The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Current issue
Displaying 1-5 of 5 articles from this issue
Original Article
  • Dan Li, Jiang Qian, Junfeng Li, Jia Wang, Wenhong Liu, Qinfei Li, Dan ...
    2022 Volume 47 Issue 5 Pages 169-181
    Published: 2022
    Released on J-STAGE: May 05, 2022
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    Supplementary material

    Dexmedetomidine (DEX) protects against acute stress-induced liver injury, but what’s less clear lies in the specific mechanism. To elucidate the specific mechanism underlying DEX on acute stress-induced liver injury, an in vivo model was constructed on rats with acute stress-induced liver injury by 15 min of exhaustive swimming and 3 hr of immobilization. DEX (30 μg/kg) or miR-34a-5p agomir was injected into model rats. Open field test was used to verify the establishment of the model. Liver injury was observed by hematoxylin-eosin (H&E) staining. Contents of norepinephrine (NE), alanine aminotransfease (ALT) and aspartate aminotransferase (AST) in serum of rats were detected by enzyme-linked immunosorbent assay (ELISA) and those of oxidative stress markers (reactive oxygen species (ROS), Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPX)) were measured using commercial kits. Apoptosis of hepatocytes was detected by Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Western blot was performed to detect the expressions of SOD2, COX-2, cytochrome C, Cleaved caspase 3, Bax, Bcl-2, P-JNK, JNK, P-p38, p38 and c-AMP, p-PKA and PKA in liver tissues. As a result, liver injury in model rat was alleviated by DEX. DEX attenuated the increase in the levels of NE, ALT, AST, MDA, ROS, apoptosis, SOD2, COX-2, Cytochrome C, cleaved caspase 3, Bax, and P-JNK, P-p38, c-AMP, P-PKA and miR-34a-5p, and the decrease in the levels of SOD, GPX, GSH and Bcl-2 in model rats. Furthermore, miR-34a-5p overexpression could partly reverse the effects of DEX. Collectively, DEX could alleviate acute stress-induced liver injury through ROS/JNK/p38 signaling pathway via downregulation of miR-34a-5p.

Original Article
  • Jing Shao, Shuli Wang, Lan Liu
    2022 Volume 47 Issue 5 Pages 183-192
    Published: 2022
    Released on J-STAGE: May 05, 2022
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    Supplementary material

    Maternal lead exposure is associated with poor outcomes in fetal brain development such as cognitive dysfunction. Here, we aimed to reveal the effect and mechanism of omega-3 fatty acids in ameliorating maternal lead exposure-induced cognitive impairment in mouse offspring. The activity levels of locomotor and anxiety, memory and learning capacity, spatial working memory, and cognitive behavioral function were determined using the open field test, Morris water maze, Y-maze, and nest-building test, respectively. The protein levels of brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were measured using enzyme-linked immunosorbent assay or Western blot. The mRNA levels of BDNF, tyrosine kinase B (TrkB) and cyclic AMP response element binding protein (CREB) were measured by real-time qPCR. Malondialdehyde (MDA) and anti-oxidants, including SOD, GSH and CAT, were measured using bioassay kits. We found that supplementing omega-3 significantly improved cognitive behavioral function in offspring after prenatal lead exposure. The protein and mRNA levels of BDNF, TrkB and CREB in the prenatal lead exposure group were significantly upregulated by omega-3 supplementation. The MDA level in the prenatal lead exposure group was markedly elevated compared with the control group, which was significantly reduced by omega-3. Omega-3 restored anti-oxidants SOD, GSH and CAT to control levels after prenatal lead exposure. Omega-3 significantly upregulated Nrf2 nuclear expression and HO-1 expression after prenatal lead exposure. Overall, omega-3 supplementation significantly elevated the BDNF/TrkB/CREB pathway and restores anti-oxidants by upregulating the Nrf2/HO-1, thereby improving cognitive function in offspring after prenatal lead exposure.

