著者

Keerthi S. Guruge Hirokazu Hikono Nobuaki Shimada Kenji Murakami Jun Hasegawa Leo W.Y. Yeung Noriko Yamanaka Nobuyoshi Yamashita

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.34, no.6, pp.687-691, 2009-12-01 (Released:2009-12-01)

参考文献数

14

被引用文献数

51 74

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Recent studies showed that perfluorooctane sulfonate (PFOS) affects the mammalian immune system at levels reportedly found in the general human population. It has been demonstrated that exposure to immunotoxic chemicals may diminish the host resistance of animals to various pathogenic challenges and enhance mortality. Therefore, the current study was carried out to characterize the effect of a 21 day pre-administration of zero, 5, or 25 μg PFOS/kg bw/day in female B6C3F1 mice on host resistance to influenza A virus infection. At the end of PFOS exposure, body/organ weights did not significantly change whereas PFOS distribution in blood plasma, spleen, thymus and lung was dose-dependently increased. PFOS exposure in mice resulted a significant increase in emaciation and mortality in response to influenza A virus. The effective plasma concentrations in female mice were at least several fold lower than reported mean blood PFOS levels from occupationally exposed humans, and fell in the upper range of blood concentrations of PFOS in the normal human population and in a wide range of wild animals. Hence, it should be important to clarify the precise mechanism(s) for excess mortality observed in the high dose group.

著者

中川 静紀 政本 浩二 住吉 博道 原田 浩

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.9, no.1, pp.57-60, 1984-02-25 (Released:2008-02-21)

参考文献数

5

被引用文献数

25 36

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The acute toxicity test of garlic extract was studied in Wistar rats and ddY mice. The LD<50> values of garlic extract by P.O., I.P. and S.C. administration were estimated over 30 ml/kg respectively in male and female of both rodents. In 30 ml/kg of I.P. group, five of ten in male rats and one of ten in female rats were died within a day after administration, however no specific signs due to garlic extract were observed in survivals for 7 days.

著者

Koichi Tomoda Kaoru Kubo Kazuo Hino Yasunori Kondoh Yasue Nishii Noriko Koyama Yoshifumi Yamamoto Masanori Yoshikawa Hiroshi Kimura

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.39, no.2, pp.331-337, 2014-04-01 (Released:2014-03-18)

参考文献数

23

被引用文献数

5 7

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Cigarette smoke induces skeletal muscle wasting by a mechanism not yet fully elucidated. Branched-chain amino acids (BCAA) in the skeletal muscles are useful energy sources during exercise or systemic stresses. We investigated the relationship between skeletal muscle wasting caused by cigarette smoke and changes in BCAA levels in the plasma and skeletal muscles of rats. Furthermore, the effects of BCAA-rich diet on muscle wasting caused by cigarette smoke were also investigated. Wistar Kyoto (WKY) rats that were fed with a control or a BCAA-rich diet were exposed to cigarette smoke for four weeks. After the exposure, the skeletal muscle weight and BCAA levels in plasma and the skeletal muscles were measured. Cigarette smoke significantly decreased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles, while a BCAA-rich diet increased the skeletal muscle weight and BCAA levels in both plasma and skeletal muscles that had decreased by cigarette smoke exposure. In conclusion, skeletal muscle wasting caused by cigarette smoke was related to the decrease of BCAA levels in the skeletal muscles, while a BCAA-rich diet may improve cases of cigarette smoke-induced skeletal muscle wasting.

著者

Anna K. Kopec Ryuji Yokokawa Nasir Khan Ikuo Horii James E. Finley Christine P. Bono Carol Donovan Jessica Roy Julie Harney Andrew D. Burdick Bart Jessen Shuyan Lu Mark Collinge Ramin Banan Sadeghian Mazin Derzi Lindsay Tomlinson John E. Burkhardt

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.46, no.3, pp.99-114, 2021 (Released:2021-03-01)

