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Journal of Toxicological Sciences

Nozomi Fujisawa, Chiharu Tohyama, Wataru Yoshioka
Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD...
2019: Journal of Toxicological Sciences
Lingling Chen, Li Zhou, Pengfei Yu, Fangfang Fang, Lei Jiang, Jian Fei, Hang Xiao, Jun Wang
Methamphetamine (METH) is a potent and highly addictive central nervous system stimulant. The association between METH exposure and Alzheimer's disease (AD) has gained more attention, but, the mechanisms behind METH-induced neuron-related adverse outcomes remain poorly understood. With the western blot assay, our results revealed that METH exposure significantly increased the expression of AD-associated pathological proteins, including the amyloid precursor protein (APP) and the phosphorylated tau protein (p-tau)...
2019: Journal of Toxicological Sciences
Qingrong Li, Hongmin Zhang, Jun Zou, Xiang Feng, Dan Feng
Bisphenol A (BPA), an environmental chemical to which humans are commonly exposed, has been shown to increase cholesterol level but the molecular mechanism is not clear. Since cholesterol biosynthesis plays an important role in elevating cholesterol level, the aim of the present study is to explore the effects of BPA on cholesterol biosynthesis in HepG2 cells and its possible mechanisms. HepG2 cells were treated with different concentrations of BPA for 24 hr, the total cholesterol level and the activity of 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) were measured using commercial enzymatic assay kits, and the mRNA and protein expression levels of sterol regulatory element binding protein-2(SREBP-2) and HMGCR were analyzed by qPCR, Western blotting and immunofluorescence, respectively...
2019: Journal of Toxicological Sciences
Takayuki Hoshi, Takashi Toyama, Youichi Shinozaki, Schuichi Koizumi, Jin-Yong Lee, Akira Naganuma, Gi-Wook Hwang
M1-microglia (neurotoxic microglia) regulate neuronal development and cell death and are involved in many pathologies in the brain. Although organotypic brain slice cultures are widely used to study the crosstalk between neurons and microglia, little is known about the properties of microglia in the mouse cerebral cortex slices. Here, we aimed to optimize the mouse cerebral slice cultures that reflect microglial functions and evaluate the effects of neurotoxic metals on M1-microglial activation. Most microglia in the cerebral slices prepared from postnatal day (P) 7 mice were similar to mature microglia in adult mice brains, but those in the slices prepared from P2 mice were immature, which is a conventional preparation condition...
2019: Journal of Toxicological Sciences
Takafumi Yamaguchi, Minoru Maeda, Keiko Ogata, Jun Abe, Toru Utsumi, Koji Kimura
Phenobarbital (PB) and Di (2-ethylhexyl) phthalate (DEHP), an anti-epileptic drug and a plasticizer used in flexible polyvinylchloride formulations, respectively, are well-known typical hepatotoxicants. This study investigated the effects of PB (100 mg/kg/day) or DEHP (500 mg/kg/day) on the endocrine system in intact juvenile/peripubertal male rats exposed for 31 days beginning on postnatal day 23. Slight hormone level changes, histopathological changes in thyroid gland or induction of UDP-glucuronosyltransferase in liver were observed in both the PB and DEHP groups...
2019: Journal of Toxicological Sciences
Kenta Watanabe, Tadashi Tsubouchi, Toru Yamada, Eiichi Hinoi, Izuru Miyawaki
The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans...
2019: Journal of Toxicological Sciences
Yuto Sekiguchi, Mayuka Yamada, Takuya Noguchi, Chise Noomote, Mei Tsuchida, Yuki Kudoh, Yusuke Hirata, Atsushi Matsuzawa
Fas/CD95 plays a pivotal role in T cell-mediated cytotoxicity. Accumulating evidence has suggested that resistance to Fas-mediated apoptosis contributes to the escape of cancer cells from immune destruction, and allows to undergo proliferation and outgrowth of cancer cells. In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis...
2019: Journal of Toxicological Sciences
Cong Lin, Dazhen Wei, Dawei Xin, Jialin Pan, Mingyuan Huang
Cardiac fibroblasts (CFs) could be activated after myocardial infarction (MI). Thus, it is necessary to explore effective drugs to suppress the activation of CFs following MI. This study was designed to investigate the impacts of ellagic acid on CFs and the underlying mechanisms. The expression of histone deacetylases (HDACs) and fibrosis-related genes was detected by qRT-PCR and western blot. The Masson's Trichrome Staining assay was used to evaluate the area of cardiac fibrosis. The proliferation and migration of CFs were measured by CCK8 Kit and Transwell assay, respectively...
