach for mutagenicity prediction of flavor chemicals Reviewed

    Atsushi Ono, Mika Takahashi, Akihiko Hirose, Eiichi Kamata, Tomoko Kawamura, Takeshi Yamazaki, Kyoko Sato, Masami Yamada, Takayuki Fukumoto, Hiroyuki Okamura, Yoshiharu Mirokuji, Masamitsu Honma

    FOOD AND CHEMICAL TOXICOLOGY   50 ( 5 )   1538 - 1546   2012.5

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    DOI： 10.1016/j.fct.2012.02.009

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  • Sub-acute oral toxicity study with fullerene C60 in rats Reviewed

    Mika Takahashi, Hina Kato, Yuko Doi, Akihiro Hagiwara, Mutsuko Hirata-Koizumi, Atsushi Ono, Reiji Kubota, Tetsuji Nishimura, Akihiko Hirose

    JOURNAL OF TOXICOLOGICAL SCIENCES   37 ( 2 )   353 - 361   2012.4

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  • Repeated dose and reproductive/developmental toxicity of perfluorooctadecanoic acid in rats Reviewed

    Mutsuko Hirata-Koizumi, Sakiko Fujii, Masatoshi Furukawa, Atsushi Ono, Akihiko Hirose

    JOURNAL OF TOXICOLOGICAL SCIENCES   37 ( 1 )   63 - 79   2012.2

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    DOI： 10.2131/jts.37.63

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  • Molecular toxicological evaluations of hepatocarcinogenesis in rat 2-stage liver carcinogenesis model -3. Comprehensive DNA methylation analysis of liver using next generation sequencer

    OMURA Ko, UEHARA Takeki, HAYASHI Hitomi, MITSUMORI Kunitoshi, KANKI Masayuki, MINAMI Keiichi, NAKATSU Noriyuki, ONO Atsushi, YAMADA Hiroshi, OHNO Yasuo, URUSHIDANI Tetsuro

    Annual Meeting of the Japanese Society of Toxicology   39   P - 240   2012

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    DOI： 10.14869/toxpt.39.1.0.P-240.0

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  • Molecular toxicological evaluations of hepatocarcinogenesis in rat 2-stage liver carcinogenesis model -4. hepatic glycan profile analysis by using lectin array

    MINAMI Keiichi, UEHARA Takeki, HAYASHI Hitomi, MITSUMORI Kunitoshi, OMURA Ko, KANKI Masayuki, ONO Atsushi, YAMADA Hiroshi, OHNO Yasuo, URUSHIDANI Tetsuro

    Annual Meeting of the Japanese Society of Toxicology   39   P - 237   2012

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  • The need for acute exposure assessment and acute reference dose

    ONO Atsushi

    Annual Meeting of the Japanese Society of Toxicology   39   S7 - 1   2012

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    DOI： 10.14869/toxpt.39.1.0.S7-1.0

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  • Combined repeated dose and reproductive/developmental toxicity screening test of perfluorododecanoic acid in rats

    HIRATA-KOIZUMI Mutsuko, FUJII Sakiko, FURUKAWA Masatoshi, TAKAHASHI Mika, KAWAMURA Tomoko, MATSUMOTO Mariko, KATOH Hina, ONO Atsushi, HIROSE Akihiko

    Annual Meeting of the Japanese Society of Toxicology   39   P - 126   2012

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  • MicroRNA expression analysis in cisplatin-treated rat urine

    MINAMI Keiichi, NITTA Hiroyuki, UEHARA Takeki, UENISHI Chiaki, IGARASHI Yoshinobu, KANKI Masayuki, KINO Jun-ichi, ABE Kaori, HORINOUCHI Akira, ONO Atsushi, YAMADA Hiroshi, URUSHIDANI Tetsuro, OHNO Yasuo

    Annual Meeting of the Japanese Society of Toxicology   39   P - 236   2012

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  • Molecular toxicological evaluations of hepatocarcinogenesis in rat 2-stage liver carcinogenesis model -1. application of toxicogenomics for sensitive detection of initiation activity of hepatocarcinogens

    UEHARA Takeki, MORIKAWA Yuji, HAYASHI Hitomi, MITSUMORI Kunitoshi, KANKI Masayuki, OMURA Ko, MINAMI Keiichi, NAKATSU Noriyuki, ONO Atsushi, YAMADA Hiroshi, OHNO Yasuo, URUSHIDANI Tetsuro