参考文献数

68

被引用文献数

1 18

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Microphysiological systems (MPS) are making advances to provide more standardized and predictive physiologically relevant responses to test articles in living tissues and organ systems. The excitement surrounding the potential of MPS to better predict human responses to medicines and improving clinical translation is overshadowed by their relatively slow adoption by the pharmaceutical industry and regulators. Collaboration between multiorganizational consortia and regulators is necessary to build an understanding of the strengths and limitations of MPS models and closing the current gaps. Here, we review some of the advances in MPS research, focusing on liver, intestine, vascular system, kidney and lung and present examples highlighting the context of use for these systems. For MPS to gain a foothold in drug development, they must have added value over existing approaches. Ideally, the application of MPS will augment in vivo studies and reduce the use of animals via tiered screening with less reliance on exploratory toxicology studies to screen compounds. Because MPS support multiple cell types (e.g. primary or stem-cell derived cells) and organ systems, identifying when MPS are more appropriate than simple 2D in vitro models for understanding physiological responses to test articles is necessary. Once identified, MPS models require qualification for that specific context of use and must be reproducible to allow future validation. Ultimately, the challenges of balancing complexity with reproducibility will inform the promise of advancing the MPS field and are critical for realization of the goal to reduce, refine and replace (3Rs) the use of animals in nonclinical research.

著者

Hideo Sugiyama Hiroshi Terada Kimio Isomura Ikuyo Iijima Jun Kobayashi Kiyoshi Kitamura

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.34, no.4, pp.417-425, 2009-08-01 (Released:2009-08-01)

参考文献数

24

被引用文献数

9 15

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The isotope 210Po was suspected of being involved in the death of a former Russian intelligence agent in 2006 in the UK. Although human exposure to this natural radionuclide in foods is estimated to be high, few studies are available. UNSCEAR Report 2000 does not contain data on 210Po concentrations of foodstuffs in Japan. We analyzed samples of the everyday Japanese diet cooked with foodstuffs purchased at supermarkets in 7 major domestic cities in 2007-2008. 210Po was quantified by alpha spectrometry and natural radionuclides such as 40K by gamma spectrometry. The daily intake and committed effective dose of 210Po, 40K, and other natural radionuclides for Japanese adults were calculated. Daily intake was 0.34-1.84 (mean ± σ : 0.66 ± 0.53) and 68.5-94.2 (81.5 ± 8.5) Bq/d and the committed effective dose was 0.15-0.81 (0.29 ± 0.24) and 0.16-0.21 (0.18 ± 0.02) mSv for 210Po and 40K, respectively, comprising a high percentage of the total exposure. The total of the mean committed effective dose for the two nuclides (0.47 mSv) was higher than the annual effective dose from ingestion of foods reported by UNSCEAR 2000 (0.29 mSv). The mean committed effective dose of 40K in the 7 major Japanese cities was comparable to the global average (0.17 mSv). The dietary exposure of Japanese adults can be characterized by a higher 210Po contribution than in other countries. Of the total daily dietary 210Po exposure (13 food categories excluding water) for adults in Yokohama, about 70% was from fish/shellfish and 20% from vegetables/mushrooms/seaweeds, reflecting preferences of Japanese to eat a considerable amount of fish/shellfish containing high 210Po concentrations.

著者

Keiichi Itoh Shoji Masumori Daisuke Mukai Hiroyuki Sakakibara Michiko Yasuda Kayoko Shimoi

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.44, no.4, pp.273-282, 2019 (Released:2019-04-03)

参考文献数

46

被引用文献数

3

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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. MNU and EMS, monofunctional alkylating agents, showed higher frequencies of MNRETs in the ZT15 than the ZT3 treatment similar to ENU. However, no differences were observed for the other chemicals. In the comet assay, more DNA damage was induced by ENU in the ZT15 than the ZT3 treatment. Furthermore, the plasma erythropoietin (EPO) level, a known effector of MN induction with anti-apoptotic activity mediated by Bcl-xL expression, was higher in the dark than in the light period. EPO did not increase the frequency of MNRETs. However, in the ENU treatment group at ZT3 following EPO injection a significant increase of MNRETs was observed similar to the ZT15 treatment. Higher expression of apoptosis-related genes such as Bcl-xL was induced in bone marrow cells from mice treated with ENU at ZT15 compared with ZT3. From these results, it was speculated that the differences in MN induction in the peripheral blood of mice exposed to monofunctional alkylating agents such as ENU depend on apoptotic or anti-apoptotic conditions related to the circadian rhythms of EPO in bone marrow.

