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Journal of Toxicological Sciences | Page 2

Keiichi Itoh, Shoji Masumori, Daisuke Mukai, Hiroyuki Sakakibara, Michiko Yasuda, Kayoko Shimoi
Previously, we reported that the frequency of micronucleated reticulocytes (MNRETs) in the peripheral blood of male C3H/He mice intraperitoneally administered ethylnitrosourea (ENU) (25 mg/kg body weight) in the dark period (zeitgeber time, ZT15) was higher than in the light period (ZT3). In this study, to clarify the mechanism underlying this phenomenon, we investigated the differences in micronucleus (MN) induction observed between ZT3 and ZT15 using five chemicals, methylnitrosourea (MNU), ethylmethane sulfonate (EMS), mitomycin C, cyclophosphamide and vincristin...
2019: Journal of Toxicological Sciences
Satoshi Yokota, Takuya Shirahata, Junko Yusa, Yuko Sakurai, Hiroshi Ito, Shigeru Oshio
Vitamin A and its derivatives contribute to many physiological processes, including vision, neural differentiation, and reproduction. Vitamin A deficiency causes early cessation of spermatogenesis, characterized by a marked depletion of germ cells. However, there has been no clear understanding about the role of chronic intake of vitamin A excess (VAE) in spermatogenesis. The objective of this study was to investigate whether chronic intake of VAE diet causes arrest of spermatogenesis. To examine the effects of VAE on spermatogenesis, we used ICR male mice fed with control (AIN-93G purified diet: 4 IU/g) diet or VAE (modified AIN-93G diet with VAE: 1,000 IU/g) diet for 7 weeks (from 3 to 10 weeks of age)...
2019: Journal of Toxicological Sciences
Kaori Ambe, Yuko Sakakibara, Aya Sakabe, Hayato Makino, Tatsuya Ochibe, Masahiro Tohkin
Phthalate esters (PEs) are widely used as plasticizers in various kinds of plastic products. Some PEs have been known to induce developmental and reproductive toxicity (DART) as well as hepatotoxicity in laboratory animals. In some cases of DART, the strength of toxicity of PEs depends on the side chain lengths, while the relationship between hepatotoxicity and side chain length is unknown. Therefore, in this study, we compared DART and hepatotoxicity in rats, focusing on 6 PEs with different side chains. We collected toxicity data of 6 PEs, namely, n-butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), di-isodecyl phthalate (DIDP), di-isononyl phthalate (DINP), and di-n-octyl phthalate (DNOP), from open data source, then, we constructed the toxicity database to comprehensively and efficiently compare the toxicity effects...
2019: Journal of Toxicological Sciences
Jin Hee Kim
Di(2-ethylhexyl) phthalate (DEHP) is widely used in polyvinylchloride-based materials and remains intact in the environment. Lungs are one route of entry of DEHP into the body; however, there is limited information on the effects and mechanism of action of DEHP on non-small cell lung cancer (NSCLC). Here, we addressed this by examining the effect of DEHP on the proliferation of A549 human lung adenocarcinoma cells by MTS assay. The induction of inflammation and epithelial-to-mesenchymal transition (EMT), as well as activation of the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways, were assessed by western blot and real-time polymerase chain reaction...
2019: Journal of Toxicological Sciences
Shelli Schomaker, Shashi Ramaiah, Nasir Khan, John Burkhardt
Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising therapeutics. Although progress has been made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant biomarker gaps still exist to monitor toxicities for testis, pancreas, etc. Several precompetitive consortia [e.g., Predictive Safety Testing Consortia (PSTC), Innovative Medicines Initiative (IMI)] are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be used in preclinical studies and clinical trials to accelerate drug development...
2019: Journal of Toxicological Sciences
Takafumi Mitachi, Mai Kouzui, Ryo Maruyama, Kunihiko Yamashita, Shinichi Ogata, Hajime Kojima, Hiroshi Itagaki
The human cell line activation test (h-CLAT) is a skin sensitization test that measures the expression of cell surface proteins CD86 and CD54 to evaluate the skin sensitization potential of test chemicals. However, some skin irritants have been reported to induce dramatically high CD54 expression leading to false-positive h-CLAT results. Furthermore, CD54 expression is strongly induced by cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α, or danger signals that activate its signaling pathways...
2019: Journal of Toxicological Sciences
Nobuyuki Kakutani, Toyomichi Nanayama, Yukihiro Nomura
This study was aimed to predict drug-induced liver injury caused by reactive metabolites. Reactive metabolites covalently bind to proteins and could result in severe outcomes in patients. However, the relation between the extent of covalent binding and clinical hepatotoxicity is still unclear. From a perspective of body burden (human in vivo exposure to reactive metabolites), we developed a risk assessment method in which reactive metabolite burden (RM burden), an index that could reflect the body burden associated with reactive metabolite exposure, is calculated using the extent of covalent binding, clinical dose, and human in vivo clearance...
