The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 43, Issue 5
Displaying 1-7 of 7 articles from this issue
Letter
  • Tomoyuki Masuda, Kazuhiro Ishii, Yukio Morishita, Nobuaki Iwasaki, Yas ...
    2018 Volume 43 Issue 5 Pages 291-298
    Published: 2018
    Released on J-STAGE: May 09, 2018
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    Organic arsenic diphenylarsinic acid (DPAA[V]) accumulates at high concentrations in the liver of primates after its subchronic administration. However, no studies on the hepatic effects of organic arsenic compounds, including DPAA(V), on primates have been reported to date. To clarify the toxicokinetics of DPAA(V) in the liver of primates, hepatic tissue specimens were collected from cynomolgus monkeys (n = 32) at 5, 29, 170, and 339 days after repeated administration of DPAA(V) for 28 days. Four histopathological changes in the specimens were observed and pathologically evaluated. Atypical ductular proliferation was found in the DPAA(V)-exposed liver throughout the period. Inflammatory cell infiltration in Glisson’s capsules and lipid droplets were seen at earlier periods after administration. Conversely, inflammatory cell infiltration in liver lobules was seen later after administration. In this experiment, we did not confirm the hepatic dysfunction of DPAA(V)-exposed monkeys by blood chemistry tests. To compensate for this, we further investigated the blood from a patient who exhibited several neurological symptoms after DPAA(V) exposure. Her blood chemistry test values for aspartate transaminase, alanine transaminase, and lactate dehydrogenase were elevated, suggesting that her liver may have been damaged by DPAA(V) exposure. Together, these findings suggest that the accumulation of DPAA(V) may induce differential histopathological changes in primate hepatocytes, resulting in decreased liver function. This is the first report to investigate the liver of primates pathologically after exposure to organic arsenic DPAA(V). Our findings will help expand our knowledge regarding the effect of DPAA(V) on the liver of primates.

Original Article
  • Takafumi Mitachi, Minori Mezaki, Kunihiko Yamashita, Hiroshi Itagaki
    2018 Volume 43 Issue 5 Pages 299-309
    Published: 2018
    Released on J-STAGE: May 09, 2018
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    To evaluate the sensitization potential of chemicals in cosmetics, using non-animal methods, a number of in vitro safety tests have been designed. Current assays are based on the expression of cell surface markers, such as CD86 and CD54, which are associated with the activation of dendritic cells, in skin sensitization tests. However, these markers are influenced by culture conditions through activating danger signals. In this study, we investigated the relationship between extracellular pH and the expression of the skin sensitization test human cell line activation test (h-CLAT) markers CD86 and CD54. We measured expression levels after THP-1 cells were exposed to representative contact allergens, i.e., 2,4-dinitrochlorobenzene and imidazolidinyl urea, under acidic conditions. These conditions were set by exposure to hydrochloric acid, lactic acid, and citric acid. An acidic extracellular pH (6-7) suppressed the augmentation of CD86 and CD54 levels by the sensitizer. Additionally, when the CD86/CD54 expression levels were suppressed, a reduction in the intracellular pH was confirmed. Furthermore, we observed that Na+/H+ exchanger 1 (NHE-1), a protein that contributes to the regulation of extracellular/intracellular pH, is involved in CD86 and CD54 expression. These findings suggest that the extracellular/intracellular pH has substantial effects on in vitro skin sensitization markers and should be considered in evaluations of the safety of mixtures and commercial products in the future.