著者

Hiroki Yoshioka Tsunemasa Nonogaki Yasuro Shinohara Masumi Suzui Yurie Mori Gi-Wook Hwang Katsumi Ohtani Nobuhiko Miura

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.43, no.2, pp.129-134, 2018 (Released:2018-02-26)

参考文献数

28

被引用文献数

7

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The aim of the present study is to investigate the “chronotoxicity” of seven metal compounds (Hg, Pb, Ni, Cr, Cu, Zn, or Fe) by assessing how their toxicity varies with circadian periodicity. Male ICR mice were injected with each metal compound intraperitoneally at 6 different time points over the course of a day (zeitgeber time [ZT]: ZT2, ZT6, ZT10, ZT14, ZT18 and ZT22). Mortality was then monitored until 14 days after the injection. Our investigation demonstrated that mice were tolerant against Ni toxicity during dark phase, on the other hand, they were tolerant against Cr toxicity during light phase. The chronotoxicity of Hg and Pb seemed to be biphasic. Further, mice were susceptible to toxicities against Cu and Zn in the time zone during which light and dark were reversed. Interestingly, no significant differences were observed for Fe exposure at any time of the day. Our results propose that the chronotoxicology may provide valuable information regarding the importance of injection timing for not only toxicity evaluation tests but also the reproducibility of animal experiments. Furthermore, our data suggests that chronotoxicology may be an important consideration when evaluating the quality of risk assessments for night shift workers who may be exposed to toxic substances at various times of the day.

著者

Satoshi Hori Kosaku Kinoshita

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.41, no.6, pp.765-773, 2016-12-01 (Released:2016-11-16)

参考文献数

12

被引用文献数

10

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OBJECTIVE: The purpose of this study was to identify the clinical aspects leading to overdose of multiple psychotropic drugs, in order to determine areas which need attention in the proper treatment of overdose patients. METHODS: Patients who were treated for overdose of psychotropic drugs at our emergency and critical center over two years were targeted. The clinical data was gathered from the medical records and database of all patients, including age, gender, vital signs, and laboratory data, drugs, and medical complications during hospital stay. In addition primary patient care at the emergency department was examined. RESULTS: Among the 277 patients treated during this study period, 255 (74.0%) used two or more types of psychotropic drugs. Risk factors associated with endotracheal intubation and aspiration pneumonitis included the use of antipsychotics and/or barbiturates as types of overdose drugs. The mean number of days in the ICU was 3.4 days. Seventy-four patients (26.7%) stayed 4 days or more in the ICU of which 16 patients (5.8%) still had suicidal thoughts. A significantly higher incidence of extended ICU stay or endotracheal intubation and aspiration pneumonitis was observed in the group who overdosed on more than 50 or 60 tablets of psychotropic drugs, respectively. CONCLUSIONS: Patients who ingested an overdose of more than 60 tablets of psychotropic drugs should be considered a high-risk group requiring intensive care with extended ICU stay. In case of including antipsychotics and/or barbiturates, the patient should be observed carefully due to a higher risk of medical complications.

著者

Jonggun Kim Yooheon Park Kyong Sup Yoon J. Marshall Clark Yeonhwa Park

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.38, no.5, pp.655-660, 2013-10-01 (Released:2013-09-11)

参考文献数

46

被引用文献数

4 36

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Recently, scientific evidence supports a connection between environmental chemical exposures, which includes insecticides, and development of type 2 diabetes. However, there is limited information about the link between influences of neonicotinoid insecticides and incidence of type 2 diabetes. Thus, the purpose of the study was to determine effects of imidacloprid, a neonicotinoid insecticide, on glucose metabolism. Three different cell models were used; adipocytes (3T3-L1), hepatocytes (HepG2), and myotubes (C2C12). These cells were treated with imidacloprid (0, 10, and 20 μM) for 4-6 days followed by treatment with insulin for 15 min to determine responses. Insulin stimulated glucose uptake was reduced by imidacloprid in all three cell culture models. Treatment with imidacloprid reduced phosphorylation of protein kinase B (AKT), one of the major regulators of insulin signaling, without changing overall AKT expression. Subsequently, imidacloprid reduced phosphorylation of ribosomal S6 kinase (S6K), which is a downstream target of AKT and also a feed-back inhibitor of insulin signaling. These results suggest that imidacloprid could induce insulin resistance by affecting the insulin signaling cascade, particularly up-stream of AKT, in adipocytes, liver, and muscle.

