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Journal of Toxicological Sciences

Hirofumi Yokoyama, Yuji Nakamura, Hiroyuki Saito, Yukitoshi Nagayama, Kiyotaka Hoshiai, Takeshi Wada, Hiroko Izumi-Nakaseko, Kentaro Ando, Yasuki Akie, Atsushi Sugiyama
We tried to establish the halothane-anesthetized microminipigs as an alternative animal model for non-clinical toxicity and/or safety pharmacology studies. In order to characterize the halothane-anesthetized microminipigs, we firstly clarified the effects of halothane anesthesia on their cardiovascular system (n = 5). Then, we examined the cardiovascular effects of dl-sotalol in doses of 0.1, 0.3 and 1 mg/kg, i.v. on the halothane-anesthetized microminipigs (n = 6). Induction of the halothane anesthesia by itself prolonged the QT interval as well as QTcF, suggesting that the halothane anesthesia can reduce the cardiac repolarization reserve in microminipigs like in dogs...
2017: Journal of Toxicological Sciences
Takao Tobe, Koji Ueda, Akira Aoki, Yoshinori Okamoto, Nakao Kojima, Hideto Jinno
Selenium (Se) is an essential trace element and is regarded as a protective agent against cancer. In particular, antioxidant effects of selenoenzymes contribute to cancer prevention. Se can also produce reactive oxygen species and, thereby, exert cancer-selective cytotoxicity. Selenodiglutathione (SDG) is a primary Se metabolite conjugated to two glutathione (GSH) moieties. SDG increases intracellular Se accumulation and is more toxic than selenous acid (H2SeO3), but the mechanisms for importing Se compounds into cells are not fully understood...
2017: Journal of Toxicological Sciences
Satoshi Tamai, Takuma Iguchi, Noriyo Niino, Kei Mikamoto, Ken Sakurai, Ayako Sayama, Hitomi Shimoda, Wataru Takasaki, Kazuhiko Mori
Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes...
2017: Journal of Toxicological Sciences
Wanida Tungkum, Pichaya Jumnongprakhon, Chainarong Tocharus, Piyarat Govitrapong, Jiraporn Tocharus
Methamphetamine (METH) is a neurotoxic drug that causes brain damage by inducing neuronal and glial cell death together with glial cell hyperactivity-mediated progressive neurodegeneration. Previous studies have shown that METH induced glial cell hyperactivity and death via oxidative stress, the inflammatory response, and endoplasmic reticulum stress (ER stress) mechanisms, and melatonin could reverse these effects. However, the exact mechanism of the protective role of melatonin in METH-mediated ER stress has not been understood...
2017: Journal of Toxicological Sciences
Jinle Lin, Jun Tian, Li Wang, Weigang Wu, Huaying Li, Xueyan Wang, Xiaobin Zeng, Wenwu Zhang
Lipopolysaccharide (LPS), a Gram-negative bacterial outer membrane component, is one of the major causes of septic shock. Herein we investigate LPS-induced apoptosis of rat alveolar epithelial type II cells (AEC II) and the effects of LPS on surfactant protein-C (SP-C) expression in AEC II, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of AEC II significantly in concentration-dependent manner embodied in increased caspase-3 expression and the activity of caspase-3...
2017: Journal of Toxicological Sciences
Jian Ji, Pei Zhu, Chao Sun, Jiadi Sun, Lu An, Yinzhi Zhang, Xiulan Sun
3-Chloropropane-1,2-diol (3-MCPD) is a heat-produced contaminant formed during the preparation of soy sauce worldwide. The present investigation was conducted to determine the molecular aspects of 3-MCPD toxicity on human embryonic kidney cells (HEK293). Cell viability and apoptosis were assessed in response to exposure to 3-MCPD using the MTT assay and high-content screening (HCS). DNA damage, intracellular reactive oxygen species (ROS) and apoptosis-related proteins were evaluated. Genes related with apoptosis were detected by qPCR-array for further understanding the 3-MCPD induced cell apoptosis signaling pathway...
2017: Journal of Toxicological Sciences
Junya Morita, Tomoko Izumi, Bunichiro Ogawa, Yoshiki Ban, Hironori Takagi, Minoru Sasaki, Shunsuke Tsutsumi
This study sought to clarify the effects of reduced feeding on physiological parameters in dogs to enable appropriate evaluations of the safety and toxicity of test compounds. We measured alkaline phosphatase isozymes and the circulating blood volume, as well as clinical signs, body weight, hematology, blood chemistry, electrocardiography, organ weight, and histopathology, in male beagle dogs fed a diet consisting of 300 g/day or 150 g/day for 4 weeks. There were no abnormal clinical signs in any of the dogs...