    Annual Meeting of the Japanese Society of Toxicology   39   P - 238   2012

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  • Toxicopathological effect of co-exposure to different phthalate esters on the liver and male genital system by 90 days repeated administration in rats

    SUZUKI Kazuhiko, TANIAI Eriko, ONO Atsushi, ISHII Yuji, MORITA Reiko, YAFUNE Atsunori, MITSUMORI Kunitoshi, SHIBUTANI Makoto

    Annual Meeting of the Japanese Society of Toxicology   39   P - 166   2012

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  • Discrimination of PPARα agonists in the human hepatocyte transcriptome database and its verification

    MIZUKAWA Yumiko, MORIKAWA Yuji, NAKATSU Noriyuki, ONO Atsushi, YAMADA Hiroshi, OHNO Yasuo, URUSHIDANI Tetsuro

    Annual Meeting of the Japanese Society of Toxicology   39   P - 233   2012

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  • Identification of genomic biomarkers for assessment of endoplasmic reticulum stress in liver using a toxicogenomics database

    MORIKAWA Yuji, UEHARA Takeki, NAKATSU Noriyuki, ONO Atsushi, YAMADA Hiroshi, OHNO Yasuo, URUSHIDANI Tetsuro

    Annual Meeting of the Japanese Society of Toxicology   39   P - 230   2012

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  • Molecular toxicological evaluations of hepatocarcinogenesis in rat 2-stage liver carcinogenesis model -2. comprehensive microRNA analysis and exploring biomarkers in the liver and plasma

    KANKI Masayuki, UEHARA Takeki, HAYASHI Hitomi, MITSUMORI Kunitoshi, OMURA Ko, MINAMI Keiichi, NAKATSU Noriyuki, ONO Atsushi, YAMADA Hiroshi, OHNO Yasuo, URUSHIDANI Tetsuro

    Annual Meeting of the Japanese Society of Toxicology   39   P - 239   2012

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    DOI： 10.14869/toxpt.39.1.0.P-239.0

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  • Repeated dose toxicityof fullerene C60 by gavage for a month in rats

    HIROSE Akihiko, TAKAHASHI Mika, KATO Hina, DOI Yuko, HAGIWARA Akihiro, HIRATA-KOIZUMI Mutsuko, ONO Atsushi, KUBOTA Reiji, NISHIMURA Tetsuji

    Annual Meeting of the Japanese Society of Toxicology   39   AP - 166   2012

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    To assess the repeated-dose toxicity of fullerene C60 by oral exposure, an OECD guideline test (TG 407) was conducted with administration of fullerene C60 at 0 (vehicle: corn oil), 1, 10, 100, or 1,000 mg/kg/day for 29 days in rats. No changes were observed in clinical observations, body weights, and food consumption in any treatment groups. Moreover, no treatment-related histopathological changes were found in any organs examined. Blackish feces and black contents of the stomach and large intestine were observed in males and females at 1,000 mg/kg/day in the treatment group. No significant changes in any organ weights were observed at the end of the administration period, but the only organ weights in liver and spleen in the 1,000 mg/kg/day group of male were increased at the end of the recovery period (14 days after the treatment period). The causal relationships between the possible absorption of fullerene C60 and those weight changes were suggested, but the pathological findings as indirect influences, such as swelling and congestion, were not also observed in the those organs. Using LC-MS/MS spectrometry analysis, fullerene C60 were not detected in the liver, spleen or kidney at the end of the administration period and also at the end of the recovery period. In conclusion, the present study revealed no toxicological effects of fullerene C60; however, with the prospective exposure by increased uses in future because of low toxic substance, more long-term exposure study is necessary to clarify the effects of fullerene C60 via oral exposure.

    DOI： 10.14869/toxpt.39.2.0.AP-166.0

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  • Prediction model of potential hepatocarcinogenicity of rat hepatocarcinogens using a large-scale toxicogenomics database Reviewed

    Takeki Uehara, Yohsuke Minowa, Yuji Morikawa, Chiaki Kondo, Toshiyuki Maruyama, Ikuo Kato, Noriyuki Nakatsu, Yoshinobu Igarashi, Atsushi Ono, Hitomi Hayashi, Kunitoshi Mitsumori, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani

    TOXICOLOGY AND APPLIED PHARMACOLOGY   255 ( 3 )   297 - 306   2011.9

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    DOI： 10.1016/j.taap.2011.07.001

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  • Evaluation of the reproductive and developmental toxicity of aluminium ammonium sulfate in a two-generation study in rats Reviewed

