首页期刊导航|The Journal of toxicological sciences.
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The Journal of toxicological sciences.
Doku Sayo Kenkyukai
The Journal of toxicological sciences.

Doku Sayo Kenkyukai

0388-1350

The Journal of toxicological sciences./Journal The Journal of toxicological sciences.
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    Lack of human relevance for rat developmental toxicity of flumioxazin is revealed by comparative heme synthesis assay using embryonic erythroid cells derived from human and rat pluripotent stem cells

    Asano, KojiTakahashi, YasuhikoUeno, ManakoFukuda, Takako...
    14页
    查看更多>>摘要：Fetal rat anemia from flumioxazin, an N-phcnylimide herbicide, is caused by suppression of heme synthesis resulting from inhibition of protoporphyrinogen oxidase (PPO). A series of studies to investigate the effects of flumioxazin have revealed that developmental toxicity is caused in rats but not in rabbits, and the adverse effects are not likely to occur in humans. In this study, as a final weight-of-evidence approach for assessing the human safety of flumioxazin, we compared the toxic potential of inhibition of heme synthesis leading to anemia between human and rat embryonic erythroid cells, which were degenerated as the target of flumioxazin in the rat developmental toxicity. To obtain embryonic erythroid cells, we established respective differentiation methods for embryonic erythroid cells from both human and rat pluripotent stein cells. Derived human and rat embryonic erythroid cells were treated with flumioxazin or dihydroartemisinin (DHA), an anti-malarial drug that causes reduction of embryonic erythroid cells and leads to anemia without species differences. In the human embryonic erythroid cells, DHA inhibited cell proliferation and heme synthesis, whereas there were no effects on heme content or cell proliferation with flumioxazin. In the rat embryonic erythroid cells, however, a dose-related reduction in heme synthesis occurred with treatment of flumioxazin and of DHA. These results confirmed that flumioxazin has no effect on heme synthesis in human embryonic erythroid cells. The present data were in accordance with the results of previous studies and demonstrated that there are no concerns in humans regarding the developmental toxicity of flumioxazin observed in rats.
      原文链接:
    • NSTL

    Post-mortem interaction between methidathion and human serum albumin in blood

    Yamagishi, YoshikazuNagasawa, SayakaIwase, HirotaroOgra, Yasumitsu...
    8页
    查看更多>>摘要：Methidathion [3-(dimethoxyphosphinothioylsulfanylmethyl)-5-methoxy-1,3,4-thiadiazol-2-one; hereinafter DMTP], one of the most widely used organophosphorus pesticides, has been detected in some clinical cases of accidental exposure and suicide in Japan. It has been reported that DMTP concentration is decreased in blood. In this study, it is difficult to recover DMTP in the free form because DMTP is bound to human serum albumin (HSA). We detected DMTP adducts in HSA by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS). The mass spectra showed that DMTP was preferably bound to the lysine (K), tyrosine (Y), and cysteinylproline (CP) residues of HSA. The concentrations of K-adduct, DMTP-Y-adduct and DMTP-CP-adduct were increased in vitro in a dose-dependent fashion when DMTP concentration was lower than the lethal dose. Furthermore, the DMTP-Y-adduct and DMTP-CP-adduct were also detected in post-mortem blood of an autopsied subject who died by intentional DMTP ingestion. The results suggested that the DMTP-Y-adduct and DMTP-CP-adduct could be used as a biomarker of DMTP poisoning, and the decrease concentration of DMTP in blood after death could be determined on the basis of the concentration of the DMTP-CP-adduct in blood.
      原文链接:
    • NSTL

    Asthma attacks: Patients who survived paraquat poisoning

    Fan, LuXu, JiyangLv, TianyiLu, Mingfeng...
    3页
    查看更多>>摘要：A patient who survived acute paraquat (PQ) poisoning for more than 5 years was followed up in the emergency room. The patient had recurrent coughing and wheezing one month after discharge. Re-examination of chest CT showed increased dual lung texture. Spirometry suggested severe ventilatory dysfunction while bronchial dilation test was positive. The serum IgE level was significantly high. It is considered that patients with acute PQ poisoning may develop asthma in the long term.
      原文链接:
    • NSTL

    Effect of secondary particle size of nickel oxide nanoparticles on cytotoxicity in A549 cells