2019: Journal of Toxicological Sciences
Ji Soo Park, Yong Joo Park, Ha Ryong Kim, Kyu Hyuck Chung
Polyhexamethylene guanidine phosphate (PHMG-p) is an active ingredient of humidifier disinfectants and causes severe lung injury resulting in pulmonary fibrosis. Current evidence indicates that pulmonary fibrosis is initiated as a result of epithelial damage, which can lead to an inflammatory response and fibrotic cell infiltration; however, the toxic mechanism of PHMG-p on the epithelium is still unknown. In this study, the toxic response of PHMG-p on human lung epithelial cells was evaluated, and its mechanisms associated with reactive oxygen species (ROS), DNA damage, and its relationship with p53 activation were investigated...
2019: Journal of Toxicological Sciences
Yunsong Zhou, Chong Peng, Zunming Zhou, Keer Huang
Several studies have demonstrated the chemopreventive role of ketoconazole in animal models of liver injury. However, the underlying molecular mechanisms of this hepatoprotective effect are poorly understood. The present study assessed the potential of ketoconazole to enhance resistance to carbon tetrachloride-induced hepatotoxicity in vivo in a rat model. Ketoconazole pretreatment adult male rats were intraperitoneally injected with carbon tetrachloride for 24 hr and various hepatic parameters were analyzed...
2019: Journal of Toxicological Sciences
Zaher A Radi, K Nasir Khan
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutic class in clinical medicine. These are sub-divided based on their selectivity for inhibition of cyclooxygenase (COX) isoforms (COX-1 and COX-2) into: (1) non-selective (ns-NSAIDs), and (2) selective NSAIDs (s-NSAIDs) with preferential inhibition of COX-2 isozyme. The safety and pathophysiology of NSAIDs on the renal and cardiovascular systems have continued to evolve over the years following short- and long-term treatment in both preclinical models and humans...
2019: Journal of Toxicological Sciences
Mariko Sugiyama, Takuro Ueki, Shinichi Ogata, Hiroshi Itagaki
To predict the results of a 24-hr closed human patch test, we previously recommended the use of in vitro test with a reconstructed human epidermis (RhE) model adopted in OECD TG 439, and proposed the margin method, which includes evaluation of twice the concentration to avoid a false positive for surfactants. Therefore, in this study, we used LabCyte EPI-MODEL as a RhE model, and confirmed the reproducibility of this method using five surfactants, including benzalkonium chloride (BC), sodium lauryl sulfate (SLS), and lauryl betaine (LB), for which false negative results have previously been reported, and three different surfactants...
2019: Journal of Toxicological Sciences
Takaharu Tanaka, Yasunori Masubuchi, Rena Okada, Kota Nakajima, Kazuki Nakamura, Sosuke Masuda, Junta Nakahara, Robert R Maronpot, Toshinori Yoshida, Mihoko Koyanagi, Shim-Mo Hayashi, Makoto Shibutani
Developmental hypothyroidism as a model of autism spectrum disorders disrupts hippocampal neurogenesis through the adult stage. The present study investigated the ameliorating effect of postweaning exposure to antioxidant on the hypothyroidism-induced disruptive neurogenesis. Mated female Sprague-Dawley rats were treated with 0 or 10 ppm 6-propyl-2-thiouracil (PTU) as an anti-thyroid agent in drinking water from gestational day 6 to postnatal day (PND) 21 on weaning. PTU-exposed male offspring were fed either basal diet, diet containing α-glycosyl isoquercitrin (AGIQ) at 5,000 ppm or α-lipoic acid (ALA) at 1,000 ppm as an antioxidant from PND 21 to PND 77...
2019: Journal of Toxicological Sciences
Akira Kubota, Yusuke K Kawai, Natsumi Yamashita, Jae Seung Lee, Daisuke Kondoh, Shuangyi Zhang, Yasunobu Nishi, Kazuyuki Suzuki, Takio Kitazawa, Hiroki Teraoka
Increasing use of zebrafish in biomedical, toxicological and developmental studies requires explicit knowledge of cytochrome P450 (CYP), given the central role of CYP in oxidative biotransformation of xenobiotics and many regulatory molecules. A full complement of CYP genes in zebrafish and their transcript expression during early development have already been examined. Here we established a comprehensive picture of CYP gene expression in the adult zebrafish liver using a RNA-seq technique. Transcriptional profiling of a full complement of CYP genes revealed that CYP2AD2, CYP3A65, CYP1A, CYP2P9 and CYP2Y3 are major CYP genes expressed in the adult zebrafish liver in both sexes...
