J Toxicol Sci [JOURNAL]
Sun
200 papers
Validation of a new protocol for a zebrafish MEFL (malformation or embryo-fetal lethality) test method that conforms to the ICH S5 (R3) guideline.
Mori K, Aoki Y, Mikashima F … +11 more , Maki K, Tanaka T, Hayashi M, Sugimoto W, Ono M, Umekita S, Niino T, Fujiwara M, Ebata T, Hirata H, Kojima H
J Toxicol Sci · 2024 · PMID 39098043 · Publisher ↗
Detecting the toxic effects of chemicals on reproduction and development without using mammalian animal models is crucial in the exploitation of pharmaceuticals for human use. Zebrafish are a promising animal model for i...
Detecting the toxic effects of chemicals on reproduction and development without using mammalian animal models is crucial in the exploitation of pharmaceuticals for human use. Zebrafish are a promising animal model for investigating pharmacological effects and toxicity during vertebrate development. Several studies have suggested the use of zebrafish embryos for the assessment of malformations or embryo-fetal lethality (MEFL). However, a reproducible protocol as a standard for the zebrafish MEFL test method that fulfills global requests has not been established based on the International Council of Harmonisation (ICH) S5 (R3) guidelines. To establish such a toxicity test method, we developed a new and easy protocol to detect MEFL caused by chemicals, especially those with teratogenic potential, using fertilized zebrafish eggs (embryos) within 5 days of development. Our toxicity test trials using the same protocol in two to four different laboratories corroborated the high inter-laboratory reproducibility. Our test method enabled the detection of 18 out of 22 test compounds that induced rat MEFL. Thus, the prediction rate of our zebrafish test method for MEFL was almost 82% compared with that of rat MEFL. Collectively, our study proposes the establishment of an easy and reproducible protocol for the zebrafish MEFL test method for reproductive and developmental toxicity that meets ICH guideline S5 (R3), which can be further considered in combination with information from other sources for regulatory use.
Effects of food restriction on toxicological parameters in juvenile rats.
Izumi Y, Sano T, Sudo Y … +1 more , Matsumoto K
J Toxicol Sci · 2024 · PMID 38945843 · Publisher ↗
To examine the effects of decreased food consumption on toxicological parameters in juvenile rats, rats on postnatal day 21 were fed 40%, 50% (only four weeks), and 60% less food, compared to that of controls for four or...
To examine the effects of decreased food consumption on toxicological parameters in juvenile rats, rats on postnatal day 21 were fed 40%, 50% (only four weeks), and 60% less food, compared to that of controls for four or eight weeks, and clinical observations, measurement of body and organ weights, morphological differentiation analysis, clinical pathology, and macroscopic and microscopic examinations were conducted. The body weight decreased depending on the degree of food restriction (FR). Cleavage of the balano-preputial skinfold was delayed, and cell debris in the epididymal lumen was noted as a related finding after four-week FR. Vaginal opening was also delayed, and some histopathological findings, such as absence of corpus luteum in the ovary, mucinous degeneration in the vagina, and immature uterus, were noted after eight-week FR. Erythrocyte count increased after four-week FR, but slightly decreased in males only after eight-week FR, and decreased leukocyte and/or reticulocyte counts, accompanied by related histopathological findings were noted after four- and eight-week FR. In blood chemistry, the levels of total protein including globulin, glucose, triglyceride, and calcium decreased, and sodium and chloride increased after four- and eight-week FR. Increases in activities of aspartate transaminase and lactate dehydrogenase and total bilirubin levels were noted after four-week FR, which were attenuated after eight-week FR. The effects of FR seemed to be more remarkable after four weeks. In drug safety evaluation, findings caused by malnutrition should be considered in juvenile toxicity studies when decreased food consumption is observed.
Dihydropyrazine induces endoplasmic reticulum stress and inhibits autophagy in HepG2 human hepatoma cells.
Takechi S, Sawai M, Miyauchi Y
J Toxicol Sci · 2024 · PMID 38945842 · Publisher ↗
Dihydropyrazines (DHPs) are formed by non-enzymatic glycation reactions in vivo and in food. We recently reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), which is a methyl-substituted DHP, caused severe oxidati...