    Kawakami, TsuyoshiMiyajima, AtsukoKato, ReikoIsama, Kazuo...
    7页
    查看更多>>摘要：The effect of nanoparticle type, shape, as well as primary and secondary particle size on toxicity remains poorly characterized. In this study, suspensions of nickel oxide (NiO) nanoparticles with the same primary particle size (< 50 nm) but different secondary particle sizes were prepared, and their cytotoxicity was investigated. A planetary ball mill wet nanopulverizer with zirconium milling balls of decreasing sizes (phi: 0.5, 0.1, and 0.05 nun) yielded NiO nanoparticles of decreasing mean particle size (310.4 +/- 6.7, 172.0 +/- 2.8, and 102.0 +/- 0.5 nm). Stock solutions were diluted to various concentrations in 10% heat-inactivated fetal bovine serum containing minimum essential medium, and shown to have the same primary particle size, but different secondary particle sizes. Tests with A549 cells revealed that cytotoxicity increased with increasing secondary particle size: milling ball diameter phi 0.05 mm (IC50: 148 mu g/mL) < phi 0.1 mm (IC50: 83.5 mu g/mL) < phi 0.5 mm (IC50: 33.4 mu g/mL). Uptake experiments indicated that the intracellular amount of Ni increased with increasing secondary particle size. In summary. the present findings show that differences in secondary particle size affected the cytotoxicity of NiO suspensions, which could be ascribed at least in part to differences in the amount of NiO taken up by the cells.
      原文链接:
    • NSTL

    Perfluorooctanoic acid (PFOA) as a stimulator of estrogen receptor-negative breast cancer MDA-MB-231 cell aggressiveness: Evidence for involvement of fatty acid 2-hydroxylase (FA2H) in the stimulated cell migration

    Sakai, GenkiHirao-Suzuki, MasayoKoga, TakayukiKobayashi, Takananobu...
    10页
    查看更多>>摘要：Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor a (PPARa) is a key process by which PFOA affects the malignancy of estrogen receptor alpha (ER alpha)-positive breast cancer cells. However, there is very little information on the PPAR alpha-regulated genes responsible for the effects of PFOA in ER alpha-negative breast cancer cell malignancy. We recently demonstrated that fatty acid 2-hydroxylase (FA2H) stimulates the migration of ER alpha-negative human MDA-MB-231 cells, and PPAR alpha is a key factor for the induction of FA2H in these cells. However, evidence for the relationship between PFOA exposure and PPAR alpha-FA2H axis-driven migration has not been obtained. Here we analyzed the effects of PFOA on PPAR alpha transcription and FA2H expression in relation to MDA-MB-231 cell migration. We found that simultaneously with stimulated migration, PFOA upregulated FA2H and activated the transcription of PPAR alpha. FA2H-selective siRNA, but not siRNA control, clearly dampened PFOA-mediated cell migration. There is an inhibitory interaction between PPAR alpha and PPAR beta/delta (i,e., PPAR beta/delta can suppress PPAR alpha-mediated transcription) in MDA-MB-231 cells, but even in the presence of PPAR beta/delta expression, PFOA appeared to free PPAR alpha to upregulate FA2H. Collectively, our findings show that i) PFOA activates PPAR alpha-mediated transcription, ii) PFOA stimulates migration dependent on FA2H expression, and iii) mechanistically, PFOA relieves PPAR beta/delta suppression of PPAR alpha activity to upregulate FA2H in MDA-MB-231 cells.
      原文链接:
    • NSTL

    Dexmedetomidine attenuates acute stress-induced liver injury in rats by regulating the miR-34a-5p/ROS/JNK/p38 signaling pathway

    Li, DanQian, JiangLi, JunfengWang, Jia...
    13页
    查看更多>>摘要：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 mu g/kg) or miR-34a-5p ago-mir was injected into model rats. Open field test was used to verify the establishment of the model. Liver injury was observed by hematoxylin-cosin (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 PICA 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.
      原文链接:
    • NSTL

    Maternal omega-3 fatty acid supplementation against prenatal lead exposure induced cognitive impairment in offspring mice

    Shao, JingWang, ShuliLiu, Lan
    10页
    查看更多>>摘要：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 immnunosorbent 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.
      原文链接:
    • NSTL

    No obvious toxicological influences of 50 mu L microsampling from rats administered phenacetin as a drug with hematological toxicity

    Ohtsuka, HirohikoTakahashi, KazuakiKitaura, HarumiKandori, Hitoshi...
    7页
    查看更多>>摘要：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 mu L 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 mu L 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.
      原文链接:
    • NSTL

    Involvement of polycyclic aromatic hydrocarbons and endotoxin in macrophage expression of interleukin-33 induced by exposure to particulate matter

    Vogel, Christoph F. A.Ishihara, YasuhiroIshihara, NamiOkuda, Tomoaki...
    10页
    查看更多>>摘要：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.
      原文链接:
    • NSTL

    Preliminary evaluation of the mechanism underlying vulnerability/resistance to methylmercury toxicity by comparative gene expression profiling of rat primary cultured cerebrocortical and hippocampal neurons

    Fujimura, MasatakeUnoki, Takamitsu
    9页
    查看更多>>摘要：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 mu M vs. 1.2 mu M), 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.
      原文链接:
    • NSTL