2017: Journal of Toxicological Sciences
Eiki Kimura, Ken-Ichiro Kubo, Toshihiro Endo, Kazunori Nakajima, Masaki Kakeyama, Chiharu Tohyama
The aryl hydrocarbon receptor (AhR) avidly binds dioxin, a ubiquitous environmental contaminant. Disruption of downstream AhR signaling has been reported to alter neuronal development, and rodent offspring exposed to dioxin during gestation and lactation showed abnormalities in learning and memory, emotion, and social behavior. However, the mechanism behind the disrupted AhR signaling and developmental neurotoxicity induced by xenobiotic ligands remains elusive. Therefore, we studied how excessive AhR activation affects neuronal migration in the hippocampal CA1 region of the developing mouse brain...
2017: Journal of Toxicological Sciences
Tomoki Takeda, Yuki Matsuo, Kyoko Nishida, Akihisa Fujiki, Yukiko Hattori, Takayuki Koga, Yuji Ishii, Hideyuki Yamada
Our previous studies demonstrated that treating pregnant rats with dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), targets the pituitary expression of luteinizing hormone (LH) to attenuate testicular steroidogenesis in fetuses, resulting in the imprinting of sexual immaturity of the offspring after reaching maturity. Furthermore, we found that although TCDD disturbs the tricarboxylic acid (TCA) cycle in the fetal hypothalamus, maternal co-treatment with α-lipoic acid (α-LA), a cofactor of the TCA cycle, restores a TCDD-produced reduction in the LH-evoked steroidogenesis as well as the TCA cycle activity in fetuses...
2017: Journal of Toxicological Sciences
Yo Shinoda, Tsutomu Takahashi, Jiro Akimoto, Megumi Ichikawa, Hiromi Yamazaki, Atsushi Narumi, Shigenobu Yano, Yasuyuki Fujiwara
Photodynamic therapy (PDT) is a Food and Drug Administration authorized method for cancer treatment, which uses photosensitizer and laser photo-irradiation to generate reactive oxygen species to induce cell death in tumors. Photosensitizers have been progressively developed, from first to third generation, with improvements in cell specificity, reduced side effects and toxicity, increased sensitivity for irradiation and reduced persistence of photosensitizer in healthy cells. These improvements have been achieved by basic comparative experiments between current and novel photosensitizers using cell lines; however, photosensitizers should be carefully evaluated because they may have cell type specificity...
2017: Journal of Toxicological Sciences
Sayoko Ito-Harashima, Yui Mizutani, Motoshi Nishimura, Hyo Jeong Kim, Yeo Jin Kim, Hyun Soo Kim, Ji Hye Bae, Preeyaporn Koedrith, Masanobu Kawanishi, Young Rok Seo, Takashi Yagi
Cadmium contamination still occurs in some parts of the world, and its concentrations in the environment are monitored in most countries due to its adverse effects on human health. We herein established yeast (Saccharomyces cerevisiae) reporter assay strains carrying plasmids with the yeast JLP1, SEO1, and CUP1 promoters connected to the bacterial lacZ reporter gene. The strain carrying the high-copy number pESC-JLP1-lacZ reporter plasmid was more responsive to cadmium than strains with other reporter plasmids...
2017: Journal of Toxicological Sciences
Takeshi Toyoda, Young-Man Cho, Jun-Ichi Akagi, Yasuko Mizuta, Kohei Matsushita, Akiyoshi Nishikawa, Katsumi Imaida, Kumiko Ogawa
3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in high-risk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals...
2017: Journal of Toxicological Sciences
Yu Haranosono, Shingo Nemoto, Masaaki Kurata, Hideyuki Sakaki
Although phospholipidosis (PLD) often affects drug development, there is no convenient in vitro or in vivo test system for PLD detection. In this study, we developed an in silico PLD prediction method based on the PLD-inducing mechanism. We focused on phospholipid (PL)-compound complex formation, which inhibits PL degradation by phospholipase. Thus, we used some molecular interactions, such as electrostatic interactions, hydrophobic interactions, and intermolecular forces, between PL and compounds as descriptors...
April 2016: Journal of Toxicological Sciences
Yui Nakajima, Hirotoshi Iguchi, Shinji Kamisuki, Fumio Sugawara, Teiichi Furuichi, Yo Shinoda
Citrinin, a natural mycotoxin that is found in fermented foods, is known as a cytotoxin and nephrotoxin. Exposure to high doses of citrinin result in apoptosis; however, the effects of low doses are not fully understood. Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders including stroke, trauma and other neurodegenerative diseases. Here, we show the neuroprotective effect of low doses of citrinin against glutamate-induced excitotoxicity. We examined the effect of citrinin exposure on glutamate-induced cell death in cultured rat cortical neurons under two conditions: simultaneous treatment with citrinin 0...