Dihydropyrazines (DHPs) are formed by non-enzymatic glycation reactions in vivo and in food. We recently reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), which is a methyl-substituted DHP, caused severe oxidative stress and cytotoxicity. However, the molecular mechanisms underlying the cytotoxic pathways of the DHP response remain elusive. Because oxidative stress induces endoplasmic reticulum (ER) stress and autophagy, we investigated the ability of DHP-3 to modulate the ER stress and autophagy pathways. DHP-3 activated the ER stress pathway by increasing inositol-requiring enzyme 1 (IRE1) and PKR-like ER kinase (PERK) phosphorylation and transcription factor 6 (ATF6) expression. Moreover, DHP-3 increased the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), which are downstream targets of PERK. In addition, DHP-3 inhibited the autophagy pathway by increasing the accumulation of microtubule-associated protein 1 light chain 3 alpha-phosphatidylethanolamine conjugate (LC3-II) and p62/sequestosome 1 (p62), while decreasing autophagic flux. Taken together, these results indicate that DHP-3 activates the ER stress pathway and inhibits the autophagy pathway, suggesting that the resulting removal of damaged organelles is inadequate.
A single dose of clothianidin exposure induces varying sex-specific behavioral changes in adulthood depending on the developmental stage of its administration.
Kaku K, Sasaki T, Hara K … +1 more , Tanemura K
J Toxicol Sci · 2024 · PMID 38945841 · Publisher ↗
Clothianidin (CLO), a neonicotinoid that is widely used in forests and agricultural areas, was recently reported to cause toxicity in mammals. Although sensitivity to chemicals varies between sexes and developmental stag...
Clothianidin (CLO), a neonicotinoid that is widely used in forests and agricultural areas, was recently reported to cause toxicity in mammals. Although sensitivity to chemicals varies between sexes and developmental stages, studies that comprehensively evaluate both males and females are limited. Therefore, in this study we utilized murine models to compare the sex-specific differences in behavioral effects following CLO exposure at different developmental stages. We orally administered CLO to male and female mice as a single high-dose solution (80 mg/kg) during the postnatal period (2-week-old), adolescence (6-week-old), or maturity (10-week-old), and subsequently evaluated higher brain function. The behavioral battery test consisted of open field, light/dark transition, and contextual/cued fear conditioning tests conducted at three and seven months of age. After the behavioral test, the brains were dissected and prepared for immunohistochemical staining. We observed behavioral abnormalities in anxiety, spatial memory, and cued memory only in female mice. Moreover, the immunohistochemical analysis showed a reduction in astrocytes within the hippocampus of female mice with behavioral abnormalities. The behavioral abnormalities observed in female CLO-treated mice were consistent with the typical behavioral abnormalities associated with hippocampal astrocyte dysfunction. It is therefore possible that the CLO-induced behavioral abnormalities are at least in part related to a reduction in astrocyte numbers. The results of this study highlight the differences in behavioral effects following CLO exposure between sexes and developmental stages.
MiR-98-3p alleviates lipopolysaccharide-induced pulmonary microvascular endothelial barrier dysfunction by targeting DKK3 in sepsis-induced acute lung injury.
Zhong D, Luo C, Wang N … +1 more , Lin J
J Toxicol Sci · 2024 · PMID 38945840 · Publisher ↗
BACKGROUND: Endothelial barrier dysfunction is critical for the pathogenesis of sepsis-induced acute lung injury (ALI). Lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cells (HPMECs) are wid...
BACKGROUND: Endothelial barrier dysfunction is critical for the pathogenesis of sepsis-induced acute lung injury (ALI). Lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cells (HPMECs) are widely used as the cell model of sepsis-associated ALI for exploration of endothelial barrier dysfunction. Dickkopf (DKK) family proteins were reported to mediate endothelial functions in various diseases. The present study explored the effect of Dickkopf-3 (DKK3) on endothelial barrier permeability, angiogenesis, and tight junctions in LPS-stimulated HPMECs. METHODS: RT-qPCR was required for detecting DKK3 and miR-98-3p expression. The angiogenesis of HPMECs was evaluated by tube formation assays. Monolayer permeability of HPMECs was examined by Transwell rhodamine assays. The protein expression of DKK3 and tight junctions in HPMECs was measured via western blotting. Luciferase reporter assay was used to verify the interaction between miR-98-3p and DKK3. RESULTS: LPS treatment inhibited angiogenetic ability while increasing the permeability of HPMECs. DKK3 expression was upregulated while miR-98-3p level was reduced in LPS-treated HPMECs. DKK3 knockdown alleviated HPMEC injury triggered by LPS stimulation. MiR-98-3p targeted DKK3 in HPMECs. Overexpression of miR-98-3p protects HPMECs from the LPS-induced endothelial barrier dysfunction, and the protective effect was reversed by DKK3 overexpression. CONCLUSIONS: MiR-98-3p ameliorates LPS-evoked pulmonary microvascular endothelial barrier dysfunction in sepsis-associated ALI by targeting DKK3.
