著者
Harumi Okuyama Naoki Ohara Kenjiro Tatematsu Shinya Fuma Tomoyuki Nonogaki Kazuyo Yamada Yuko Ichikawa Daisuke Miyazawa Yuko Yasui Seijiro Honma
出版者
The Japanese Society of Toxicology
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.35, no.5, pp.743-747, 2010-10-01 (Released:2010-10-01)
参考文献数
25
被引用文献数
5 8 5

Canola and some other types of oil unusually shorten the survival of stroke-prone spontaneously hypertensive rats (SHRSP), compared with soybean oil, perilla oil and animal fats. Since differential effects of canola and soybean oil on steroid hormone metabolism were suggested by a preliminary DNA microarray analysis as a reason for this, the steroid hormone levels in the serum and tissues of SHRSP fed different oils were investigated. The testosterone levels in the serum and the testes were found to be significantly lower in the canola oil group than in the soybean oil group, while no significant differences were detected in the corticosterone and estradiol levels in tissues. In a second experiment, it was found that hydrogenated soybean oil, with a survival-shortening activity comparable to that of canola oil, also decreased the testosterone level in testes to a similar degree. The testosterone-lowering activity of canola and hydrogenated soybean oil observed in SHRSP was considered in relation to other factors possibly affecting the physiology of SHRSP.
著者
Sanghwa Kim Seong-Ho Hong Choon-Keun Bong Myung-Haing Cho
出版者
The Japanese Society of Toxicology
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.40, no.5, pp.535-550, 2015-10-01 (Released:2015-09-10)
参考文献数
100
被引用文献数
16 20

Air freshener could be one of the multiple sources that release volatile organic compounds (VOCs) into the indoor environment. The use of these products may be associated with an increase in the measured level of terpene, such as xylene and other volatile air freshener components, including aldehydes, and esters. Air freshener is usually used indoors, and thus some compounds emitted from air freshener may have potentially harmful health impacts, including sensory irritation, respiratory symptoms, and dysfunction of the lungs. The constituents of air fresheners can react with ozone to produce secondary pollutants such as formaldehyde, secondary organic aerosol (SOA), oxidative product, and ultrafine particles. These pollutants then adversely affect human health, in many ways such as damage to the central nervous system, alteration of hormone levels, etc. In particular, the ultrafine particles may induce severe adverse effects on diverse organs, including the pulmonary and cardiovascular systems. Although the indoor use of air freshener is increasing, deleterious effects do not manifest for many years, making it difficult to identify air freshener-associated symptoms. In addition, risk assessment recognizes the association between air fresheners and adverse health effects, but the distinct causal relationship remains unclear. In this review, the emitted components of air freshener, including benzene, phthalate, and limonene, were described. Moreover, we focused on the health effects of these chemicals and secondary pollutants formed by the reaction with ozone. In conclusion, scientific guidelines on emission and exposure as well as risk characterization of air freshener need to be established.
著者
Masayo Hirao-Suzuki Shuso Takeda Takayuki Koga Masufumi Takiguchi Akihisa Toda
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.227-236, 2020 (Released:2020-04-01)
参考文献数
38
被引用文献数
1 1

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. It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in some cancerous cells, although there is “no” modulatory element for PPARβ/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARβ/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells. We confirmed, for the first time, that COX-2 expression is positively modulated by PPARβ/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARβ/δ-mediated transcriptional activation stimulated by the PPARβ/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARβ/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARβ/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARβ/δ and AP-1 in regulation of COX-2. These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARβ/δ-related signaling, at least in part, in MDA-MB-231 cells.
著者
Galen Guo Emmanuel Yumvihoze Alexandre J. Poulain Hing Man Chan
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.12, pp.717-725, 2018 (Released:2018-12-04)
参考文献数
45
被引用文献数
7