2019: Journal of Toxicological Sciences
Yo Shinoda, Shunsuke Ehara, Satoshi Tatsumi, Eiko Yoshida, Tsutomu Takahashi, Komyo Eto, Toshiyuki Kaji, Yasuyuki Fujiwara
Exposure to organic mercury, especially methylmercury (MeHg), causes Minamata disease, a severe chronic neurological disorder. Minamata disease predominantly affects the central nervous system, and therefore, studies on the mechanisms of MeHg neurotoxicity have focused primarily on the brain. Although the peripheral nervous system is also affected by the organometallic compound and shows signs of neural degeneration, the mechanisms of peripheral MeHg neurotoxicity remain unclear. In the present study, we performed quantitative immunohistochemical analyses of the dorsal root ganglion (DRG) and associated sensory and motor fibers to clarify the mechanisms of MeHg-induced peripheral neurotoxicity in Wistar rats...
2019: Journal of Toxicological Sciences
Qi Yu, Namin Feng, Yan Hu, Foquan Luo, Weihong Zhao, Weilu Zhao, Zhiyi Liu, Mengyuan Li, Lin Xu, Liuqing Wu, Yulin Liu
Recent studies have shown that sevoflurane can cause long-term neurotoxicity and learning and memory impairment in developing and progressively neurodegenerative brains. Sevoflurane is a widely used volatile anesthetic in clinical practice. Late gestation is a rapidly developing period in the fetal brain, but whether sevoflurane anesthesia during late gestation affects learning and memory of offspring is not fully elucidated. Histone deacetylase 2 (HDAC2) plays an important regulatory role in learning and memory...
2019: Journal of Toxicological Sciences
Xiaoyu Qu, Huan Gao, Lina Tao, Yueming Zhang, Jinghui Zhai, Jingmeng Sun, Yanqing Song, Sixi Zhang
The aim of this study was to explore the role of the NOD-like receptor family, pyrin domain containing (NLRP3) inflammasome and autophagy in Astragaloside IV (AS IV)-mediated protection against cisplatin-induced liver and kidney injury in rats. Rats were intraperitoneally administered cisplatin at a dose of 15 mg/kg and orally administered AS IV for 7 days. Histopathological and biochemical analysis were used to assess liver and kidney function. The levels and localization of NLRP3 and autophagy-associated protein were determined by Western blot and immunohistochemistry...
2019: Journal of Toxicological Sciences
Juan Tang, Xiangjun Lu, Bin Chen, Enqi Cai, Wenli Liu, Jinxiao Jiang, Feifei Chen, Xiaodong Shan, Hangjun Zhang
Silver nanoparticles (AgNPs) are increasingly utilized in a number of applications. This study was designed to investigate AgNPs induced cytotoxicity, oxidative stress and apoptosis in rat tracheal epithelial cells (RTE). The RTE cells were treated with 0, 100 μg/L and 10,000 μg/L of the AgNPs with diameters of 10 nm and 100 nm for 12 hr. The cell inhibition level, apoptosis ratio, reactive oxygen species (ROS), malondialdehyde (MDA) and metallothionein (MT) content were determined. The mRNA expression of cytoc, caspase 3, and caspase 9 was measured by quantitative real-time polymerase chain reaction (qRT-PCR)...
2019: Journal of Toxicological Sciences
Yuki Kishino, Tomoko Hasegawa, Shingo Arakawa, Yukari Shibaya, Takashi Yamoto, Kazuhiko Mori
A high incidence of positive results is obtained with in vitro genotoxicity tests, which do not correlate with the in vivo negative results in many cases. To address this issue, the metabolic profile of rat liver 9000 × g supernatant fraction (S9) pretreated with phenobarbital (PB) and 5,6-benzoflavone (BNF) was characterized. Furthermore, the in vitro micronucleus tests of 10 compounds were performed with PB-BNF-induced rat S9. PB-BNF increased cytochrome P450 (CYP) activity and CYP1A1, CYP1A2, CYP2B1/2, CYP2C6, CYP3A1, and CYP3A2 expression in rat S9, whereas it decreased CYP2C11 and CYP2E1 expression...
2019: Journal of Toxicological Sciences
Wei Zhang, Ruiguo Wang, John P Giesy, Yang Li, Peilong Wang
Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) is the most widely used organophosphorus flame retardant, which is now used instead of polybrominated diphenyl ethers (PBDEs). TDCPP has frequently been detected in inorganic environmental matrices, such as soil, water and air as well as biota. In vitro effects of TDCPP on cells had not been previously elucidated. Therefore, in the present study, cytotoxicity, DNA damage, cell cycle distribution, apoptosis caused by TDCPP was studied in RAW264.7 macrophage cells...
2019: Journal of Toxicological Sciences
Takeshi Tanaka, Kota Nakajima, Yasunori Masubuchi, Yuko Ito, Satomi Kikuchi, Maky Ideta-Ohtsuka, Gye-Hyeong Woo, Toshinori Yoshida, Katsuhide Igarashi, Makoto Shibutani
Maternal exposure to 3,3'-iminodipropionitrile (IDPN) affects hippocampal neurogenesis in mouse offspring, with biphasic disruption, which facilitates neurogenesis during exposure and reduces the broad range of the granule cell lineage population at the adult stage. The present study investigated the epigenetically hypermethylated and downregulated genes related to the IDPN-induced disrupted neurogenesis. Mated female mice were treated with IDPN at 0 or 1200 ppm in drinking water from gestational day 6 to postnatal day (PND) 21 on weaning...