著者

Kent R. Walters Jr. S. Indu Rupassara R.J. Cody Markelz Andrew D.B. Leakey William M. Muir Barry R. Pittendrigh

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.37, no.4, pp.773-790, 2012-08-01 (Released:2012-08-01)

参考文献数

55

被引用文献数

1 9 1

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Methamphetamine (MA) appears to produce neurotoxic effects, in part, through disruptions of energy metabolism. A recent study of the whole-body proteome of Drosophila melanogaster showed many changes in energy metabolism-related proteins, leading us to hypothesize that MA toxicity may cause whole-body disruptions of energy metabolism. To test this, we monitored the response of energy reserves and other metabolites to MA-exposure with and without the addition of dietary glucose. We also monitored changes in feeding behavior, locomotor activity and respiration rates associated with MA-exposure to investigate how MA affects energy balance. We observed that glycogen and triglyceride levels decreased dramatically within 48 hr of MA-exposure, indicating a strongly negative caloric balance. Behavioral assays revealed that MA-treated flies decreased food consumption by 60-80% and exhibited a 2-fold increase in locomotion. Caloric expenditure decreased with MA-exposure, apparently due to a compensatory decrease in resting metabolism, showing that anorexia was the primary driver of the negative caloric balance. Additionally, we observed that glucose supplementation of MA-containing diet increased glycogen reserves by 44% at 48 hr, leading to a commensurate increase in survivorship. We conclude that dietary sugar supplementation enhances survivorship by partially compensating for decreased caloric intake resulting from MA-induced anorexia. The observation that MA produces similar behavioral changes in Drosophila and humans, i.e. increased locomotor activity and anorexia, further supports the use of Drosophila as a model organism for the study of the effects of MA.

著者

Takato Hara Reina Kumagai Tohru Tanaka Tsuyoshi Nakano Tomoya Fujie Yasuyuki Fujiwara Chika Yamamoto Toshiyuki Kaji

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.48, no.12, pp.655-663, 2023 (Released:2023-12-01)

参考文献数

39

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Vascular endothelial cell growth is essential for the repair of intimal injury. Perlecan, a large heparan sulfate proteoglycan, intensifies fibroblast growth factor-2 (FGF-2) signaling as a co-receptor for FGF-2 and its receptor, and promotes the proliferation of vascular endothelial cells. Previously, we reported that 2 µM of lead, a toxic heavy metal, downregulated perlecan core protein expression and then suppressed the growth of vascular endothelial cells. However, since the mechanisms involved in the repression of perlecan by lead remains unclear, we analyzed its detailed signaling pathway using cultured bovine aortic endothelial cells. Our findings indicate that 2 µM of lead inhibited protein tyrosine phosphatase (PTP) activity and induced cyclooxygenase-2 (COX-2) via phosphorylation of the epidermal growth factor receptor (EGFR) and its downstream extracellular signal-regulated kinases (ERK1/2). In addition, among the prostanoids regulated by COX-2, prostaglandin I2 (PGI2) specifically contributes to the downregulation of perlecan expression by lead. This study revealed an intracellular pathway—the EGFR-ERK1/2-COX-2-PGI2 pathway activated by inhibition of PTP by lead—as a pathway that downregulates endothelial perlecan synthesis. The pathway is suggested to serve as a mechanism for the repression of perlecan expression, which leads to a delay in cell proliferation by lead.

著者

Hirokatsu Saito Kentaro Tanemura Yusuke Furukawa Takahiro Sasaki Jun Kanno Satoshi Kitajima

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.48, no.4, pp.203-210, 2023 (Released:2023-04-03)

参考文献数

32

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Acetamiprid (ACE), a neonicotinoid chemical, is widely used as a pesticide due to its rapid insecticidal activity. Although neonicotinoids exert very low toxicity in mammals, the effects of early exposure to neonicotinoids on the adult central nervous system are poorly understood. This study investigated the effects of ACE exposure in early life on brain function in adult mice. We exposed male C57BL/6N mice to ACE (10 mg/kg) orally when they were two (postnatal lactation) or 11 weeks old (adult). We examined the effects of ACE on the central nervous system using the mouse behavioral test battery, consisting of the open field test, light/dark transition test, elevated plus-maze test, contextual/cued fear conditioning test, and pre-pulse inhibition test at 12–13 weeks old. In the mouse behavioral test battery, learning memory abnormalities were detected in the mature treatment group. In addition, learning memory and emotional abnormalities were detected in the postnatal lactation treatment group. These results suggest that the behavioral effects of postnatal lactation treatment with ACE were qualitatively different from the behavioral abnormalities in the mature treatment group.