Original Article
  • Qiang Niu, Ping He, Shangzhi Xu, Ruling Ma, Yusong Ding, Lati Mu, Shug ...
    2018 Volume 43 Issue 5 Pages 311-319
    Published: 2018
    Released on J-STAGE: May 09, 2018
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    Emerging evidence has demonstrated that iron overload plays an important role in oxidative stress in the liver. This study aimed to explore whether fluoride-induced hepatic oxidative stress is associated with iron overload and whether grape seed proanthocyanidin extract (GSPE) alleviates oxidative stress by reducing iron overload. Forty Kunming male mice were randomly divided into 4 groups and treated for 5 weeks with distilled water (control), sodium fluoride (NaF) (100 mg/L), GSPE (400 mg/kg bw), or NaF (100 mg/L) + GSPE (400 mg/kg bw). Mice exposed to NaF showed typical poisoning changes of morphology, increased aspartate aminotransferase and alanine aminotransferase activities in the liver. NaF treatment also increased MDA accumulation, decreased GSH-Px, SOD and T-AOC levels in liver, indicative of oxidative stress. Intriguingly, all these detrimental effects were alleviated by GSPE. Further study revealed that NaF induced disorders of iron metabolism, as manifested by elevated iron level with increased hepcidin but decreased ferroportin expression, which contributed to hepatic oxidative stress. Importantly, the iron dysregulation induced by NaF could be normalized by GSPE. Collectively, these data provide a novel insight into mechanisms underlying fluorosis and highlight the potential of GSPE as a naturally occurring prophylactic treatment for fluoride-induced hepatotoxicity associated with iron overload.

Original Article
  • Hiroyuki Okazaki, Masayo Hirao-Suzuki, Shuso Takeda, Yukimi Takemoto, ...
    2018 Volume 43 Issue 5 Pages 321-327
    Published: 2018
    Released on J-STAGE: May 09, 2018
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    Bisphenol AF (BPAF) is now recognized as one of the replacements for bisphenol A (BPA). Although considerable experimental evidence suggests that BPA is an endocrine-disrupting chemical, the toxicological profile of BPAF has been investigated in less detail than that of BPA, even at the in vitro level. BPAF has been established as an activator of estrogen receptor α (ERα) in many cell lines; however, controversy surrounds its effects on the other isoform, ERβ (i.e., whether it functions as a stimulator). Five human ERβ isoforms have been cloned and characterized. Of these, we focused on the interactions between BPAF and the two isoforms, ERβ1 and ERβ2. We demonstrated that i) BPAF functioned as a stimulator of ERβ1 (and ERα), which is transiently expressed in the two types of human breast cancer cells (MDA-MB-231 and SK-BR-3 cells) (EC50 values for ERβ: 6.87 nM and 2.58 nM, respectively, and EC50 values for ERα: 24.7 nM and 181 nM, respectively), ii) the stimulation of ERβ1 by BPAF (1-25 nM) was abrogated by PHTPP (an ERβ selective antagonist), and iii) the expression of ERβ1 and ERβ2 was not modulated by BPAF at nanomolar concentrations up to 25 nM. These results indicate that BPAF activates not only human ERα, but also the ERβ1 isoform in breast cancer cells, and exhibits higher activation potency for ERβ1.

Original Article
  • Liu Xianchu, Zheng Lan, Liu Ming, Mo Yanzhi
    2018 Volume 43 Issue 5 Pages 329-337
    Published: 2018
    Released on J-STAGE: May 09, 2018
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    Rutin has a wide range of beneficial health properties in the amelioration of multi-organ injury owing to its various biological effects. The aim of this study was to investigate the effects of rutin on lipopolysaccharide (LPS)-induced heart injury and clarify its potential cardioprotective mechanism. The mouse model of heart injury was intraperitoneal infection with LPS, and rutin was orally administered for 8 consecutive days. One day after LPS injection, heart histopathology, cardiac marker enzymes and cardiac fibrosis related genes were determined to evaluate the cardioprotective effects of rutin. In addition, oxidative parameters and inflammatory cytokines were tested to explore its possible underlying mechanism. The presented results showed that rutin significantly improved morphological changes of myocardium and relieved cardiac marker enzymes [creatine kinase (CK) and lactate dehydrogenase (LDH)] level to protect heart in LPS-induced sepsis. And more, rutin observably mitigated fibrosis related genes [matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9)] expression in the heart to prevent against LPS-induced cardiac fibrosis. In addition, rutin markedly increased antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] activity, and improved oxidative production [malondialdehyde (MDA) and H2O2] level to balance the oxidation and anti-oxidation systems in the heart. Lastly, rutin dramatically ameliorated [tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)] activity to restrain inflammatory responses in the heart. In conclusion, rutin possessed anti-oxidant and anti-inflammatory properties to improve LPS-induced heart injury, which suggested rutin could be used as a potential cardioprotective medicine in sepsis.