2019: Journal of Toxicological Sciences
Hiromasa Tsuyama, Hitomi Fujishiro, Seiichiro Himeno, Daigo Sumi
Immunological functions are disturbed in humans who have been chronically exposed to arsenic via contaminated groundwater. Little is known about the specific mechanisms underlying the impairment of immunological defense system caused by arsenic. The activation of macrophage cells upon infection with bacteria and viruses plays important roles in the defense against these pathogens. Here we show that exposure to arsenite (As(III)) suppresses nitric oxide (NO) production in murine RAW264.7 macrophage cells stimulated with lipopolysaccharide (LPS) and poly(I:C), the compounds mimicking bacterial and viral infection, respectively...
2019: Journal of Toxicological Sciences
Tadashi Hirata, Young-Man Cho, Isamu Suzuki, Takeshi Toyoda, Jun-Ichi Akagi, Yasushi Nakamura, Satoshi Numazawa, Kumiko Ogawa
To investigate the chemopreventive mechanisms of 4-Methylthio-3-butenyl isothiocyanate (MTBITC), we analyzed cell viability, cell cycle distribution, and expression levels for cell cycle and apoptosis-related proteins in MTBITC-treated malignant esophageal KYSE510 cells, with and without the reactive oxygen species (ROS) scavenger N-acethyl-L-Cysteine (NAC). MTBITC dose-dependently reduced cell viability and Bcl2 protein expression, while it induced cleavages of caspase-3, caspase-9, and PARP-1, suggesting that reduced cell viability occurred through the mitochondrial apoptotic pathway in KYSE510 cells...
2019: Journal of Toxicological Sciences
Qingshu Li, Chunxia Gao, Hong Deng, Quancai Song, Li Yuan
Benzo(α)pyrene (BaP) possesses a forceful hepatotoxicity, and is ubiquitous in foods and ambient air. Our previous study found that BaP induced pyroptotic and autophagic death in HL-7702 human liver cells; the relevant mechanisms, however, remain unknown. This work was therefore to unravel the effects of the PI3K/Akt signaling pathway on pyroptotic and autophagic death triggered by BaP. Cells were treated with or without LY294002 (PI3K/Akt inhibitor) and IGF-1 (PI3K/Akt activator) before BaP exposure, and the results showed that compared with the control, the protein expression of p-Akt was markedly decreased by BaP (p < 0...
2019: Journal of Toxicological Sciences
Tomoya Fujie, Taro Yamamoto, Chika Yamamoto, Toshiyuki Kaji
Although cytotoxicity of inorganic metals has been well investigated, little is known about the cytotoxicity of organic-inorganic hybrid molecules. The cytotoxicity of zinc complexes was evaluated using a culture system of vascular endothelial cells. We found that bis(1,4-dihydro-2-methyl-1-phenyl-4-thioxo-3-pyridiolato)zinc(II), termed Zn-06, exhibited strong cytotoxicity in vascular smooth muscle cells, epithelial cells, fibroblastic cells, and vascular endothelial cells. This study showed that the tetracoordinate structure of the Zn-06 molecule, which contains two sulfur and two oxygen atoms attached to the zinc atom, facilitated its accumulation within vascular endothelial cells whereas the whole structure of the zinc complex was involved in its cytotoxicity in the cells...
2019: Journal of Toxicological Sciences
Kana Unuma, Toshihiko Aki, Ayaka Yamashita, Ayaka Yoshikawa, Koichi Uemura
Inhalation of toxic gases is dangerous to humans; experiments using toxic gases themselves are also hazardous to researchers. Gas-releasing molecules are widely used as alternatives to toxic gases, but their impacts on the whole body remain to be examined. To investigate responses during hydrogen sulfide (H2 S) poisoning, rats (Sprague-Dawley, male, 8-week-old) were intraperitoneally (i.p.) administered H2 S donor, NaHS, and sacrificed 24 hr after the administration. The main histopathological finding commonly observed in NaHS-administered rat heart, liver, brain, and lung was congestion...
2019: Journal of Toxicological Sciences
Sung Ha Ryu, Jung Dae Lee, Ji Won Kim, Siwon Kim, Suhkmann Kim, Kyu-Bong Kim
Cisplatin (CP) is an anti-cancer drug used for treatment of solid tumors, but the major adverse effect is drug-induced nephrotoxicity. The current study aimed to determine biomarkers that might predict nephrotoxicity induced by CP using serum or urinary proton nuclear magnetic resonance (1 H NMR) spectral data in male Sprague-Dawley (S-D) rats. CP (0, 0.5 or 5 mg/kg) was intraperitoneally (i.p.) administered for single dose. Animals were sacrificed 2 days (D2) or 8 days (D8) after administration of CP in order to perform analysis of serum biochemistries and histopathologic examination...
2019: Journal of Toxicological Sciences
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