Monomethylmercury (MMHg) is a potent neurotoxicant that can be bioaccumulated and biomagnified through trophic levels. Human populations whose diets contain MMHg are at risk of MMHg toxicity. The gut microbiota was identified as a potential factor causing variation in MMHg absorption and body burden. However, little is known about the role of gut microbiota on Hg transformations. We conducted a series of in vitro experiments to study the effects of dietary nutrient change on Hg metabolism and the human gut microbiota using anoxic fecal slurry incubations. We used stable Hg isotope tracers to track MMHg production and degradation and characterized the microbiota using high throughput sequencing of the 16S rRNA gene. We show that the magnitude of MMHg degradation is individual dependent and rapidly responds to changes in nutrient amendments, leading to complete degradation of the MMHg present. Although the mechanism involved remains unknown, it does not appear to involve the well-known mer operon. Our data are the first to show a nutrient dependency on the ability of the simulated human gut microbiota to demethylate MMHg. This work provides much-needed insights into individual variations in Hg absorption and potential toxicity.
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

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
3

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
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 2

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
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 3

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.
著者
Yoshitaka Hirasawa Atsushi Fujiwara Kazuya Tabata Kenji Yoshida Tsutomu Negama Takayuki Anzai Shin-ichi Sato
出版者
The Japanese Society of Toxicology
雑誌
Fundamental Toxicological Sciences (ISSN:2189115X)
巻号頁・発行日
vol.7, no.2, pp.105-114, 2020 (Released:2020-03-27)
参考文献数
33

The purpose of this study was to profile cytokine storms (cytokine release syndrome) in the LPS-induced disseminated intravascular coagulation (DIC)-cynomolgus monkey model by measuring changes in 22 cytokines using Luminex. In this study, increases were noted in 20 cytokines, excluding IL-4 and IL-17A. Specifically, IL-6, IL-8, G-CSF and TNF-α, pro-inflammatory cytokines, and IL-10, an anti-inflammatory cytokine, as well as MCP-1, markedly increased by 10,000 pg/mL or more. In addition to the marked increases in the pro-inflammatory cytokines IL-6 and G-CSF, the concentrations of IL-5, IL-18, IFN-γ, VEGF and IL-15 increased continuously. Also, in addition to the marked increases in the pro-inflammatory cytokine IL-8 as well as in MCP-1, the concentrations of IL-1ra, IL-2, IL-1β, IL-12/23 (p40), GM-CSF and TGF-α gradually decreased after initially increasing. On the other hand, in addition to the marked increases in the pro-inflammatory cytokine TNF-α and anti-inflammatory cytokine IL-10, MIP-1β and MIP-1α transiently increased and then rapidly disappeared from serum. IL-13 increased at 6 hr after administration only. Since the behavior of cytokines in this monkey model was similar to those noted in DIC in humans, this model will be useful for evaluating the efficacy of anti-DIC drugs. In addition, this model will also be useful for assessing the risk of cytokine storm development, which is a serious adverse effect of certain types of antibody drugs and CAR-T cell-based therapies.
著者
Kazunori Fujimoto Hiroyuki Kishino Kazuyuki Hashimoto Kyoko Watanabe Takashi Yamoto Kazuhiko Mori
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.6, pp.339-347, 2020 (Released:2020-06-04)
参考文献数
23

The metabolomic profiles of rat primary hepatocytes following treatment with rotenone, FCCP, or (+)-usnic acid were determined using liquid chromatography-mass spectrometry/mass spectrometry and gas chromatography-mass spectrometry. Significant and similar changes in the levels of 283 biochemical metabolites were associated with the three treatments compared with solvent control samples. Overall, the three treatments generated similar global biochemical profiles, with some minor differences associated with rotenone treatment. All three treatments resulted in a shift in energy metabolism as demonstrated by decreased glycogen stores and glycolysis. A reduced antioxidant response was detected in cells following all treatments. In addition, bile acid biosynthesis decreased as a potential consequence of increased oxidative stress by all three treatments. Conversely, rotenone treatment induced a number of changes after 1 hr, which were not detected in FCCP- or (+)-usnic acid-treated samples; these changes were not sustained over time and included increased NAD+ salvage and lysine degradation. In conclusion, these biochemical profiles could provide new insights into the mechanism(s) of mitochondrial toxicity.
著者
Nobuo Aikawa
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.187-199, 2020 (Released:2020-04-01)
参考文献数
42