Transcriptome analysis in various cell lines exposed to nitric oxide.
Mizushima T, Kubota S, Iijima Y … +2 more , Takasugi N, Uehara T
J Toxicol Sci · 2024 · PMID 38825487 · Publisher ↗
Nitric oxide (NO) plays a physiological role in signal transduction and excess or chronic NO has toxic effects as an inflammatory mediator. NO reversibly forms protein S-nitrosylation and exerts toxicological functions r...
Nitric oxide (NO) plays a physiological role in signal transduction and excess or chronic NO has toxic effects as an inflammatory mediator. NO reversibly forms protein S-nitrosylation and exerts toxicological functions related to disease progression. DNA methyltransferases, epigenome-related enzymes, are inhibited in enzymatic activity by S-nitrosylation. Therefore, excess or chronic NO exposure may cause disease by altering gene expression. However, the effects of chronic NO exposure on transcriptome are poorly understood. Here, we performed transcriptome analysis of A549, AGS, HEK293T, and SW48 cells exposed to NO (100 μM) for 48 hr. We showed that the differentially expressed genes were cell-specific. Gene ontology analysis showed that the functional signature of differentially expressed genes related to cell adhesion or migration was upregulated in several cell lines. Gene set enrichment analysis indicated that NO stimulated inflammation-related gene expression in various cell lines. This finding supports previous studies showing that NO is closely involved in inflammatory diseases. Overall, this study elucidates the pathogenesis of NO-associated inflammatory diseases by focusing on changes in gene expression.
Analysis of cardiohemodynamic and electrophysiological effects of morphine along with its toxicokinetic profile using the halothane-anesthetized dogs.
Goto A, Kambayashi R, Fujishiro M … +5 more , Hasegawa C, Izumi-Nakaseko H, Takei Y, Kurosaki K, Sugiyama A
J Toxicol Sci · 2024 · PMID 38825486 · Publisher ↗
Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-...
Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through I inhibition in vivo, but its potential to develop torsade de pointes will be small.
Identification of post-mortem product of zolpidem degradation by hemoglobin via the Fenton reaction.
Yamagishi Y, Nagasawa S, Iwase H … +1 more , Ogra Y
J Toxicol Sci · 2024 · PMID 38825485 · Publisher ↗
Zolpidem, N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide, is a hypnotic agent widely used in clinical practice but is detected in many clinical cases of fatal intoxication and suicide. In...
Zolpidem, N,N-dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide, is a hypnotic agent widely used in clinical practice but is detected in many clinical cases of fatal intoxication and suicide. In forensic toxicology, the precise determination of zolpidem concentration in blood is a must to provide concrete evidence of death by zolpidem poisoning. However, the concentrations of zolpidem in blood at autopsy often differ from those at the estimated time of death. In the present study, we found that zolpidem was degraded by hemoglobin (Hb) via the Fenton reaction at various temperatures. The mechanism underlying zolpidem degradation involved the oxidation of its linker moiety. The MS and MS/MS spectra obtained by liquid chromatography quadrupole-Orbitrap mass spectrometry (LC-Q-Orbitrap-MS) showed the formation of 2-hydroxy-N,N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetamide (2-OH ZOL) in Hb/HO solution incubated with zolpidem and in the blood of several individuals who died from ingestion of zolpidem. These results suggest that 2-OH ZOL is the post-mortem product of zolpidem degradation by Hb via the Fenton reaction.
Investigation of normalization procedures for transcriptome profiles of compounds oriented toward practical study design.
Mizuno T, Kusuhara H
J Toxicol Sci · 2024 · PMID 38825484 · Publisher ↗
The transcriptome profile is a representative phenotype-based descriptor of compounds, widely acknowledged for its ability to effectively capture compound effects. However, the presence of batch differences is inevitable...