著者

Toshi WATANABE

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.20, no.2, pp.135-142, 1995-05-25 (Released:2008-02-21)

参考文献数

8

被引用文献数

8 13

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Alkaline ionized water (AKW) produced by electrolysis was given to gestational and lactational rats, and its effect on dams, growth of fetuses and offsprings were investigated. The results showed that the intake of food and water in dams increased significantly when AKW was given from the latter half of the gestation period and from the former half of the lactation period. Body weight of the offsprings in the test group, both males and females, increased significantly from the latter half of the lactation period. During the lactation period and after weaning, the offsprings in the test group showed significantly hastened appearance of abdominal hair, eruption of upper incisors, opening of eyelids and other postnatal morphological developments both in males and females, as well as earlier separation of auricle and descent of testes in males compared with the control was noted. As mentioned above, it was suggested from the observations conducted that the AKW has substantial biological effects on postnatal growth, since intake of food and water and body weight of the offsprings increased and postnatal morphological development was also accelerated.

著者

Yuto Ishibashi Shingo Kimura Ikuro Suzuki

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.10, pp.429-437, 2022 (Released:2022-10-01)

参考文献数

28

被引用文献数

1

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Antibiotic-associated encephalopathy (AAE) is a central nervous system disorder caused by antibiotics administration and classified into three types based on clinical symptoms. Type 1 AAE causes seizures and myoclonus, type 2 causes psychiatric symptoms, and type 3 is characterized by cerebellar ataxia. In this study, we investigated whether the electrical activity of in vitro human iPSC-derived neurons to antibiotics could be classified based on the 3 types of AAEs classified by clinical symptoms. Glutamatergic, GABAergic neurons and astrocytes differentiated from human iPS cells were seeded on micro-electrode array (MEA). The cumulative administration of 13 different antimicrobials detected changes in neural activity that differed according to AAE type. Next, we classified the antimicrobials by principal component analysis (PCA) and confirmed the AAE type of each agent. We found that Types 1–3 AAE agents were distributed separately. The classification of antibiotics depending on electrophysiological response characteristics was consistent with the clinical practice classification of AAEs. In conclusion, the combination of electrophysiological responses of human iPS cell-derived neural networks measured by MEA plus multivariate analysis methods will effectively detect and classify antibiotics developmental risks.

著者

Tomoka Hisaki Maki Aiba née Kaneko Morihiko Hirota Masato Matsuoka Hirokazu Kouzuki

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.2, pp.95-108, 2020 (Released:2020-02-15)

参考文献数

48

被引用文献数

8

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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. Similarity between the target and analogues is readily defined computationally, and data uncertainties associated with the similarities in structural, physico-chemical and toxicological properties, including toxicophores, were low. Uncertainty associated with metabolic similarity is low-to-moderate, largely because the approach was limited to in silico prediction to enable systematic and objective data collection. Uncertainty associated with completeness of read-across was reduced by including in vitro and in silico metabolic data and expanding the experimental animal database. Taking the “worst-case” approach, the smallest NOAEL values among the analogs (i.e., 200 and 100 mg/kg/day for repeated-dose and developmental toxicity, respectively) were read-across to valproic acid. Our previous QSAR models predict repeated-dose NOAEL of 148 (males) and 228 (females) mg/kg/day, and developmental toxicity NOAEL of 390 mg/kg/day for valproic acid. Based on read-across and QSAR, the conservatively predicted NOAEL is 148 mg/kg/day for repeated-dose toxicity, and 100 mg/kg/day for developmental toxicity. Experimental values are 341 mg/kg/day and 100 mg/kg/day, respectively. The present approach appears promising for quantitative and qualitative in silico systemic toxicity prediction of untested chemicals.

著者

Yuto Amano Hiroshi Honda Ryusuke Sawada Yuko Nukada Masayuki Yamane Naohiro Ikeda Osamu Morita Yoshihiro Yamanishi

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.3, pp.137-149, 2020 (Released:2020-03-06)

参考文献数

47

被引用文献数

5

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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. First, the potential CPIs were comprehensively estimated by chemometrics based on the known CPI data (1,179,848 interactions involving 3,905 proteins and 824,143 chemicals). Second, the predictive models for 61 side effects in the cardiovascular system (CVS), gastrointestinal system (GIS), and central nervous system (CNS) were constructed by sparsity-induced classifiers based on the known and potential CPI data. The cross validation experiments showed that the proposed CPI-based models had a higher or comparable performance than the traditional chemical structure-based models. Moreover, our enrichment analysis indicated that the highly weighted proteins derived from predictive models could be involved in the corresponding functions of the side effects. For example, in CVS, the carcinogenesis-related pathways (e.g., prostate cancer, PI3K-Akt signal pathway), which were recently reported to be involved in cardiovascular side effects, were enriched. Therefore, our predictive models are biologically valid and would be useful for predicting side effects and novel potential underlying mechanisms of chemical-induced side effects.