Original Article
  • Masahiro Segawa, Shuichi Sekine, Tomoyuki Sato, Kousei Ito
    2018 Volume 43 Issue 5 Pages 339-351
    Published: 2018
    Released on J-STAGE: May 09, 2018
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    Supplementary material

    Troglitazone, a member of the thiazolidinedione class of antidiabetic drugs, was withdrawn from the market because it causes severe liver injury. One of the mechanisms for this adverse effect is thought to be mitochondrial toxicity. To investigate the characteristics of troglitazone-induced liver toxicity in more depth, the toxicological effects of troglitazone on hepatocytes and liver mitochondria were investigated using a rat model of type 2 diabetes mellitus (T2DM). Troglitazone was found to increase mitochondrial permeability transition (MPT) in the liver mitochondria of diabetic rats to a greater extent than in control rats, whereas mitochondrial membrane potential and oxidative phosphorylation were not affected. To identify the factors associated with this increase in susceptibility to MPT in diabetic rats, we assessed the oxidative status of the liver mitochondria and found a decrease in mitochondrial glutathione content and an increase in phospholipid peroxidation. Moreover, incorporation of oxidized cardiolipin, a mitochondrion-specific phospholipid, was involved in the troglitazone-induced alteration in susceptibility to MPT. In conclusion, liver mitochondria display disease-associated mitochondrial lipid peroxidation in T2DM, which facilitates the higher susceptibility to troglitazone-induced MPT. Thus, greater susceptibility of liver mitochondria may be a host factor leading to troglitazone-induced hepatotoxicity in T2DM.

Letter
  • Tsutomu Takahashi, Saki Suzuki, Suzuka Misawa, Jiro Akimoto, Yo Shinod ...
    2018 Volume 43 Issue 5 Pages 353-358
    Published: 2018
    Released on J-STAGE: May 09, 2018
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Photodynamic therapy (PDT) using talaporfin sodium (TS) is tumor cell-selective less invasive therapy for the treatment of malignant glioma. We previously demonstrated that PDT using TS (TS-PDT) treatment exhibits anti-tumor activity against not only glioblastoma cells but also malignant meningioma cells. In general, various stress response proteins have been reported to affect the sensitivity determination for anticancer agents against tumor cells. However, the relationship between the therapeutic effect of TS-PDT and stress response systems in tumor cells is not adequately investigated. In this study, we investigated the gene expression of stress response proteins, including Sod1, Cat1, Gstp1, Gpx1, Nqo1, and Hmox1, in rat malignant meningioma KMY-J cells after treatment of TS-PDT. TS-PDT treatment significantly decreased the cell viability when compared with the no laser irradiation group. In morphological observation, TS at 25.6 µM treatment exhibited a significant cytotoxic effect after 12 hr of laser irradiation to KMY-J cells. After 3 and 6 hr of TS-PDT treatment, mRNA expression of heme oxygenase-1 (HO-1, encoded by Hmox1) was significantly increased by TS-PDT treatment. We also demonstrated that zinc protoporphyrin IX (ZnPPIX), a HO-1 inhibitor, significantly augmented the cytotoxic effect of TS-PDT treatment. These data suggest that HO-1 induction may contribute to a protective response against TS-PDT treatment in the malignant meningioma cells and may attenuate the therapeutic effect for TS-PDT treatment.

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