The transcriptome profile is a representative phenotype-based descriptor of compounds, widely acknowledged for its ability to effectively capture compound effects. However, the presence of batch differences is inevitable. Despite the existence of sophisticated statistical methods, many of them presume a substantial sample size. How should we design a transcriptome analysis to obtain robust compound profiles, particularly in the context of small datasets frequently encountered in practical scenarios? This study addresses this question by investigating the normalization procedures for transcriptome profiles, focusing on the baseline distribution employed in deriving biological responses as profiles. Firstly, we investigated two large GeneChip datasets, comparing the impact of different normalization procedures. Through an evaluation of the similarity between response profiles of biological replicates within each dataset and the similarity between response profiles of the same compound across datasets, we revealed that the baseline distribution defined by all samples within each batch under batch-corrected condition is a good choice for large datasets. Subsequently, we conducted a simulation to explore the influence of the number of control samples on the robustness of response profiles across datasets. The results offer insights into determining the suitable quantity of control samples for diminutive datasets. It is crucial to acknowledge that these conclusions stem from constrained datasets. Nevertheless, we believe that this study enhances our understanding of how to effectively leverage transcriptome profiles of compounds and promotes the accumulation of essential knowledge for the practical application of such profiles.
Comparative study of susceptibility to methylmercury cytotoxicity in cell types composing rat peripheral nerves: a higher susceptibility of dorsal root ganglion neurons.
Yoshida E, Aoki K, Sasaki Y … +8 more , Izuhara H, Takahashi T, Fujiwara Y, Fujie T, Du K, Eto K, Shinoda Y, Kaji T
J Toxicol Sci · 2024 · PMID 38692911 · Publisher ↗
Methylmercury is an environmental polluting organometallic compound that exhibits neurotoxicity, as observed in Minamata disease patients. Methylmercury damages peripheral nerves in Minamata patients, causing more damage...
Methylmercury is an environmental polluting organometallic compound that exhibits neurotoxicity, as observed in Minamata disease patients. Methylmercury damages peripheral nerves in Minamata patients, causing more damage to sensory nerves than motor nerves. Peripheral nerves are composed of three cell types: dorsal root ganglion (DRG) cells, anterior horn cells (AHCs), and Schwann cells. In this study, we compared cultured these three cell types derived from the rat for susceptibility to methylmercury cytotoxicity, intracellular accumulation of mercury, expression of L-type amino acid transporter 1 (LAT1), which transports methylmercury into cells, and expression of multidrug resistance-associated protein 2 (MRP2), which transports methylmercury-glutathione conjugates into the extracellular space. Of the cells examined, we found that DRG cells were the most susceptible to methylmercury with markedly higher intracellular accumulation of mercury. The constitutive level of LAT1 was higher and that of MRP2 lower in DRG cells compared with those in AHC and Schwann cells. Additionally, decreased cell viability caused by methylmercury was significantly reduced by either the LAT1 inhibitor, JPH203, or siRNA-mediated knockdown of LAT1. On the other hand, an MRP2 inhibitor, MK571, significantly intensified the decrease in the cell viability caused by methylmercury. Our results provide a cellular basis for sensory neve predominant injury in the peripheral nerves of Minamata disease patients.
Novel predictive approaches for drug-induced convulsions in non-human primates using machine learning and heart rate variability analysis.
Kuga K, Shiotani M, Hori K … +6 more , Mizuno H, Matsushita Y, Ozaki H, Hayashi K, Kubo T, Kano M
J Toxicol Sci · 2024 · PMID 38692910 · Publisher ↗
Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated the potential use of an index derived from heart rate...
Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated the potential use of an index derived from heart rate variability (HRV) analysis in non-human primates as a biomarker for convulsions induced by GABA receptor antagonists. The present study aimed to explore the application of this methodology to other convulsants and evaluate its specificity by testing non-convulsants that affect the autonomic nervous system. Telemetry-implanted males were administered various convulsants (4-aminopyridine, bupropion, kainic acid, and ranolazine) at different doses. Electrocardiogram data gathered during the pre-dose period were employed as training data, and the convulsive potential was evaluated using HRV and multivariate statistical process control. Our findings show that the Q-statistic-derived convulsive index for 4-aminopyridine increased at doses lower than that of the convulsive dose. Increases were also observed for kainic acid and ranolazine at convulsive doses, whereas bupropion did not change the index up to the highest dose (1/3 of the convulsive dose). When the same analysis was applied to non-convulsants (atropine, atenolol, and clonidine), an increase in the index was noted. Thus, the index elevation appeared to correlate with or even predict alterations in autonomic nerve activity indices, implying that this method might be regarded as a sensitive index to fluctuations within the autonomic nervous system. Despite potential false positives, this methodology offers valuable insights into predicting drug-induced convulsions when the pharmacological profile is used to carefully choose a compound.
