The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 48, Issue 7
Displaying 1-6 of 6 articles from this issue
Original Article
  • Ryuichi Kambayashi, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, A ...
    2023 Volume 48 Issue 7 Pages 375-385
    Published: 2023
    Released on J-STAGE: July 03, 2023
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    Supplementary material

    Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.

Original Article
  • Sen Guan, Fan Miao, Dongmei Wang, Jie Hu, Huimiao Wang
    2023 Volume 48 Issue 7 Pages 387-398
    Published: 2023
    Released on J-STAGE: July 03, 2023
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    Morphine-induced microglia activation and neuroinflammation have been considered as the contributors of morphine tolerance. Corilagin (Cori) has been reported to exhibit strong anti-inflammatory property. The present study aims to investigate whether and how Cori alleviates morphine-induced neuroinflammation and microglia activation. Mouse BV-2 cells were exposed to different concentrations of Cori (0.1, 1 and 10 μM) prior to morphine stimulation (200 μM). Minocycline (10 μM) acted as the positive control. Cell viability was determined by CCK-8 assay and trypan blue assay. The levels of inflammatory cytokines were determined using ELISA. IBA-1 level was examined via immunofluorescence. TLR2 expression level was examined by quantitative real-time PCR and western blot. The expression levels of corresponding proteins were measured by western blot. It was found that Cori was non-toxic to BV-2 cells but greatly inhibited morphine-induced IBA-1 expression, overproduction of pro-inflammatory cytokines, activation of NLRP3 inflammasome and endoplasmic reticulum stress (ERS), and upregulation of COX-2 and iNOS. TLR2 was negatively regulated by Cori, and could promote the activation of ERS. A high affinity between Cori and TLR2 protein was confirmed via Molecular docking investigation. Moreover, TLR2 overexpression or tunicamycin (TM), an agonist of ERS, partly abolished the inhibitory effects of Cori on morphine-induced alternations on neuroinflammation and microglial activation in BV-2 cells as above. In summary, our study suggested that Cori effectively alleviated morphine-induced neuroinflammation and microglia activation through inhibiting TLR2-mediated ERS in BV-2 cells, providing a novel potential drug to overcome morphine tolerance.

Original Article
  • Yoshika Iwata, Hitoshi Katada, Momoko Okuda, Yoshiaki Doi, Tim Jang Ch ...
    2023 Volume 48 Issue 7 Pages 399-409
    Published: 2023
    Released on J-STAGE: July 03, 2023
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    Supplementary material

    Fc-engineering is commonly used to improve the therapeutic potency of antibody (Ab) treatments. Because FcγRIIb is the only inhibitory FcγR that contains an immunoreceptor tyrosine-based inhibition motif (ITIM), Fc-engineered Abs with enhanced binding affinity to FcγRIIb might provide immune suppression in clinical contexts. GYM329 is an anti-latent myostatin Fc-engineered Ab with increased affinity to FcγRIIb which is expected to improve muscle strength in patients with muscular disorders. Cross-linking of FcγRIIb by immune complex (IC) results in phosphorylation of ITIM to inhibit immune activation and apoptosis in B cells. We examined whether the IC of Fc-engineered Abs with enhanced binding affinity to FcγRIIb causes phosphorylation of ITIM or B cell apoptosis using GYM329 and its Fc variant Abs in human and cynomolgus-monkey (cyno) immune cells in vitro. IC of GYM329 with enhanced binding affinity to human FcγRIIb (×5) induced neither ITIM phosphorylation nor B cell apoptosis. As for GYM329, FcγRIIb should work as an endocytic receptor of small IC to sweep latent myostatin, so it is preferable that GYM329 induces neither ITIM phosphorylation nor B cell apoptosis to prevent immune suppression. In contrast, IC of myo-HuCy2b, the Ab with enhanced binding affinity to human FcγRIIb (×4), induced ITIM phosphorylation and B cell apoptosis. The result of the present study demonstrated that Fc-engineered Abs with similar binding affinity to FcγRIIb had different effects. Thus, it is important to also investigate FcγR-mediated immune functions other than binding to fully understand the biological effects of Fc-engineered Abs.