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. In the present study, the potential developmental toxicity of drugs was divided into three classes (1: non-developmentally toxic, 2: weakly developmentally toxic and 3: strongly developmentally toxic) according to the EST criteria. In addition, the type of developmental toxicity of drugs was grouped into three types (1: non-effective, 2: embryotoxic [inducing growth retardation/dysfunction]/deadly or 3: teratogenic [inducing malformation]/deadly) by comparing the three endpoints. The present study was intended to validate the clinical predictability of the iPST. The traditionally developmentally toxic drugs of aminopterin, methotrexate, all-trans-retinoic acid, thalidomide, tetracycline, lithium, phenytoin, 5-fluorouracil, warfarin and valproate were designated as class 2 or 3 according to the EST criteria, and their developmental toxicity was type 3. The non-developmentally toxic drugs of ascorbic acid, saccharin, isoniazid and penicillin G were designated as class 1, and ascorbic acid, saccharin and isoniazid were grouped as type 1 while penicillin G was type 2 but not teratogenic. These results suggest that the iPST is useful for predicting the human developmental toxicity of drug candidates in a preclinical setting.
著者
Hiroshi Iwasaki Masaki Wakamatsu Kazunari Sugihara Kyohei Kamio Satoshi Tsuji Junya Morita Yasuhiro Kurihara Tomoko Izumi Tomohiro Nishimoto Kohnosuke Kinoshita Yutaka Nakanishi Minoru Sasaki
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.201-218, 2020 (Released:2020-04-01)
参考文献数
32

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. The results of liquid chromatography-tandem mass spectrometry analysis revealed an increase in the amplitudes of 3 unknown peaks in a dose- and time-dependent manner in the lens, with no remarkable changes in the other chemical components tested. In addition, the content of cholesterol, alterations of which have been reported to be associated with cataract, remained unchanged. The mass spectral data and chromatographic behavior of the 3 peaks indicated that these peaks corresponded to sterol-related substances, and that one of them was 7-dehydrocholesterol, a precursor of cholesterol biosynthesis. This finding suggested that TP0446131 exerts some effects on the cholesterol biosynthesis pathway, which could be involved in the development of the cataracts. Furthermore, increases in the levels of these sterol-related substances were also detected in the serum, and were, in fact, noted prior to the onset of the cataract, suggesting the possibility that these substances in the serum could be used as potential safety biomarkers for predicting the onset of cataract induced by TP0446131.
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

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
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

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
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
44 54

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
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 9

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
Tomoaki Tochitani Akihito Yamashita Izumi Matsumoto Mami Kouchi Yuta Fujii Toru Yamada Izuru Miyawaki
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.9, pp.575-584, 2019 (Released:2019-09-02)
参考文献数
26
被引用文献数
1

The adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. However, methods to evaluate the adrenal toxicity are limited. The aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys. With this aim, physiological and drug-induced changes in blood levels of adrenal steroids, including cortisol, aldosterone, androgen, and their precursors were examined. First, for physiological changes, intraday and interday changes in blood steroid levels were examined in male and female cynomolgus monkeys. The animals showed circadian changes in steroid levels that are similar to those in humans, while interday changes were relatively small in males. Next, using males, changes in blood steroid levels induced by ketoconazole and metyrapone were examined, which suppress adrenal steroidogenesis via inhibition of CYP enzymes. Consistent with rats and humans, both ketoconazole and metyrapone increased the deoxycorticosterone and deoxycortisol levels, probably via CYP11B1 inhibition, and the increase was observed earlier and with greater dynamic range than the changes in cortisol level. Changes in other steroid levels reflecting the drug mechanisms were also observed. In conclusion, this study showed that in cynomolgus monkeys, simultaneous measurement of blood levels of adrenal steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms.
著者
Zaher A. Radi K. Nasir Khan
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.373-391, 2019 (Released:2019-06-04)
参考文献数
184
被引用文献数
7