Integrating mathematical approaches (IMAS): Novel methodology for predicting dermal absorption rates of chemicals under finite dose conditions.
Kunita R, Nishijima T, Todo H … +1 more , Miyazawa M
J Toxicol Sci · 2024 · PMID 38692909 · Publisher ↗
Quantitative structure permeation relationship (QSPR) models have gained prominence in recent years owing to their capacity to elucidate the influence of physicochemical properties on the dermal absorption of chemicals....
Quantitative structure permeation relationship (QSPR) models have gained prominence in recent years owing to their capacity to elucidate the influence of physicochemical properties on the dermal absorption of chemicals. These models facilitate the prediction of permeation coefficient (Kp) values, indicating the skin permeability of a chemical under infinite dose conditions. Conversely, obtaining dermal absorption rates (DAs) under finite dose conditions, which are crucial for skin product safety evaluation, remains a challenge when relying solely on Kp predictions from QSPR models. One proposed resolution involves using Kroes' methodology, categorizing DAs based on Kp values; however, refinement becomes necessary owing to discreteness in the obtained values. We previously developed a mathematical model using Kp values obtained from in vitro dermal absorption tests to predict DAs. The present study introduces a new methodology, Integrating Mathematical Approaches (IMAS), which combines QSPR models and our mathematical model to predict DAs for risk assessments without conducting in vitro dermal absorption tests. Regarding 40 chemicals (76.1 ≤ MW ≤ 220; -1.4 ≤ Log K ≤ 3.1), IMAS showed that 65.0% (26/40) predictions of DA values were accurate to within twofold of the observed values in finite dose experiments. Compared to Kroes' methodology, IMAS notably mitigated overestimation, particularly for hydrophilic chemicals with water solubility exceeding 57.0 mg/cm. These findings highlight the value of IMAS as a tool for skin product risk assessments, particularly for hydrophilic compounds.
Breast milk-mediated exposure to dioxins and antigen in infancy enhances antigen-specific antibody production capacity in adulthood in mice.
Kakutani H, Yuzuriha T, Nakao T
J Toxicol Sci · 2024 · PMID 38692908 · Publisher ↗
The immune system is sensitive to many chemicals. Among dioxin compounds, 2,3,7,8-tetrachlorodizenzo-p-dioxin (TCDD) is the most toxic environmental pollutant. The effects of perinatal maternal exposure to dioxins may pe...
The immune system is sensitive to many chemicals. Among dioxin compounds, 2,3,7,8-tetrachlorodizenzo-p-dioxin (TCDD) is the most toxic environmental pollutant. The effects of perinatal maternal exposure to dioxins may persist into childhood. However, there have been no reports to date on the effects of exposure to dioxins during infancy, when the immune organs are developing. Therefore, we investigated the effects of TCDD and antigen exposure during lactation on immune function, especially antibody production capacity, in adult mice. Beginning the day after delivery, lactating mothers were orally administered TCDD or a mixture of TCDD and ovalbumin (OVA) daily for 4 weeks, until the pups were weaned. At 6 weeks of age, progeny mice were orally administered OVA daily for 10 weeks, while non-progeny mice were orally administered OVA or a mixture of TCDD and OVA daily for 10 weeks. Production of serum OVA-specific IgG was examined weekly. The amount of TCDD transferred from the mother to the progeny via breast milk was determined by measuring TCDD in the gastric contents of the progeny. A trend toward increasing IgA titer was observed in TCDD-treated mice, and production of IgE was observed only in progeny whose mothers were treated with TCDD and OVA. The results suggest that exposure to TCDD and OVA in breast milk can affect immune function in newborns.
Transcriptome analysis of cultured human vascular endothelial cells after γ-ray irradiation and correlation analysis with ATP, ADP, and adenosine as secondary soluble factors.
