Journal of Toxicological Sciences

Ping Geng, Fen Yu, Dingyu Tan, Jiyang Xu, Yan Yang, Min Xu, Huihui Wang, Bingyu Ling
Acute exposure to hydrogen sulfide (H2 S) can cause fatal acute lung injury (ALI). However, the mechanisms of H2 S-induced ALI are still not fully understood. This study aims to investigate the role of the tight junction protein claudin-5 in H2 S-induced ALI. In our study, Sprague-Dawley (SD) rats were exposed to H2 S to establish the ALI model, and in parallel, human pulmonary microvascular endothelial cells (HPMECs) were incubated with NaHS (a H2 S donor) to establish a cell model. Lung immunohistochemistry and electron microscopy assays were used to identify H2 S-induced ALI, and the expression of claudin-5, p-AKT/t-AKT and p-FoxO1/t-FoxO1 was detected...
2020: Journal of Toxicological Sciences
Qinghua Xu, Baosheng Zhu, Xudong Dong, Suyun Li, Xiaoxiao Song, Xia Xiao, Chao Zhang, Yan Lv, Xiong Zhang, Yan Li
Despite the developmental toxicity reported in animals, few epidemiologic studies have investigated the potential effects of prenatal exposure to pyrethroid pesticides (PYRs) on fetal growth. A birth cohort study was conducted to examine the association between prenatal exposure to PYRs and birth outcomes, and a nested case-control study was conducted in this cohort to evaluate the effects of PYR on congenital defects. The assessment of PYR exposure was based on self-reported household pesticide use and urinary PYR metabolite levels...
2020: Journal of Toxicological Sciences
Xiaoni Zhan, Gehua Wen, Enzhu Jiang, Fengrui Li, Xu Wu, Hao Pang
Environmental neurotoxins such as paraquat (PQ), manganese, and 1-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are associated with a higher risk of Parkinson's disease (PD). These parkinsonian toxins exert certain common toxicological effects on astroglia; however, their role in the regulatory functions of astroglial secretory proteins remains unclear. In a previous study, we observed that secretogranin II (SCG2) and secretogranin III (SCG3), which are important components of the regulated secretory pathway, were elevated in PQ-activated U118 astroglia...
2020: Journal of Toxicological Sciences
Junzo Kinoshita, Katsumi Fujita, Kyohei Yasuno, Takami Suzuki, Takuma Iguchi, Takayoshi Nishiya, Kazuhiko Mori
This study was aimed to investigate morphological alteration of the retina with N-methyl-D-aspartate (NMDA)-induced injury in rabbits by optical coherence tomography (OCT). The right and left eyes of a total of 12 rabbits received single-intravitreal injection of vehicle and NMDA, respectively. Four out of the 12 animals underwent OCT and quantification of plasma microRNA repeatedly (4, 48, and 168 hr after dosing), followed by ocular histopathology at the end of the study. Ocular histopathology was also conducted in the eyes collected 4 or 48 hr after dosing from 4 animals at each time period...
2020: Journal of Toxicological Sciences
Kazuma Kondo, Naohito Yamada, Yusuke Suzuki, Tatsuji Hashimoto, Kaoru Toyoda, Tadakazu Takahashi, Akio Kobayashi, Shoichiro Sugai, Kouichi Yoshinari
Some patients encounter hepatotoxicity after repeated acetaminophen (APAP) dosing even at therapeutic doses. In the present study, we focused on the diabetic state as one of the suggested risk factors of drug-induced liver injury in humans and investigated the contribution of accelerated gluconeogenesis to the susceptibility to APAP-induced hepatotoxicity using an animal model of type 2 diabetes patients. Sprague-Dawley (SD) rats and spontaneously diabetic torii (SDT) rats were each given APAP at 0 mg/kg, 300 and 500 mg/kg for 35 days by oral gavage...
2020: Journal of Toxicological Sciences
Tsutomu Takahashi, Tsuyoshi Nakano, Go Katoh, Yo Shinoda, Chika Yamamoto, Eiko Yoshida, Toshiyuki Kaji, Yasuyuki Fujiwara
Blood coagulation and the fibrinolytic system contribute to vascular lesions. Fibrinolysis in normal circulating blood strongly depends on the balance between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) secreted from vascular endothelial cells; however, the mechanisms by which endothelial fibrinolysis is regulated remain to be fully understood. In the present study, human vascular endothelial EA.hy926 cells were transfected with small interfering RNA for nuclear factor erythroid 2-related factor 2 (NRF2) and the expression of t-PA and PAI-1 and fibrinolytic activity in the conditioned medium were examined...
2020: Journal of Toxicological Sciences
Masayo Hirao-Suzuki, Shuso Takeda, Takayuki Koga, Masufumi Takiguchi, Akihisa Toda
A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities. We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer. Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established...
2020: Journal of Toxicological Sciences
Mei Tsuchida, Takumi Yokosawa, Takuya Noguchi, Tatsuya Shimada, Mayuka Yamada, Yuto Sekiguchi, Yusuke Hirata, Atsushi Matsuzawa
Tumor necrosis factor receptor-associated factor 2 (TRAF2) is an essential component of tumor necrosis factor-α (TNF-α) signaling that regulates nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, and compelling evidence has demonstrated that TRAF2 suppresses TNF-α-induced cytotoxicity. On the other hand, it has been reported that oxidative stress-induced cytotoxicity is potentiated by TRAF2, indicating that TRAF2 both positively and negatively regulates stress-induced cytotoxicity in a context-specific manner...