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. This review summarizes major learnings on cardiac and renal complications associated with pharmaceutical inhibition of COX-1 and COX-2 with focus on preclinical to clinical translatability of cardio-renal data.
著者
Naoya Hirata Shigeru Yamada Yuko Sekino Yasunari Kanda
出版者
The Japanese Society of Toxicology
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.42, no.2, pp.193-204, 2017-04-01 (Released:2017-03-17)
参考文献数
45
被引用文献数
7 15

Epidemiological studies suggest that lung cancer, which is a major cause of cancer death, has a critical association with cigarette smoking. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cigarette smoke is a major risk factor for carcinogenesis. However, the mechanisms by which NNK promotes cancer development have not been fully elucidated. Growing evidence suggests that lung cancer originates from cancer stem cells (CSCs), which are a minor population of lung cancer cells. In the present study, we investigated the effects of NNK on the CSCs in A549 human lung cancer cells using flow cytometry with aldehyde dehydrogenase (ALDH), a functional marker of CSCs. We found that NNK increased the proportion of ALDH-positive cells in a dose-dependent manner. A Wnt inhibitor PNU74654 reduced NNK-induced expression levels of Wnt target gene Dkk1 and increase in ALDH-positive cells. We next examined the signaling pathway that mediates the NNK-induced increase in ALDH-positive cells via Wnt signaling. DCF assay revealed that NNK induced reactive oxygen species (ROS) production. The ROS scavenger N-acetylcysteine (NAC) inhibited the NNK-induced Wnt activation and increase in ALDH-positive cells. These data suggest that NNK-induced ROS activate the Wnt signaling pathway in A549 cells. These findings would provide new insights into the role of NNK in the lung CSCs.
著者
Hidetoshi SHINDOH Akira KAWASHIMA Nobuyuki SHISHIDO Kounosuke NAKANO Kazuko KOBAYASHI Ikuo HORII
出版者
The Japanese Society of Toxicology
雑誌
The Journal of Toxicological Sciences (ISSN:03881350)
巻号頁・発行日
vol.31, no.3, pp.265-285, 2006 (Released:2006-09-08)
参考文献数
30
被引用文献数
5 7

Capecitabine is an oral fluoropyrimidine carbamate which is converted to 5-fluorouracil (5-FU) via 3 enzymatic step to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU. We performed 4-week toxicity studies of capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorouridine), galocitabine (trimethoxybenzyl-5'-deoxy-5-fluorocytidine), 4 different fluoropyrimidine carbamate analogs (R=butyl, isopentyl, propyl, or phenethyl), and 5'-DFUR in cynomolgus monkeys with toxicokinetic measurements of intact molecules, 5'-DFCR, and 5'-DFUR. Four-week toxicity data for capecitabine in rats and mice were also obtained for comparison. Capecitabine, galocitabine, butyl, and isopentyl analogs showed similar toxicities in hematopoietic and intestinal organs at 1.0 mmol/kg and the AUCs of 5'-DFUR were approximately 40 to 60 μg*hr/ml. These compounds showed slight toxicity at 0.5 mmol/kg and no toxicity at 0.1 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 5 μg*hr/ml, respectively. Propyl and phenethyl analogs showed slight toxicity at 1.0 mmol/kg and no toxicity at 0.5 mmol/kg, and AUCs of 5'-DFUR were approximately 30 and 10 μg*hr/ml, respectively. On the other hand, severe and slight-to-moderate toxicity was observed at 0.5 and 0.25 mmol/kg in 5'-DFUR-treated monkeys and AUCs of 5'DFUR were 35.6 and 5.2 μg*hr/ml, respectively. In mice and rats, the toxicity of capecitabine was less than in monkeys relative to dose, but 5'-DFUR AUCs were almost the same. In conclusion, 5'-DFUR AUC correlated with toxicity following oral administration of capecitabine and its analogs in monkeys, mice, and rats, although this relationship is not seen in humans. Capecitabine was less toxic in monkeys than oral 5'-DFUR according to dose (mmol/kg) and 5'-DFUR AUC.