Fujie T, Kobayashi M, Ikeuchi L … +7 more , Nakano T, Kitabatake K, Shinoda Y, Fujiwara Y, Yamamoto C, Tsukimoto M, Kaji T
J Toxicol Sci · 2024 · PMID 38556355 · Publisher ↗
Vascular endothelial cells serve as barriers between blood components and subendothelial tissue and regulate the blood coagulation-fibrinolytic system. Ionizing radiation is a common physical stimulant that induces a bys...
Vascular endothelial cells serve as barriers between blood components and subendothelial tissue and regulate the blood coagulation-fibrinolytic system. Ionizing radiation is a common physical stimulant that induces a bystander effect whereby irradiated cells influence neighboring cells through signalings, including purinergic receptor signaling, activated by adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), and adenosine as secondary soluble factors. Human vascular endothelial EA.hy926 cells were cultured and irradiated with γ-rays or treated with ATP, ADP, or adenosine under non-toxic conditions. RNA-seq, gene ontology, and hierarchical clustering analyses were performed. The transcriptome analysis of differentially expressed genes in vascular endothelial cells after γ-ray irradiations suggests that the change of gene expression by γ-irradiation is mediated by ATP and ADP. In addition, the expression and activity of the proteins related to blood coagulation and fibrinolysis systems appear to be secondarily regulated by ATP and ADP in vascular endothelial cells after exposure to γ-irradiation. Although it is unclear whether the changes of the gene expression related to blood coagulation and fibrinolysis systems by γ-irradiation affected the increased hemorrhagic tendency through the exposure to γ-irradiation or the negative feedback to the activated blood coagulation system, the present data indicate that toxicity associated with γ-irradiation involves the dysfunction of vascular endothelial cells related to the blood coagulation-fibrinolytic system, which is mediated by the signalings, including purinergic receptor signaling, activated by ATP and ADP.
Reversible and monitorable nephrotoxicity in rats by the novel potent transcriptional enhanced associate domain (TEAD) inhibitor, K-975.
Otsuki H, Uemori T, Inai Y … +4 more , Suzuki Y, Araki T, Nan-Ya KI, Yoshinari K
J Toxicol Sci · 2024 · PMID 38556354 · Publisher ↗
The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Transcriptional enhanced associate domain (TEAD), a transcription activator of the Hippo pathway, forms the comp...
The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Transcriptional enhanced associate domain (TEAD), a transcription activator of the Hippo pathway, forms the complex with a transcriptional coactivator yes-associated protein (YAP) or a transcriptional coactivator PDZ-binding motif (TAZ). Their excessive activations are involved in carcinogenesis such as malignant pleural mesothelioma (MPM), and thus inhibition of the TEAD complex is expected to have potent anticancer activity against MPM. On the other hand, YAP or TAZ conditional knockout mice have been reported to show abnormal findings in various tissues, including the kidney, liver, and lung. In the present study, we evaluated the systemic toxicity of K-975, a novel TEAD inhibitor, in rats. When K-975 was administered orally to rats for 1 week, proteinuria suggestive of nephrotoxicity was observed. Electron microscopy revealed that K-975 at 300 mg/kg induced glomerular podocyte foot process effacement. After a 2-week recovery period, proteinuria with foot process effacement was recovered completely. Urinalysis and urinary biomarker evaluation suggested that the urinary albumin index (urinary albumin/urinary creatinine) was the most sensitive marker for detecting K-975-induced nephrotoxicity. After 3 cycles of 1-week administration followed by 2-week recovery periods, nephrotoxicity was reversible; however, incomplete reversibility was observed in rats with severe proteinuria. In conclusion, this study revealed that in rats, oral K-975 treatment induced severe proteinuria by podocyte foot process effacement, which was reversible and monitorable by the urinary albumin index, suggesting important information for developing K-975 as an anticancer drug.
Effective in vitro evaluation of the risk of histamine release related to valemetostat tosylate using MRGPRX2-expressing cells.
Hamamura-Yasuno E, Kinoshita J, Goto K … +4 more , Fujimoto K, Pignatello M, Tsuchiya Y, Mori K
J Toxicol Sci · 2024 · PMID 38556353 · Publisher ↗
Mas-related G-protein-coupled receptor X2 (MRGPRX2), expressed on mast cells, is associated with drug-induced pseudo-allergic reactions. Although it is well known that there are differences of sensitivity between species...