Original Article
  • Aki Miyauchi, Toshi Akashi, Satoshi Yokota, Yuhji Taquahashi, Akihiko ...
    2023 Volume 48 Issue 7 Pages 411-420
    Published: 2023
    Released on J-STAGE: July 03, 2023
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    Multi-walled carbon nanotubes (MWCNTs), a kind of nanomaterial, are widely used in battery electrodes and composite materials, but the adverse effects associated with their accumulation in the living body have not been sufficiently investigated. MWCNTs are a fibrous material with molecules similar to asbestos fibers, and there are concerns about its effects on the respiratory system. In this study, we conducted a risk assessment by exposing mice using a previously developed nanomaterial inhalation exposure method. We quantified the exposure in the lungs by a lung burden test, evaluated the deterioration due to pneumonia using respiratory syncytial virus (RSV) infection, and measured inflammatory cytokines in bronchoalveolar lavage fluid (BALF). As a result, in the lung burden test, the amount of MWCNT in the lung increased according to the inhalation dose. In the RSV infection experiment, CCL3, CCL5, and TGF-β, which are indicators of inflammation and lung fibrosis, were elevated in the MWCNT-exposed group. Histological examination revealed cells phagocytosing MWCNT fibers. These phagocytic cells were also seen during the recovery period from RSV infection. The present study found that MWCNT remained in the lungs for about a month or more, suggesting that the fibers may continue to exert immunological effects on the respiratory system. Furthermore, the inhalation exposure method enabled the exposure of nanomaterials to the entire lung lobe, allowing a more detailed evaluation of the effects on the respiratory system.

Letter
  • Takehito Terajima, Hirofumi Inoue, Kenji Shimomura, Fuki Iwasaki, Aya ...
    2023 Volume 48 Issue 7 Pages 421-428
    Published: 2023
    Released on J-STAGE: July 03, 2023
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    Organophosphate (OP) agents are continuously utilized in large amount throughout the globe for crop protection and public health, thereby creating a potential concern on human health. OP agent as an anticholinesterase also acts on the endocannabinoid (EC)-hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), to reveal unexpected adverse effects including ADHD-like behaviors in adolescent male rats. The present investigation examines a hypothesis that OP compound inhibiting the EC-hydrolase(s) dysregulates the EC-signaling system, triggering apoptosis in neuronal cells. Ethyl octylphosphonofluoridate (EOPF), as an OP probe, preferably acts on FAAH over MAGL in intact NG108-15 cells. Anandamide (AEA), an endogenous FAAH substrate, is cytotoxic in a concentration-dependent manner, although 2-arachidonoylglycerol, an endogenous MAGL substrate, gives no effect in the concentrations examined here. EOPF pretreatment markedly enhances AEA-induced cytotoxicity. Interestingly, the cannabinoid receptor blocker AM251 diminishes AEA-induced cell death, whereas AM251 does not prevent the cell death in the presence of EOPF. The consistent results are displayed in apoptosis markers evaluation (caspases and mitochondrial membrane potential). Accordingly, FAAH inhibition by EOPF suppresses AEA-metabolism, and accumulated excess AEA overstimulates both the cannabinoid receptor- and mitochondria-mediated apoptotic pathways.

Original Article
  • Ke Du, Takashi Hirooka, Yu Sasaki, Akira Yasutake, Takato Hara, Chika ...
    2023 Volume 48 Issue 7 Pages 429-439
    Published: 2023
    Released on J-STAGE: July 03, 2023
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    Granule cell-selective toxicity of methylmercury in the cerebellum is one of the main unresolved issues in the pathogenesis of Minamata disease. Rats were orally administered methylmercury chloride (10 mg/kg/day) for 5 consecutive days, and their brains were harvested on days 1, 7, 14, 21, or 28 after the last administration for histological examination of the cerebellum. It was found that methylmercury caused a marked degenerative change to the granule cell layers but not to the Purkinje cell layers. The generative change of the granule cell layer was due to cell death, including apoptosis, which occurred at day 21 and beyond after the methylmercury administration. Meanwhile, cytotoxic T-lymphocytes and macrophages had infiltrated the granule cell layer. Additionally, granule cells are shown to be a cell type susceptible to TNF-α. Taken together, these results suggest that methylmercury causes small-scale damage to granule cells, triggering the infiltration of cytotoxic T-lymphocytes and macrophages into the granule cell layer, which secrete tumor necrosis factor-α (TNF-α) to induce apoptosis in granule cells. This chain is established based on the susceptibility of granule cells to methylmercury, the ability of cytotoxic T lymphocytes and macrophages to synthesize and secrete TNF-α, and the sensitivity of granule cells to TNF-α and methylmercury. We propose to call the pathology of methylmercury-induced cerebellar damage the “inflammation hypothesis.”

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