著者

Mei Tsuchida Takumi Yokosawa Takuya Noguchi Tatsuya Shimada Mayuka Yamada Yuto Sekiguchi Yusuke Hirata Atsushi Matsuzawa

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.4, pp.219-226, 2020 (Released:2020-04-01)

参考文献数

47

被引用文献数

2 16

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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. However, the causal role of TRAF2 in DNA damage response (DDR) remains to be explored. In this study, we assessed the function of TRAF2 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that TRAF2 exerts pro-apoptotic activity through p53-dependent mechanisms at least in human fibrosarcoma cell line HT1080. TRAF2 deficient cells exhibit significant resistance to cell death induced by cisplatin, accompanied by the reduction of both p53 protein level and caspase-3 activation. Moreover, cisplatin-induced JNK activation was attenuated in TRAF2-deficient cells, and pharmacological inhibition of JNK signaling suppressed p53 stabilization. These results suggest that TRAF2 promotes p53-dependent apoptosis by activating the JNK signaling cascade in HT1080 cells. Thus, our data demonstrate a novel function of TRAF2 in cisplatin-induced DDR as a pro-apoptotic protein.

著者

Yuto Sekiguchi Mayuka Yamada Takuya Noguchi Chise Noomote Mei Tsuchida Yuki Kudoh Yusuke Hirata Atsushi Matsuzawa

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.44, no.6, pp.435-440, 2019 (Released:2019-06-04)

参考文献数

24

被引用文献数

3 15

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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. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downregulated heat shock protein 70 (HSP70) as previously reported. Considering that HSP70 contributes to protection of cells against Fas-mediated apoptosis, gefitinib may increase the sensitivity to Fas-mediated apoptosis by downregulating HSP70. Thus, our findings reveal novel properties of gefitinib, which may provide insight into the alternative therapeutic approaches of gefitinib for Fas-resistant tumors.

著者

関田 清司 井上 達

出版者

日本毒性学会

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.24, no.5, pp.app.147-app.158, 1999-12-20

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今日,コカインや覚せい剤などの薬物乱用問題は世界的な取り組の対象となっている。わが国においても,一時,減少傾向にあった覚せい剤の乱用者数が,特にこの数年,増加傾向と低年齢化を示しており危機に直面している。こうした,乱用される薬物は,生体に摂取されることにより,その薬理作用による高揚感や多幸感などの精神的「満足感」を引き起こす。脱し難い薬物依存の形成機序はともかくとして,薬物乱用はこの自覚効果の再体験への欲求にもとづく行動と考えられている。ところで近年,コカインや覚せい剤などのように麻薬及び向精神薬取締法などの法規の取締対象物として所持や使用が厳しく規制を受ける「違法な薬物」とは別に,これらの法的規制外で、多幸感や気分の高揚が得られるなどとの標傍のもとに,いわゆる「合法ドラッグ」と称する「商品」が流通している実態がある。現在取締対象となっている「乱用薬物」も、多くは今日の「合法ドラッグ」に似た位置づけにあったものと考えられるので、本稿では,代表的な「乱用薬物」であるコカインや覚せい剤などが乱用される機構を整理し,それらが法規制の対象になるに至った経緯などについて通覧することにより,今日の「合法ドラッグ」の性質やその危険性を明らかにすることを目的としている。

著者

Jin Hee Kim

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.44, no.4, pp.237-244, 2019 (Released:2019-04-03)

参考文献数

43

被引用文献数

2 23

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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. Although there were discrepancies in the concentration, DEHP treatment enhanced A549 cell viability accompanied by increased mRNA and protein levels of inflammation-related factors, such as matrix metalloproteinase-9 and nuclear factor-κB. Additionally, EMT was activated in cells according to decreased E-cadherin and increased vimentin expression. Furthermore, MAPK pathway components, including phosphorylated p38 and c-Jun N-terminal kinase, and Wnt/β-catenin pathway components, including phosphorylated glycogen synthase kinase 3β and β-catenin, as well as their downstream genes c-Myc and cyclin D1, were upregulated in the presence of DEHP. These results suggest that DEHP promotes NSCLC progression by promoting cell proliferation, inflammation, and EMT via activation of Wnt/β-catenin signaling.