    Mutsuko Hirata-Koizumi, Sakiko Fujii, Atsushi Ono, Akihiko Hirose, Toshio Imai, Kumiko Ogawa, Makoto Ema, Akiyoshi Nishikawa

    FOOD AND CHEMICAL TOXICOLOGY   49 ( 9 )   1948 - 1959   2011.9

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    DOI： 10.1016/j.fct.2011.04.035

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  • Two-generation reproductive toxicity study of aluminium sulfate in rats Reviewed

    Mutsuko Hirata-Koizumi, Sakiko Fujii, Atsushi Ono, Akihiko Hirose, Toshio Imai, Kumiko Ogawa, Makoto Ema, Akiyoshi Nishikawa

    REPRODUCTIVE TOXICOLOGY   31 ( 2 )   219 - 230   2011.2

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    DOI： 10.1016/j.reprotox.2010.11.004

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  • Proposal of new uncertainty factor application to derive tolerable daily intake Reviewed

    Ryuichi Hasegawa, Mutsuko Hirata-Koizumi, Michael L. Dourson, Ann Parker, Lisa M. Sweeney, Akiyoshi Nishikawa, Midori Yoshida, Atsushi Ono, Akihiko Hirose

    REGULATORY TOXICOLOGY AND PHARMACOLOGY   58 ( 2 )   237 - 242   2010.11

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    DOI： 10.1016/j.yrtph.2010.06.006

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  • The Japanese toxicogenomics project: Application of toxicogenomics Reviewed

    Takeki Uehara, Atsushi Ono, Toshiyuki Maruyama, Ikuo Kato, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani

    MOLECULAR NUTRITION & FOOD RESEARCH   54 ( 2 )   218 - 227   2010.2

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    DOI： 10.1002/mnfr.200900169

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  • Perspective of predictive toxicity assessment of in vivo repeated dose toxicity using structural activity relationship Reviewed

    Atsushi Ono

    Bulletin of National Institute of Health Sciences   ( 128 )   44 - 49   2010

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  • Identification of genomic biomarkers for concurrent diagnosis of drug-induced renal tubular injury using a large-scale toxicogenomics database Reviewed

    Chiaki Kondo, Yohsuke Minowa, Takeki Uehara, Yasushi Okuno, Noriyuki Nakatsu, Atsushi Ono, Toshiyuki Maruyama, Ikuo Kato, Jyoji Yamate, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani

    TOXICOLOGY   265 ( 1-2 )   15 - 26   2009.11

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    DOI： 10.1016/j.tox.2009.09.003

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  • Gene expression profiling in rat liver treated with various hepatotoxic-compounds inducing coagulopathy Reviewed

    Mitsuhiro Hirode, Ko Omura, Naoki Kiyosawa, Takeki Uehara, Toshinobu Shimuzu, Atsushi Ono, Toshikazu Miyagishima, Taku Nagao, Yasuo Ohno, Tetsuro Urushidani

    JOURNAL OF TOXICOLOGICAL SCIENCES   34 ( 3 )   281 - 293   2009.6

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    DOI： 10.2131/jts.34.281

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  • A toxicogenomics approach for early assessment of potential non-genotoxic hepatocarcinogenicity of chemicals in rats Reviewed

    Takeki Uehara, Mitsuhiro Hirode, Atsushi Ono, Naoki Kiyosawa, Ko Omura, Toshinobu Shimizu, Yumiko Mizukawa, Toshikazu Miyagishima, Taku Nagao, Tetsuro Urushidani

    TOXICOLOGY   250 ( 1 )   15 - 26   2008.8

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    DOI： 10.1016/j.tox.2008.05.013

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  • Gene expression profiling in rat liver treated with compounds inducing phospholipidosis Reviewed

    Mitsuhiro Hirode, Atsushi Ono, Toshikazu Miyagishima, Taku Nagao, Yasuo Ohno, Tetsuro Urushidani

    TOXICOLOGY AND APPLIED PHARMACOLOGY   229 ( 3 )   290 - 299   2008.6

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    DOI： 10.1016/j.taap.2008.01.036

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  • Gene expression profiling of methapyrilene-induced hepatotoxicity in rat Reviewed

    Takeki Uehara, Naoki Kiyosawa, Mitsuhiro Hirode, Ko Omura, Toshinobu Shimizu, Atsushi Ono, Yumiko Mizukawa, Toshikazu Miyagishima, Taku Nagao, Tetsuro Urushidani

