The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 45, Issue 3
Displaying 1-6 of 6 articles from this issue
Original Article
  • Fangfang Zhang, Xinyue You, Tengteng Zhu, Sumeng Gao, Yu Wang, Ruoyang ...
    2020 Volume 45 Issue 3 Pages 117-129
    Published: 2020
    Released on J-STAGE: March 06, 2020
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    Silica nanoparticles (SiO2 NPs) are widely used in daily life and can enter organisms through several pathways, often causing unpredictable toxicity. Although SiO2 NPs are known to cause damage to the respiratory system, little is known about their oral toxicity, and their potential harm to the reproductive system is unclear. In this study, we used a Caenorhabditis elegans model to clarify SiO2 NPs oral toxicity in vivo and explore their effect on the reproductive system. We exposed C. elegans to 0.25, 0.5 and 1 mg /mL SiO2 NPs for 24 hr. Our results showed that SiO2 NPs exposure for 24 hr did not affect nematode survival rates, but did affect, to varying degrees, the reproduction, development, and movement of nematodes, with nematode fecundity being the most sensitive to SiO2 NPs toxicity. The NPs exposed group showed enhanced germ cell apoptosis and increased oxidative stress as seen through an increase in ROS and malondialdehyde (MDA), and decrease in reduced glutathione (GSH). N-acetyl-L-cysteine (NAC), an antioxidant, negated SiO2 NPs effect on germ cells and restored nematodes reproductive ability. We also found that SiO2 NPs could affect the expression of genes related to metal detoxification, oxidative stress, and apoptosis. The expression of metallothionein coding genes mtl-1 and mtl-2 changed most significantly among the tested genes. We demonstrated that SiO2 NPs could enhance germ cell apoptosis by inducing oxidative stress, providing a new area for studies of the mechanism of SiO2 NP toxicity.

Letter
  • Ryo Kamata, Fujio Shiraishi, Kazuichi Nakamura
    2020 Volume 45 Issue 3 Pages 131-136
    Published: 2020
    Released on J-STAGE: March 06, 2020
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    Reproductive disorders in birds are the most characteristic effects of DDT contamination of wildlife. Experimental exposure of avian eggs to the estrogenic substance o,p′-DDT causes abnormal development of the reproductive tract (shortening of the left oviduct and aberrant development of the right oviduct) and eggshell thinning in mature birds, but it is still not known how eggshell thinning occurs in the abnormal oviduct. To fill this information gap, we examined the histology of the uterine part of the oviduct in Japanese quail treated in ovo with o,p′-DDT or a synthetic estrogen, diethylstilbestrol (DES), and we performed immunohistochemical staining for the calcium-binding proteins CALB1, SPP1, and TRPV6. Both o,p′-DDT-treated and DES-treated quail had few, and scattered, gland cells in the left uterus, unlike vehicle controls, in which gland cells tightly occupied the lamina propria. The aberrantly developed right uterus retained all the components of the normal left uterus, but in immature form. Immunostaining for CALB1, SPP1, and TRPV6 was greatly reduced by both o,p′-DDT and DES; SPP1 and TRPV6 immunostaining patterns, in particular, differed distinctly from those in the controls. These findings suggest that CALB1, SPP1, and TRPV6 are molecular factors, decreased production of which is responsible for eggshell thinning. Our findings also could contribute to understanding of the eggshell formation mechanism in birds.

Original Article
  • Yuto Amano, Hiroshi Honda, Ryusuke Sawada, Yuko Nukada, Masayuki Yaman ...
    2020 Volume 45 Issue 3 Pages 137-149
    Published: 2020
    Released on J-STAGE: March 06, 2020
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    Supplementary material

    In silico models for predicting chemical-induced side effects have become increasingly important for the development of pharmaceuticals and functional food products. However, existing predictive models have difficulty in estimating the mechanisms of side effects in terms of molecular targets or they do not cover the wide range of pharmacological targets. In the present study, we constructed novel in silico models to predict chemical-induced side effects and estimate the underlying mechanisms with high general versatility by integrating the comprehensive prediction of potential chemical-protein interactions (CPIs) with machine learning. First, the potential CPIs were comprehensively estimated by chemometrics based on the known CPI data (1,179,848 interactions involving 3,905 proteins and 824,143 chemicals). Second, the predictive models for 61 side effects in the cardiovascular system (CVS), gastrointestinal system (GIS), and central nervous system (CNS) were constructed by sparsity-induced classifiers based on the known and potential CPI data. The cross validation experiments showed that the proposed CPI-based models had a higher or comparable performance than the traditional chemical structure-based models. Moreover, our enrichment analysis indicated that the highly weighted proteins derived from predictive models could be involved in the corresponding functions of the side effects. For example, in CVS, the carcinogenesis-related pathways (e.g., prostate cancer, PI3K-Akt signal pathway), which were recently reported to be involved in cardiovascular side effects, were enriched. Therefore, our predictive models are biologically valid and would be useful for predicting side effects and novel potential underlying mechanisms of chemical-induced side effects.