Mas-related G-protein-coupled receptor X2 (MRGPRX2), expressed on mast cells, is associated with drug-induced pseudo-allergic reactions. Although it is well known that there are differences of sensitivity between species in the pseudo-allergic reactions, no platform for evaluating a human risk of the pseudo-allergic reactions observed in nonclinical studies has been established. Valemetostat tosylate, developed as an anti-cancer drug, induced histamine release in a nonclinical study with dogs. The purpose of the current study was to identify the mechanism and assess the human risk of valemetostat-tosylate-induced histamine release using dog and human MRGPRX2-expressing cells. In an experiment with human or dog MRGPRX2-expressing cells, valemetostat tosylate caused activation of human and dog MRGPRX2. Importantly, the EC for dog MRGPRX2 was consistent with the C value at which histamine release was observed in dogs. Furthermore, the EC for human MRGPRX2 was ca. 27-fold higher than that for dog MRGPRX2, indicating a species difference in histamine-releasing activity. In a clinical trial, histamine release was not observed in patients receiving valemetostat tosylate. In conclusion, an in vitro assay using human and animal MRGPRX2-expressing cells would be an effective platform to investigate the mechanism and predict the human risk of histamine release observed in nonclinical studies.
Comparison of the fecal bacterial microbiota in mice, rats, and pigs after oral administration of alpha-glycosyl isoquercitrin.
Liu H, Inoue R, Koyanagi M … +3 more , Hayashi SM, Watanabe G, Nagaoka K
J Toxicol Sci · 2024 · PMID 38556352 · Publisher ↗
Alpha-glycosyl isoquercitrin (AGIQ) is composed of isoquercitrin and its glucosylated derivatives and has many biological activities, including anti-inflammatory, antioxidant, and anti-cancer properties. However, the eff...
Alpha-glycosyl isoquercitrin (AGIQ) is composed of isoquercitrin and its glucosylated derivatives and has many biological activities, including anti-inflammatory, antioxidant, and anti-cancer properties. However, the effect of AGIQ administered orally on gut microbiota composition remains unclear. The objective of this study was to evaluate the effect of AGIQ on the gut microbiota of animals in different dose groups. Male rats and mice received different doses of AGIQ (1.5%, 3%, or 5% w/v) in diet for carcinogenic or chronic toxicity studies (rasH2 mice: 6 months; Sprague-Dawley rats: 12 months). Male minipigs received 100, 300, or 1000 mg/kg/day for 28 days. Fecal samples were collected from the different animal species and analyzed using 16S-rRNA gene sequencing. No significant changes were observed in alpha and beta diversity of the gut microbiota. Characteristic bacteria that responded to AGIQ were identified in each animal species, and, interestingly, Kineothrix alysoides, a butyrate-producing bacterium, was commonly detected in all three species, suggesting that it may be related to the biological activities of AGIQ. AGIQ selectively modulated the number of beneficial butyrate-producing commensal bacterium beneficial bacteria without changing the diversity of gut microbiota, which further supports the safe use of AGIQ in food products.
Histological differences between the central and peripheral areas of the testes of busulfan-administered mice.
Miyaso H, Yokota S, Suga K … +5 more , Hashimoto Y, Kouno C, Nagahori K, Itoh M, Kitajima S
J Toxicol Sci · 2024 · PMID 38556351 · Publisher ↗
Busulfan is an anticancer drug known to cause serious damage to seminiferous tubules in the testes and deplete germ cells in human and animal models. The testicular artery is anastomosed with deferential and cremasteric...
Busulfan is an anticancer drug known to cause serious damage to seminiferous tubules in the testes and deplete germ cells in human and animal models. The testicular artery is anastomosed with deferential and cremasteric arteries and is divided into capsular arteries, which give rise to the centripetal arteries and then recurrent arteries. The arterial blood in the testicular tissue is supplied by such a consequent system of arterial vessels, in order from the peripheral to the central area. As anticancer drugs are generally distributed throughout the whole body via the bloodstream and the running and distribution of arteries differ among the testicular areas, we hypothesized that the efficacy of busulfan differs in different testicular areas, particularly between the central and peripheral areas. In this study, busulfan was intraperitoneally injected at 40 mg/kg body weight into C57BL/6J male mice. After 28 days, in busulfan-treated mice, the diameters of seminiferous tubules were significantly higher in the central than in the peripheral area of the testes. The seminiferous tubular areas also significantly decreased in the peripheral areas compared with the central areas. The number of germ cells per seminiferous tubule was significantly higher in the central than in the peripheral area. Sertoli cell nuclei were detached into the lumen in the peripheral area. The number of Leydig cells was significantly lower in the peripheral areas. These data suggest that the effects of busulfan differ between the central and peripheral areas of the testis at 4 weeks after busulfan administration.