    JOURNAL OF TOXICOLOGICAL SCIENCES   33 ( 1 )   37 - 50   2008.2

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    DOI： 10.2131/jts.33.37

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  • Identification of glutathione depletion-responsive genes using phorone-treated rat liver Reviewed

    Naoki Kiyosawa, Takeki Uehara, Weihua Gao, Ko Omura, Mitsuhiro Hirode, Toshinobu Shimizu, Yumiko Mizukawa, Atsushi Ono, Toshikazu Miyagishima, Taku Nagao, Tetsuro Urushidani

    Journal of Toxicological Sciences   32 ( 5 )   469 - 486   2007.12

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    DOI： 10.2131/jts.32.469

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  • Gene expression profiling of rat liver treated with serum triglyceride-decreasing compounds Reviewed

    Ko Omura, Naoki Kiyosawa, Takeki Uehara, Mitsuhiro Hirode, Toshinobu Shimizu, Toshikazu Miyagishima, Atsushi Ono, Taku Nagao, Tetsuro Urushidani

    Journal of Toxicological Sciences   32 ( 4 )   387 - 399   2007.10

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    DOI： 10.2131/jts.32.387

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  • Evaluation of methods for duration of preservation of RNA quality in rat liver used for transcriptome analysis Reviewed

    Toshihiko Kasahara, Toshiko Miyazaki, Hiroyuki Nitta, Atsushi Ono, Toshikazu Miyagishima, Taku Nagao, Tetsuro Urushidani

    Journal of Toxicological Sciences   31 ( 5 )   509 - 519   2006.12

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    DOI： 10.2131/jts.31.509

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  • Utilization of a one-dimensional score for surveying chemical-induced changes in expression levels of multiple biomarker gene sets using a large-scale toxicogenomics database Reviewed

    Naoki Kiyosawa, Kouji Shiwaku, Mitsuhiro Hirode, Ko Omura, Takeki Uehara, Toshinobu Shimizu, Yumiko Mizukawa, Toshikazu Miyagishima, Atsushi Ono, Taku Nagao, Tetsuro Urushidani

    Journal of Toxicological Sciences   31 ( 5 )   433 - 448   2006.12

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    DOI： 10.2131/jts.31.433

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  • Comparison of gene expression profiles among papilla, medulla and cortex in rat kidney Reviewed

    Kotaro Tamura, Atsushi Ono, Toshikazu Miyagishima, Taku Nagao, Tetsuro Urushidani

    Journal of Toxicological Sciences   31 ( 5 )   449 - 469   2006.12

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    DOI： 10.2131/jts.31.449

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  • Profiling of gene expression in rat liver and rat primary cultured hepatocytes treated with peroxisome proliferators Reviewed

    Kotaro Tamura, Atsushi Ono, Toshikazu Miyagishima, Taku Nagao, Tetsuro Urushidani

    Journal of Toxicological Sciences   31 ( 5 )   471 - 490   2006.12

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    DOI： 10.2131/jts.31.471

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  • "Per cell" normalization method for mRNA measurement by quantitative PCR and microarrays Reviewed

    J Kanno, K Aisaki, K Igarashi, N Nakatsu, A Ono, Y Kodama, T Nagao

    BMC GENOMICS   7   64   2006.3

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    DOI： 10.1186/1471-2164-7-64

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  • Screening of endocrine disrupting chemicals using a surface plasmon resonance sensor Reviewed

    K Asano, A Ono, S Hashimoto, T Inoue, J Kanno

    ANALYTICAL SCIENCES   20 ( 4 )   611 - 616   2004.4

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    DOI： 10.2116/analsci.20.611

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  • Hemopoietic stem cells and ageing with a special reference to the mechanism of aging.

    Inoue Tohru, Ono Atsushi, Hirabayashi Yoko

    The journal of the Japanese Society of Lymphoreticular Tissue research   36 ( 4 )   217 - 225   1996

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    DOI： 10.3960/jslrt1961.36.217

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Books

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Awards

  • Pfizer Prize

    2024.7   Japanese society of toxicology  

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  • 学会賞

    2020.11   日本実験動物代替法学会  

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    2020.6   日本毒性学会  

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Research Projects

  • 内分泌かく乱in vitroスクリーニング

    厚生労働科学研究費補助金 

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  • 構造活性相関

    厚生労働科学研究費補助金 

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  • トキシコゲノミクス

    厚生労働科学研究費補助金 

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