Original Article
  • Sosuke Kishi, Keiko Yamakawa, Yuko Nakano-Narusawa, Shohei Kanie, Nozo ...
    2020 Volume 45 Issue 3 Pages 151-162
    Published: 2020
    Released on J-STAGE: March 06, 2020
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    Information on the safety of chemical substances in patients with various preexisting conditions remains limited. Acetaminophen was added to the basal diet at 0, 80, 253, 800, 2530, or 8000 ppm and administered to type 2 diabetes mellitus rats (GK/Jcl) and the control male rats (Wistar) for 13 weeks. Both strains treated with 8000 ppm acetaminophen (561.4 and 567.7 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) showed decreased levels of red blood cell counts, blood urea nitrogen, creatinine, and total bilirubin compared to those of non-treated rats. Treatment with 8000 ppm of acetaminophen reduced the blood glucose and hemoglobin A1c levels of GK/Jcl rats. An increase in the relative weights of the kidneys and liver, and a decrease in the weight of the salivary glands were observed in both GK/Jcl and Wistar rats treated with 8000 ppm acetaminophen relative to those of non-treated control rats. Microscopically, both strains treated with 2530 (174.3 and 164.2 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) or 8000 ppm acetaminophen showed hepatocellular hypertrophy and degenerative lesions in the salivary glands, whereas similar lesions were not observed in non-treated rats. In conclusion, the no-observed-adverse-effect-level of acetaminophen was 800 ppm in both diabetic and control rats.

Original Article
  • Yan-Xia Gao, Yi-Bo Wang, You-Dong Wan, Tong-Wen Sun, Yi Li, Lin-Lin Ho ...
    2020 Volume 45 Issue 3 Pages 163-175
    Published: 2020
    Released on J-STAGE: March 06, 2020
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    The benefits and adverse effects of immunosuppressive drugs (ISDs) in patients with paraquat (PQ) poisoning have not been thoroughly assessed. This meta-analysis study aims to evaluate the effect of ISDs in patients with moderate to severe PQ poisoning. We searched PubMed, Embase, Cochrane Library, Ovid Medline, CNKI and Wanfang Data from inception to January 2019. The Mantel-Haenszel method with a random-effects model was used to calculate the pooled relative risks (RRs) and 95% Confidence Intervals (CIs) as described by DerSimonian and Laird. An L’Abbé plot was drawn to explore the relationship between the degree of poisoning and mortality. Four randomized controlled trials, two prospective and seven retrospective studies were identified. ISDs were significantly associated with reduced mortality (RR 0.76; 95% CI, 0.58-0.99) and the incidence rate of multiple-organ dysfunction syndrome (MODS) (RR 0.63; 95% CI, 0.48-0.83) in patients with moderate to severe PQ poisoning. They were not associated with an increased incidence rate of hepatitis and reduced incidence rate of acute renal failure and hypoxia. The L’Abbé plot results showed a slight increase in mortality rate in the ISD group with increased mortality in the placebo group. This indicates a possible advantage of ISDs in most of the patients with severe PQ poisoning. These findings suggest that ISDs may reduce the mortality and incidence rate of MODS in moderate to severe PQ poisoning patients, and severe PQ poisoning patients might benefit more from ISDs.

Original Article
  • Junhong Lin, Junzheng Peng, Guosheng Liu, Li Deng
    2020 Volume 45 Issue 3 Pages 177-186
    Published: 2020
    Released on J-STAGE: March 06, 2020
    JOURNAL FREE ACCESS FULL-TEXT HTML

    MECP2 (Methyl-CpG-binding protein 2) has been shown to have a critical role in regulating DNA methylation against smoke exposed lung injury. However, the biological function of MECP2 and the underlying molecular mechanism remains elusive. Human bronchial epithelial (16HBE) and alveolar type II epithelial cells (AECII) were exposed to increasing concentrations of cigarette smoke extracts (CSE) solution to establish CSE-induced lung epithelial cell injury models. Our findings revealed that MECP2 was down-regulated, while CYP1B1 was up-regulated in CSE-induced lung epithelial cell injury models by quantitative real time PCR, western blotting and immunofluorescence staining. Down-regulated CYP1B1 was ascribed to the demethylation of its promoter by methylation-specific PCR (MSP). The in vitro experiments further showed that MECP2 overexpression significantly attenuated CSE-triggered cell growth attenuation, cell cycle arrest, apoptosis and ROS generation in lung epithelial cells by CCK-8 and flow cytometry assays. In molecular level, we further demonstrated that MECP2 overexpression obviously suppressed the expression of CYP1B1 through enhancing DNA methylation. Therefore, our data suggest that MECP2 protects against CSE-induced lung epithelial cell injury possibly through down-regulating CYP1B1 expression via elevating its methylation status.

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