The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 43 , Issue 12
Showing 1-7 articles out of 7 articles from the selected issue
Original Article
  • Abdelli Nouara, Peng Lü, Liang Chen, Yan Pan, Yanhua Yang, Keping Chen
    2018 Volume 43 Issue 12 Pages 697-709
    Published: 2018
    Released: December 04, 2018
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    Silver nanoparticles (Ag-NPs) are known as a noble metal, and owing to their exclusive properties, their use is widespread in consumer products and they are mostly incorporated into food packaging and food contact products. The aim of this work was to evaluate the effects of direct ingestion of Ag-NPs through food to assess their toxicity effects on the growth and development of silkworms at different concentrations (1 mg·L-1 to 100 mg·L-1), in addition to the examination of the distribution of Ag-NPs in the silkworm body and midgut histopathological analysis. RNA sequencing was performed to investigate the transcriptomic responses to Ag-NPs exposure. Our results show that the highest Ag-NPs’ concentrations induced a significant increase in the silkworm body weight with histopathological changes in the midgut compared to the control group. The gene ontology (GO) and pathway enrichment analysis for differentially expressed genes showed that Ag-NPs altered the gene expressions and that they were significantly involved in carbohydrate metabolism, digestive system, and energy metabolism. These findings indicate that the Ag-NPs may induce harmful effects on the primary target organs (alimentary system) with energy deregulation and nutrition digestion and absorption imbalance. This study is an important step in understanding the molecular mechanisms of Ag-NPs’ toxicity in vivo.

Letter
  • Tomofumi Fujino, Rina Yokokawa, Toshiyuki Oshima, Makio Hayakawa
    2018 Volume 43 Issue 12 Pages 711-715
    Published: 2018
    Released: December 04, 2018
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    SIRT1, an NAD+-dependent deacetylase, causes deacetylation and down-regulation of its target p53. Given that p53 is an upstream regulator of the transcription of the cyclin-dependent kinase inhibitor p21/Cip1, SIRT1 is hypothesized to play a stimulatory role in carcinoma cell proliferation. We previously reported that down-regulation of SIRT1 caused the increase in p21/Cip1 in a post-transcriptional manner, suggesting that p53 is not involved in the p21/Cip1 increase and raising the question whether SIRT1 exhibits the activity other than deacetylase. In the present study, we examined whether SIRT1 down-regulation and the inhibitor for SIRT1 deacetylase activity affects p21/Cip1 and p53 expression in renal adenocarcinoma cells and normal renal cells. SIRT1 knockdown caused an increase in p53 and p21/Cip1 protein levels in renal adenocarcinoma ACHN cells but not normal renal-derived HK-2 cells. The increase in p53 in ACHN cells is unlikely to contribute to the upregulation of p21/Cip1 expression, given that SIRT1 knockdown did not increase p21/Cip1 mRNA levels in these cells. In contrast to the SIRT1-knock down assay, SIRT1 deacetylase inhibitor did not affect p53 or p21/Cip1 protein levels in ACHN cells. Therefore, SIRT1-knockdown likely stimulates p53 and p21/Cip1 protein expression in a deacetylase-independent manner.

Original Article
  • Galen Guo, Emmanuel Yumvihoze, Alexandre J. Poulain, Hing Man Chan
    2018 Volume 43 Issue 12 Pages 717-725
    Published: 2018
    Released: December 04, 2018
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    Monomethylmercury (MMHg) is a potent neurotoxicant that can be bioaccumulated and biomagnified through trophic levels. Human populations whose diets contain MMHg are at risk of MMHg toxicity. The gut microbiota was identified as a potential factor causing variation in MMHg absorption and body burden. However, little is known about the role of gut microbiota on Hg transformations. We conducted a series of in vitro experiments to study the effects of dietary nutrient change on Hg metabolism and the human gut microbiota using anoxic fecal slurry incubations. We used stable Hg isotope tracers to track MMHg production and degradation and characterized the microbiota using high throughput sequencing of the 16S rRNA gene. We show that the magnitude of MMHg degradation is individual dependent and rapidly responds to changes in nutrient amendments, leading to complete degradation of the MMHg present. Although the mechanism involved remains unknown, it does not appear to involve the well-known mer operon. Our data are the first to show a nutrient dependency on the ability of the simulated human gut microbiota to demethylate MMHg. This work provides much-needed insights into individual variations in Hg absorption and potential toxicity.

Original Article
  • Shigeru Yamada, Daiju Yamazaki, Yasunari Kanda
    2018 Volume 43 Issue 12 Pages 727-734
    Published: 2018
    Released: December 04, 2018
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    5-fluorouracil (5-FU) has been widely used for the treatment of tumors. Regardless of its widespread use as an anti-cancer drug, 5-FU therapy can cause several side effects, including developmental toxicity and neurotoxicity. However, the potential action of 5-FU at the early fetal stage has not yet been completely elucidated. In the present study, we investigated the effect of 5-FU exposure on neural induction, using human induced pluripotent stem cells (iPSCs) as a model of human fetal stage. 5-FU exposure reduced the expression of several neural differentiation marker genes, such as OTX2, in iPSCs. Since the neural differentiation process requires ATP as a source of energy, we next examined intracellular ATP content using iPSCs. We found that 5-FU decreased intracellular ATP levels in iPSCs. We further focused on the effects of 5-FU on mitochondrial dynamics, which plays a role of ATP production. We found that 5-FU induced mitochondrial fragmentation and reduced the level of mitochondrial fusion proteins, mitofusin 1 and 2 (Mfn1/2). Double knockdown of Mfn1/2 genes in iPSCs downregulated the gene expression of OTX2, suggesting that Mfn mediates neural differentiation in iPSCs. Taken together, these results indicate that 5-FU has a neurotoxicity via Mfn-mediated mitochondria dynamics in iPSCs. Thus, mitochondrial dysfunction in iPSCs could be used as a possible marker for cytotoxic effects of drugs.