Octanol/water partition coefficients estimated using retention times in reverse-phase liquid chromatography and calculated in silico as one of the determinant factors for pharmacokinetic parameter estimations of general chemical substances.
Adachi K, Shimizu M, Shono F … +2 more , Funatsu K, Yamazaki H
J Toxicol Sci · 2024 · PMID 38556350 · Publisher ↗
The octanol/water partition coefficient P (logP) is a hydrophobicity index and is one of the determining factors for the pharmacokinetics of orally administered substances because it influences membrane permeability. To...
The octanol/water partition coefficient P (logP) is a hydrophobicity index and is one of the determining factors for the pharmacokinetics of orally administered substances because it influences membrane permeability. To illustrate the wide-ranging variety of compounds in the chemical space, a two-dimensional data plot consisting of 25 blocks was previously proposed based on a substance's in silico chemical descriptors. The logP values of approximately 200 diverse chemicals (test plus reference compounds covering all 25 blocks of the chemical space) were estimated experimentally using retention times in reverse-phase liquid chromatography; these values were compared with those of authentic reference compounds with established logP values (available for 17 of 60 reference substances in the Organization for Economic Co-operation and Development Test Guideline 117). The logP values of 140 of 165 chemicals successfully estimated using four different mobile phase conditions (pH 2, 4, 7, and 10 for molecular forms) correlated significantly with those calculated using the in silico packages ChemDraw and ACD/Percepta (r > 0.72). Although substances that neighbored authentic compounds in the chemical space had precisely correlated logP values estimated experimentally and in silico, some compounds that were more distant from authentic substances showed lower logP values than those estimated in silico. These results indicate that additional authentic reference materials with wider ranging chemical diversity and their logP values from reverse-phase liquid chromatography should be included in the international test guidance to promote simple and reliable estimation of octanol/water partition coefficients, which are important determinant factors for the pharmacokinetics of general chemicals.
Possible nonimmunological toxicological mechanisms of vesnarinone-associated agranulocytosis in HL-60 cells: role of reduced glutathione as cytotoxic defense.
Koga T, Sahara Y, Ohtani T … +2 more , Yosuke K, Umehara K
J Toxicol Sci · 2024 · PMID 38432956 · Publisher ↗
This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr, little cytotoxicity was observed, although reduced gl...
This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr, little cytotoxicity was observed, although reduced glutathione (GSH) content decreased in a concentration-dependent manner. Significant cytotoxicity and reactive oxygen species (ROS) production were observed when intracellular GSH content was reduced by treatment with L-buthionine-(S, R)-sulphoximine. The involvement of myeloperoxidase (MPO) metabolism was suggested, as when HL-60 cells were exposed to a reaction mixture of vesnarinone-MPO/HO/Cl, cytotoxicity was also observed. In contrast, the presence of GSH (1 mM) protected against these cytotoxic effects. Liquid chromatography-mass spectrometry analysis of the MPO/HO/Cl reaction mixture revealed that vesnarinone was converted into two metabolites, (4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 1: M1] and 1-chloro-4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 2: M2]). M2 was identified as the N-chloramine form, a reactive metabolite of M1. Interestingly, M2 was converted to M1, which was accompanied by the conversion of GSH to oxidized GSH (GSSG). Furthermore, when HL-60 cells were exposed to synthetic M1 and M2 for 24 hr, M2 caused dose-dependent cytotoxicity, whereas M1 did not. Cells were protected from M2-derived cytotoxicity by the presence of GSH. In conclusion, we present the first demonstration of the cytotoxic effects and ROS production resulting from the MPO/HO/Cl metabolic reaction of vesnarinone and newly identified the causative metabolite, M2, as the N-chloramine metabolite of M1, which induces cytotoxicity in HL-60 cells. Moreover, a protective role of GSH against the cytotoxicity was revealed. These findings suggest a possible nonimmunological cause of vesnarinone agranulocytosis.
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