The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Volume 43 , Issue 11
Showing 1-6 articles out of 6 articles from the selected issue
Review
  • Liyun He, Zhenying Chen, Bo Dai, Guilin Li, Gaochun Zhu
    2018 Volume 43 Issue 11 Pages 623-630
    Published: 2018
    Released: November 07, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Lead exposure contributing to cardiovascular diseases is known and recognized widely. As the deleterious effects of low lead exposure attained increasing attention over the last decades, there have been numerous studies exploring the association of low levels of lead exposure and cardiovascular diseases. Moreover, it has been observed that lead exposure could cause telomere shortening and lipid disturbance, and that telomere shortening and lipid disturbance are closely related with cardiovascular diseases. Hence, telomere shortening and lipid disturbance might play an important role in the pathophysiological process of chronic low levels of lead exposure contributing to cardiovascular diseases. This review is intended to explore views of the rarely mentioned mechanism, telomere shortening and lipid disturbance, and the cardiovascular effects of low levels of lead exposure.

Original Article
  • Tin-Tin Win-Shwe, Nay Chi Nway, Motoki Imai, Thet-Thet Lwin, Ohn Mar, ...
    2018 Volume 43 Issue 11 Pages 631-643
    Published: 2018
    Released: November 07, 2018
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Autism is a complex neurodevelopmental disorder characterized by impaired social communication and social interactions, and repetitive behaviors. The etiology of autism remains unknown and its molecular basis is not yet well understood. Pregnant Sprague-Dawley (SD) rats were administered 600 mg/kg of valproic acid (VPA) by intraperitoneal injection on day 12.5 of gestation. Both 11- to 13-week-old male and female rat models of VPA-induced autism showed impaired sociability and impaired preference for social novelty as compared to the corresponding control SD rats. Significantly reduced mRNA expressions of social behavior-related genes, such as those encoding the serotonin receptor, brain-derived neurotrophic factor and neuroligin3, and significantly increased expression levels of proinflammatory cytokines, such as interleukin-1 β and tumor necrosis factor-α, were noted in the hippocampi of both male and female rats exposed to VPA in utero. The hippocampal expression level of gamma amino butyric acid (GABA) enzyme glutamic acid decarboxylase (GAD) 67 protein was reduced in both male and female VPA-exposed rats as compared to the corresponding control animals. Our results indicate that developmental exposure to VPA affects the social behavior in rats by modulating the expression levels of social behavior-related genes and inflammatory mediators accompanied with changes in GABA enzyme in the hippocampus.

Original Article
Original Article
  • Guigang Yan, Lianzhi Yu, Songmei Jiang, Jianfeng Zhu
    2018 Volume 43 Issue 11 Pages 659-669
    Published: 2018
    Released: November 07, 2018
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    High energy-consumption in retinal pigmented epithelium (RPE) cells poses oxidative stress (OS) and contributes to mitochondrial dysfunction (MD) for retinal degeneration-associated diseases. In the present study, we evaluated the protective role of Melatonin, a natural antioxidant, against the hydrogen peroxide (H2O2)-induced damage to RPE cells. The cellular viability, apoptosis, the expression of apoptosis-associated proteins and mitochondrial function were examined in the retinal ARPE-19 cells, post the treatment with H2O2 or (and) with Melatonin. The regulation by Melatonin receptor 1 (MT1) on the Melatonin-mediated protection was also examined via MT1 knockdown with siRNA. Results demonstrated that Melatonin significantly ameliorated cell viability reduction, reduced apoptosis and downregulated the apoptosis-associated proteins in H2O2-treated ARPE-19 cells. The H2O2-induced mitochondrial dysfunction was also significantly blocked by the Melatonin treatment, presenting as a reduced accumulation of reactive oxygen species (ROS) and mitochondrial superoxide and an ameliorated reduction of mitochondrial membrane potential (MMP). In addition, the knockdown of MT1 with MT1-specific siRNA inhibited the Melatonin-mediated protection against OS damage in ARPE-19 cells. In summary, we confirmed the protective role of Melatonin against H2O2-induced mitochondrial dysfunction in RPE cells. MT1 knockdown blocked such protective role of Melatonin. It is implied that Melatonin exerts a protective role against oxidative stress via Melatonin-MT1 signaling in RPE cells.

Original Article
  • Ana Mara Islas-Espinoza, Carolina Campos-Rodriguez, Eduardo Ramírez Sa ...
    2018 Volume 43 Issue 11 Pages 671-684
    Published: 2018
    Released: November 07, 2018
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    Thalidomide was originally developed to treat primary neurological and psychiatric diseases. There are reports of anticonvulsant effects of thalidomide in rats and antiepileptic effects in patients. Hence, thalidomide (100, 200 and 400 mg/kg) was herein administered to mice to evaluate possible protection against seizures induced by the systemic administration of neurotoxins: 10 mg/kg of 4-aminopyridine (4-AP), 90 mg/kg of pentylenetetrazol (PTZ), or 380 mg/kg of pilocarpine. The effect of an NO and COX inhibitor (7-NI and ibuprofen, respectively) was also examined. The results show that thalidomide (1) induces the typical sedative effects, (2) has no anticonvulsant effect in mice treated with 4-AP, and (3) has anticonvulsant effect (400 mg/kg) in mice treated with PTZ and pilocarpine. It was found that 7-NI has an anticonvulsant effect in the pilocarpine model and that thalidomide’s effect is not enhanced by its presence. However, thalidomide (200 mg/kg) plus 7-NI or ibuprofen tend to have a toxic effect in PTZ model. On the other hand, the combination of thalidomide and 7-NI or ibuprofen protects against pilocarpine-induced seizures. In conclusion, thalidomide did not exert an anticonvulsant effect for clonic-tonic type convulsions (4-AP), but it did so for seizures induced by PTZ and pilocarpine (representing absence seizures and status epilepticus, respectively). NO and prostaglandins were involved in the convulsive process elicited by pilocarpine.

Original Article
  • Hidemi Mochizuki, Naoya Murota, Shin-ichi Sato, Kazuo Nii, Yoko Kouhei ...
    2018 Volume 43 Issue 11 Pages 685-695
    Published: 2018
    Released: November 07, 2018
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    We investigated the viability of a combined repeated dose toxicity study, including toxicokinetics (TK), in common marmosets according to the ICH-S4, ICH-S3A and ICH-S7A Guidelines using valsartan as test article whose non-clinical repeated dose toxicity studies had been conducted using this species for regulatory purpose. Valsartan was administered orally to 3 animals/sex at 200 mg/kg/day for 2 weeks. In addition to the routine parameters in repeated dose toxicity studies, safety pharmacology parameters (examinations of the central nervous, respiratory and cardiovascular systems) were also evaluated. The Plasma Micro Sampling Toxicokinetics (PMS-TK) method required ultrasensitive quantitation, was employed to evaluate the relationship between toxic changes and plasma concentrations as well as the effects of frequent blood sampling in individual animals. In valsartan, toxic findings (a deteriorated physical condition; moribundity of one male and one female on Day 14; sporadic vomitus; decreases in body weights and food consumption; decreases in erythrocytic parameters; and renal changes such as an increase in urea nitrogen, dilation of the tubules and hypertrophy of the tubular epithelium) were similar and plasma concentrations comparable to the results in the approval information. Furthermore, no side effects caused by frequent blood sampling were confirmed in the negative control group. Consequently, a combined repeated dose toxicity study including TK analysis using the PMS-TK method is viable in common marmosets and contributes to animal welfare.

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