Original Article
  • Takato Hara, Yoshihiro Nonaka, Shuji Yasuike, Toshiyuki Kaji, Chika Ya ...
    2018 Volume 43 Issue 12 Pages 735-740
    Published: 2018
    Released: December 04, 2018
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    It has been well established that organic-inorganic hybrid molecules can exhibit biological activities that are different from those of either their intramolecular metals in inorganic forms or their organic structures. We have previously reported that organoantimony compound Sb-phenyl-N-methyl-5,
6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine (PMTAS) is nontoxic, but that the compound exhibits cytotoxicity in vascular endothelial cells when the antimony atom is replaced with a bismuth atom. In the present study, we investigated the cytotoxicity and intracellular accumulation of PMTAS and its analogs and found that the cytotoxicity of PMTAS analogs also decrease depending on the electron-withdrawing property of the substituent bound to the intramolecular antimony atom. On the other hand, with the exception of the phenyl group, and depending on the carbon number of hydrocarbon group bound to the intramolecular nitrogen atom, cytotoxicity was enhanced. Furthermore, the cytotoxicity of PMTAS analogs correlated with their intracellular accumulation values. These results suggested that the low cytotoxicity effects of PMTAS on vascular endothelial cells is due to the characteristics of substituents bound to intramolecular antimony and nitrogen atoms.

Original Article
  • Yutaka Kimura, Mika Watanabe, Noriyuki Suzuki, Tomoko Iwaki, Kohji Yam ...
    2018 Volume 43 Issue 12 Pages 741-749
    Published: 2018
    Released: December 04, 2018
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    In all current in vitro skin sensitisation assays, DMSO is used to dissolve water-insoluble chemicals. However, our previous study suggested the superiority of the modified IL-8 Luc assay (mIL-8 Luc), in which X-VIVOTM 15 is used to dissolve chemicals, over the original assay using DMSO (oIL-8 Luc). In this study, to confirm the superiority of the mIL-8 Luc, we first increased the number of chemicals examined and demonstrated the superiority of the mIL-8 Luc, in which the mIL-8 Luc provided 87.6% of sensitivity, 74.2% of specificity, and 84.6% of accuracy. Next, to clarify the cause of false negative judgment by the mIL-8 Luc, we examined the effects of physical properties of chemicals on judgment. The results demonstrated that high molecular weight, high LogKo/w, or poor water solubility, did not cause false negative judgment. When it was accepted as an OECD test guideline, the criteria of the mIL-8 Luc to determine sensitisers were modified to further decrease false negative judgment by poor solubility. By applying the new criteria, the test guideline IL-8 Luc assay (tgIL-8 Luc) improved sensitivity but decreased specificity and increased the number of chemicals that cannot be judged. To overcome this problem, we examined a simple combination of the tgIL-8 Luc with direct peptide reactive assay (DPRA), which could improve specificity and decrease the number of the chemicals that cannot be judged. These data suggest that the tgIL-8 Luc is a promising in vitro skin sensitisation assay in combination with other in vitro or in chemico methods.

Original Article
  • Mariko Sugiyama, Masaharu Akita, Nathalie Alépée, Miyuki Fujishiro, Sh ...
    2018 Volume 43 Issue 12 Pages 751-768
    Published: 2018
    Released: December 04, 2018
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    The Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) 439 is an in vitro test method of reconstructed human epidermis (RhE), which was developed for hazard identification of irritating chemicals in accordance with a primary skin irritation test using rabbits with 4-hr exposure. A regulation for quasi-drugs in Japan requires data from primary skin irritation tests using rabbits to undergo 24-hr exposure, and this is used as an evidence for 24-hr closed patch tests in humans. In this study with the same chemicals, primary skin irritation test data using rabbits undergoing 24-hr exposure and a 24-hr occlusive human patch test data were analyzed by comparing the results obtained with four test methods adopted in OECD TG 439. The performances of in vitro test methods showed a positive predictive value of 72.7-85.7% to predict the results of 24-hr primary rabbit skin irritation test knowing that its positive predictive value was 57.1% against humans only. The prediction factors of in vitro test methods were higher for the human patch test data with a sensitivity reaching 60 to 80%. Three surfactants gave false negatives in some of the RhE methods evaluated with the human patch test, but in each case, they were correctly classified as positive when evaluated at double concentration. Therefore, the approach of setting the margin to 2 was effective in eliminating false negatives. This suggests that in vitro test methods are useful for assessing skin irritation potential without animal testing for the application of quasi-drugs in Japan.

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