Letter
  • Hirohiko Ohtsuka, Kazuaki Takahashi, Harumi Kitaura, Hitoshi Kandori, ...
    2022 Volume 47 Issue 5 Pages 193-199
    Published: 2022
    Released on J-STAGE: May 05, 2022
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    Supplementary material

    According to ICH S3A Q&A focusing on microsampling, its application should be avoided in main study animals for test drugs that could exacerbate hematological parameters with frequent blood sampling. However, no study has reported the effects of microsampling on toxicity parameters of drugs known to induce hematological toxicity. Therefore, we assessed the toxicological effects of serial microsampling on rats treated with phenacetin as a model drug. In a common 28-day study, 50 µL of microsampling was performed at 6-time points on days 1 to 2 and 7-time points on days 27 to 28 from the jugular vein of Sprague Dawley rats. The study was performed independently by two organizations. The toxicological influence of microsampling was evaluated on body weight, food consumption, hematology, blood clinical chemistry, urine parameters, organ weights, and tissue pathology. Phenacetin treatments induced significant changes of various hematological parameters (including hemoglobin and reticulocytes), some organ weights (including liver and spleen), and some hematology-related pathological parameters in the liver, spleen and bone marrow. Meanwhile, serial microsampling exhibited minimal influence on the assessed parameters, although 20 parameters showed statistical differences mostly at one organization. The current results support the notion that serial 50 μL microsampling from the jugular vein had minimal impacts on overall toxicological profiles even in rats treated with a drug inducing hematological toxicity, but the potential adverse effect on certain parameters could not be fully excluded. Accordingly, this microsampling technique has possibility to be employed even for non-clinical rat toxicity studies using drugs with potentially hematological toxicity.

Original Article
  • Nami Ishihara, Tomoaki Okuda, Hiroyuki Hagino, Ami Oguro, Yuto Tani, H ...
    2022 Volume 47 Issue 5 Pages 201-210
    Published: 2022
    Released on J-STAGE: May 05, 2022
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    Air pollutants are important factors that contribute to the development and/or exacerbation of allergic inflammation accompanied by asthma, but experimental evidence still needs to be collected. Interleukin 33 (IL-33) is closely involved in the onset and progression of asthma. In this study, we examined the effects of particulate matter (PM) on IL-33 expression in macrophages. PM2.5 collected in Yokohama, Japan by the cyclone device significantly induced IL-33 expression in human THP-1 macrophages, and the induction was clearly suppressed by pretreatment with the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the Toll-like receptor 4 (TLR4) antagonist TAK-242. PM2.5-induced IL-33 expression was significantly attenuated in AhR-knockout or TLR4-mutated macrophages, suggesting an important role of polycyclic aromatic hydrocarbons (PAHs) and endotoxin in IL-33 stimulation. PM samples derived from tunnel dust slightly but significantly induced IL-33 expression, while road dust PM did not affect IL-33 expression. The PAH concentration in tunnel dust was higher than that in road dust. Tunnel dust or road dust PM contained less endotoxin than PM2.5 collected in Yokohama. These data suggest that the potency of IL-33 induction could depend on the concentration of PAHs as well as endotoxin in PMs. Caution regarding PAHs and endotoxin levels in air pollutants should be taken to prevent IL-33-induced allergic inflammation.

Letter
  • Masatake Fujimura, Takamitsu Unoki
    2022 Volume 47 Issue 5 Pages 211-219
    Published: 2022
    Released on J-STAGE: May 05, 2022
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    Supplementary material

    Methylmercury (MeHg), an environmentally toxic substance, causes site-specific neuronal cell death; while MeHg exposure causes death in cerebrocortical neurons, interestingly, it does not in hippocampal neurons, which are generally considered to be vulnerable to toxic substances. This phenomenon of site-specific neuronal cell death can be reproduced in animal experiments; however, the mechanism underlying the resistance of hippocampal neurons to MeHg toxicity has not been clarified. In this study, we comparatively analyzed the response to MeHg exposure in terms of viability and the expression characteristics of primary cultured cerebrocortical neurons and hippocampal neurons derived from fetal rat brain. Neuronal differentiated hippocampal neurons were more resistant to MeHg toxicity than cerebrocortical neurons, as indicated by a 2‒3 fold higher half-maximal inhibitory concentration (IC50; 3.3 μM vs. 1.2 μM), despite similar intracellular mercury concentrations in both neuronal cell types. Comprehensive RNA sequencing-based gene expression analysis of non-MeHg-exposed cells revealed that 80 out of 15,208 genes showed at least 10-fold higher expression in hippocampal neurons than in cerebrocortical neurons, whereas six genes showed at least 10-fold higher expression in cerebrocortical neurons than in hippocampal neurons. In particular, genes related to neuronal function, including those encoding transthyretin and brain-derived neurotrophic factor, showed approximately 50-fold higher expression in hippocampal neurons than in cerebrocortical neurons. In conclusion, the resistance of hippocampal neurons to MeHg toxicity may be related to the high expression of neuronal function-related proteins.

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