2020: Journal of Toxicological Sciences
Hiroshi Iwasaki, Masaki Wakamatsu, Kazunari Sugihara, Kyohei Kamio, Satoshi Tsuji, Junya Morita, Yasuhiro Kurihara, Tomoko Izumi, Tomohiro Nishimoto, Kohnosuke Kinoshita, Yutaka Nakanishi, Minoru Sasaki
TP0446131, developed as an antidepressant agent, was found to cause lenticular opacity in a 13-week repeated-dose study in dogs. Histopathologically, the lenticular opacity was observed as a degeneration of the lens fibers, characterized by irregularity in the ordered arrangement of the fibers which is necessary to maintain the transparency of the lens, and was considered to manifest clinically as cataract. To evaluate the development mechanism of the lenticular opacity, the chemical constituents of the lens, which is known to be associated with the development of cataract, were examined...
2020: Journal of Toxicological Sciences
Nobuo Aikawa
In vitro human induced pluripotent stem (iPS) cells testing (iPST) to assess developmental toxicity, e.g., the induction of malformation or dysfunction, was developed by modifying a mouse embryonic stem cell test (EST), a promising animal-free approach. The iPST evaluates the potential risks and types of drugs-induced developmental toxicity in humans by assessing three endpoints: the inhibitory effects of the drug on the cardiac differentiation of iPS cells and on the proliferation/survival of iPS cells and human fibroblasts...
2020: Journal of Toxicological Sciences
Junhong Lin, Junzheng Peng, Guosheng Liu, Li Deng
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...
2020: Journal of Toxicological Sciences
Yan-Xia Gao, Yi-Bo Wang, You-Dong Wan, Tong-Wen Sun, Yi Li, Lin-Lin Hou, Pei Sun, Ding Yuan, Guo-Yu Duan, Chang-Hua Sun, Lu Che, Yan Zhang
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...
2020: Journal of Toxicological Sciences
Sosuke Kishi, Keiko Yamakawa, Yuko Nakano-Narusawa, Shohei Kanie, Nozomi Hashimoto, Kousuke Saoo, Masanao Yokohira, Katsumi Imaida, Yoko Matsuda
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...
2020: Journal of Toxicological Sciences
Yuto Amano, Hiroshi Honda, Ryusuke Sawada, Yuko Nukada, Masayuki Yamane, Naohiro Ikeda, Osamu Morita, Yoshihiro Yamanishi
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...
2020: Journal of Toxicological Sciences
Ryo Kamata, Fujio Shiraishi, Kazuichi Nakamura
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...
2020: Journal of Toxicological Sciences
Fangfang Zhang, Xinyue You, Tengteng Zhu, Sumeng Gao, Yu Wang, Ruoyang Wang, Herbert Yu, Biyun Qian
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...
2020: Journal of Toxicological Sciences
Tomoka Hisaki, Maki Aiba Née Kaneko, Morihiko Hirota, Masato Matsuoka, Hirokazu Kouzuki
We present a systematic, comprehensive and reproducible weight-of-evidence approach for predicting the no-observed-adverse-effect level (NOAEL) for systemic toxicity by using read-across and quantitative structure-activity relationship (QSAR) models to fill gaps in rat repeated-dose and developmental toxicity data. As a case study, we chose valproic acid, a developmental toxicant in humans and animals. High-quality in vivo oral rat repeated-dose and developmental toxicity data were available for five and nine analogues, respectively, and showed qualitative consistency, especially for developmental toxicity...
2020: Journal of Toxicological Sciences
Masaaki Miyata, Akihiro Funaki, Chiaki Fukuhara, Yukino Sumiya, Yoshimasa Sugiura
Mice lacking the farnesoid X receptor (FXR) are used as a genetic model for nonalcoholic fatty liver disease because their livers exhibit hepatic steatosis and inflammation. The influence of taurine drinking on disrupted hepatic function was investigated using female Fxr-null mice. Significant decreases in the levels of hepatic damage-associated diagnostic markers, hepatic triglycerides, non-esterified fatty acids, and total bile acids were found in Fxr-null mice that had drunk water containing 0.5% taurine for four weeks...
2020: Journal of Toxicological Sciences
Chenghui Leng, Junli Sun, Keke Xin, Jianlin Ge, Ping Liu, Xiaojing Feng
Sepsis-induced acute lung injury (ALI) has high morbidity and mortality rates, and there remains a need for therapeutic methods to improve the outcome of ALI patients. miR-483-5p is an important regulator for the development of various diseases such as sepsis. Nevertheless, it is not known whether miR-483-5p has an effect on sepsis-induced ALI. To explore this issue, this study used cecal ligation and puncture (CLP)-treated mice and lipopolysaccharide (LPS)-treated pulmonary microvascular endothelial cells (PMVECs) cells to simulate the models of sepsis-induced ALI in vivo and in vitro...
2020: Journal of Toxicological Sciences
Dongyi Fan, Simin Yang, Yuxiang Han, Ru Zhang, Lukun Yang
MicroRNAs (miRNAs) are widely known as critical regulators in isoflurane-induced neurotoxicity during the development of brain. Moreover, isoflurane could aggravate cognitive impairment in diabetic rats. The present study was designed to investigate the role and mechanism of miR-140-5p on isoflurane-induced neurotoxicity in diabetic rats. Firstly, a diabetic rat model was established by injection of streptozotocin (STZ) and identified by Morris water maze test. The result indicated that isoflurane treatment exacerbated STZ-induced cognitive impairment, as demonstrated by increase of the latency to the platform and decrease of the proportion of time spent in the target quadrant...
2020: Journal of Toxicological Sciences
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