2019: Journal of Toxicological Sciences
Do-Hee Kim, Juthika Kundu, In Gyeong Chae, Jong Kwon Lee, Jung Sun Heo, Kyung-Soo Chun
Titanium dioxide nanoparticles (TiO2 -NPs) are used to improve the aesthetic of toothpaste. While TiO2 -NPs have been used safely in toothpaste products for a long time, there haven't been studies to determine whether absorption of TiO2 -NPs by the mucous membranes in the mouth induces pathogenic conditions. Here, we assessed whether TiO2 -NPs induce cyclooxygenase-2 (COX-2) and investigated the molecular mechanisms underlying the pro-inflammatory effect of TiO2 -NPs on human periodontal ligament (PDL) cells...
2019: Journal of Toxicological Sciences
Tomoya Fujie, Fukuta Takenaka, Eiko Yoshida, Shuji Yasuike, Yasuyuki Fujiwara, Yasuhiro Shinkai, Yoshito Kumagai, Chika Yamamoto, Toshiyuki Kaji
Metallothionein (MT) is a low-molecular-weight, cysteine-rich, and metal-binding protein that protects cells from the cytotoxic effects of heavy metals and reactive oxygen species. Previously, we found that transcriptional induction of endothelial MT-1A was mediated by not only the metal-regulatory transcription factor 1 (MTF-1)-metal responsive element (MRE) pathway but also the nuclear factor-erythroid 2-related factor 2 (Nrf2)-antioxidant response element/electrophile responsive element (ARE) pathway, whereas that of MT-2A was mediated only by the MTF-1-MRE pathway, using the organopnictogen compounds tris(pentafluorophenyl)stibane, tris(pentafluorophenyl)arsane, and tris(pentafluorophenyl)phosphane as molecular probes in vascular endothelial cells...
2019: Journal of Toxicological Sciences
Bodong Li, Haibo Xie, Xian Wang, Xiaodong Yang, Ling Yang, Jiaxiang Zhang, Feng Wang, Tong Shen, Qixing Zhu
The purpose of this study was to explore whether renal endothelial cell injury is associated with oxidative stress in trichloroethylene (TCE)-induced immune kidney damage by detecting adhesion molecules and oxidative stress indexes. In this study, a mouse model of skin sensitization with the antioxidant Tempol was used to explore the mechanism. Blood urea nitrogen (BUN), creatinine (Cre), and histological examination were used for kidney function evaluation. Kidney homogenates were used for detecting renal nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD) and malondialdehyde (MDA)...
2019: Journal of Toxicological Sciences
Tomoki Kimura, Takuomi Hosaka, Tsuyoshi Nakanishi, Osamu Aozasa
Cadmium, a ubiquitous heavy metal, is a toxic industrial and environmental pollutant. The initial biological response to cadmium exposure is induction of metallothioneins (MTs), a family of cysteine-rich, low-molecular-weight proteins that bind primarily zinc, cadmium, or both. This MT induction protects against cadmium toxicity by quenching cadmium. However, the effects of long-term cadmium exposure on MT1 gene expression are largely unknown. To investigate these effects, we used P1798 mouse lymphosarcoma cells, in which the MT1 gene is suppressed...
2019: Journal of Toxicological Sciences
Nana Long, Huaqiao Tang, Lin Lin, Jianlong Li, Lijuan Guo, Fenghui Sun, Min Dai
Methicillin-resistant Staphylococcus aureus (MRSA) leads to serious infections, but it is not known whether it changes the expression of kidney drug metabolizing enzymes during infection. The mice were infected with different doses of MRSA and the oxidative stress and inflammation levels in the kidney were examined. The mRNA expression and activity of cytochrome P450 enzyme was analysed. Mice infected with high levels of MRSA showed a decrease in renal antioxidant capability and an elevated level of oxidative metabolites, which was accompanied by the release of inflammatory cytokines...
2019: Journal of Toxicological Sciences
Hanae Kobayashi-Tsukumo, Kanami Oiji, Dan Xie, Yuka Sawada, Kunihiko Yamashita, Shinichi Ogata, Hajime Kojima, Hiroshi Itagaki
We previously developed a test for detecting naturally occurring protein-induced skin sensitization based on the markers and criteria of the human cell-line activation test (h-CLAT) and showed that the h-CLAT was useful for assessing the allergenic potency of proteins. However, test proteins were contaminated with varying amounts of lipopolysaccharide (LPS), which might have contributed to the stimulation of CD86 and CD54 expression. In this study, we developed a method to exclude the effects of LPS in the assessment of skin sensitization by naturally occurring proteins...
2019: Journal of Toxicological Sciences
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