April 2016: Journal of Toxicological Sciences
Ruili Dang, Yujin Guo, Hualin Cai, Ranyao Yang, Donglou Liang, Chuanfeng Lv, Pei Jiang
Patients with schizophrenia (SCZ) are at higher risk for developing cardiovascular disease (CVD) and neuregulin-1 (NRG1)/ErbB signaling has been identified as a common susceptibility pathway for the comorbidity. Antipsychotic treatment can change NRG1/ErbB signaling in the brain, which has been implicated in their therapeutic actions, whereas the drug-induced alterations of NRG1/ErbB pathway in cardiovascular system might be associated with the prominent cardiac side-effects of antipsychotic medication. To test this hypothesis, we examined NRG1/ErbB system in rat prefrontal cortex (PFC) and myocardium following 4-week intraperitoneal administration of haloperidol, risperidone or clozapine...
April 2016: Journal of Toxicological Sciences
Yan Cai, Chao Zhang, Le Hao, Jun Chen, Ping Xie, Zhidong Chen
Microcystin-LR (MCLR) is one of the most toxic cyanotoxins produced in algal blooms. The toxic effects of MCLR on the expression of some organelles genes (mitochondrion, endoplasmic reticulum, and cytoskeleton etc) have been widely investigated, but little is known how it impacts on the expression of ribosomal genes. In this study we identified seven ribosomal protein genes RPS6, RPS12, RPS24, RPS27a, RPL12, RPL27 and RPL29 in bighead carp (Aristichthys nobilis), whose expression was regulated by MCLR. The amino acid sequences of those 7 genes shared more than 90% identity with corresponding sequences from zebrafish, and were well conserved throughout evolution...
April 2016: Journal of Toxicological Sciences
Masayuki Kanki, Min Gi, Masaki Fujioka, Hideki Wanibuchi
Several studies have successfully detected hepatocarcinogenicity in rats based on gene expression data. However, prediction of hepatocarcinogens with certain mechanisms of action (MOAs), such as enzyme inducers and peroxisome proliferator-activated receptor α (PPARα) agonists, can prove difficult using a single model and requires a highly toxic dose. Here, we constructed a model for detecting non-genotoxic (NGTX) hepatocarcinogens and predicted their MOAs in rats. Gene expression data deposited in the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) was used to investigate gene marker sets...
April 2016: Journal of Toxicological Sciences
Kei-ichi Sugiyama, Masashi Muroi, Mawo Kinoshita, Osamu Hamada, Yuji Minai, Yoshiko Sugita-Konishi, Yoichi Kamata, Ken-ichi Tanamoto
Macrophages induce the innate immunity by recognizing pathogens through Toll-like receptors (TLRs), which sense pathogen-associated molecular patterns. Myeloid differentiation factor 88 (MyD88), which is an essential adaptor molecule for most TLRs, mediates the induction of inflammatory cytokines through nuclear factor κB (NF-κB). Trichothecene mycotoxin deoxynivalenol (DON) shows immunotoxic effects by interrupting inflammatory mediators produced by activated macrophages. The present study investigates the effect of DON on NF-κB in activated macrophages through MyD88-dependent pathways...
April 2016: Journal of Toxicological Sciences
Fusako Mitsunaga, Masakazu Umezawa, Ken Takeda, Shin Nakamura
To investigate the influence of nanomaterial exposure during fetal development, diesel exhaust particles (DEPs), carbon black (CB), or titanium dioxide (TiO2) was injected intradermally to pregnant rhesus macaques. The hippocampus and cerebellum of newborn infants were then examined. DNA microarray and quantitative real-time RT-PCR, western blot, and immunohistochemical analyses were used to measure the expression of the hemoglobin genes, HBA, HBB, and HBG. Of the nanomaterials tested, DEP elicited the greatest increase in mRNA and protein levels of hemoglobin genes in the brain tissues...
April 2016: Journal of Toxicological Sciences
Kanae Umeda, Yaichiro Kotake, Masatsugu Miyara, Keishi Ishida, Seigo Sanoh, Shigeru Ohta
GluR2, an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, plays important roles in neuronal survival. We previously showed that exposure of cultured rat cortical neurons to several chemicals decreases GluR2 protein expression, leading to neuronal toxicity. Methoxychlor, the bis-p-methoxy derivative of dichlorodiphenyltrichloroethane, and fenvalerate, a synthetic pyrethroid chemical, have been used commercially as agricultural pesticides in several countries. In this study, we investigated the effects of long-term methoxychlor and fenvalerate exposure on neuronal glutamate receptors...
April 2016: Journal of Toxicological Sciences
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