J Toxicol Sci [JOURNAL]
Sun
200 papers
miRNA-214-3p targets BNIP3 to affect autophagy and thus drive gastric cancer progression.
Chen C, Guan S, Zhuang Y … +5 more , Xie M, Huang Q, Li X, Yang C, Jian J
J Toxicol Sci · 2025 · PMID 40307014 · Publisher ↗
With a fourth-place death rate among all malignancies, gastric cancer (GC) is one of the most prevalent tumors globally. As a primary malignant characteristic of GC, metastasis contributes substantially to a high death r...
With a fourth-place death rate among all malignancies, gastric cancer (GC) is one of the most prevalent tumors globally. As a primary malignant characteristic of GC, metastasis contributes substantially to a high death rate and unfavorable prognosis. miRNA-214-3p can influence cell apoptosis since it is an autophagy-regulating molecule. Its significance in GC malignant development has not, however, been investigated in terms of mechanism. qRT-PCR was utilized to confirm expression of miRNA-214-3p in GC tissues and cells. Bioinformatics analysis was then implemented to examine BNIP3 expression in GC as well as binding interaction between BNIP3 and miRNA-214-3p. The targeting capability of miRNA-214-3p on BNIP3 was confirmed using the dual-luciferase assay. Capacities of cells to proliferate, migrate, and invade were assayed using Transwell assays and colony formation. In order to determine if GC cells were capable of autophagy, immunofluorescence and western blot were employed. In GC, miRNA-214-3p was substantially expressed in GC tissues and cells, but BNIP3 was downregulated, as shown by bioinformatics analysis and verified by cell tests. MiRNA-214-3p targeted BNIP3, as shown by further bioinformatics analysis, and dual-luciferase experiment verified this binding connection. MicroRNA-214-3p facilitated cell invasion, migration, and proliferation, as shown by Transwell tests and colony formation. MiRNA-214-3p accelerated malignant development of GC by targeting BNIP3 to impact autophagy, as demonstrated by immunofluorescence and western blot analyses. By targeting BNIP3 to affect autophagy, miRNA-214-3p aided in the malignant growth of GC. This suggested that miRNA-214-3p may function as a likely therapeutic target or biomarker for the disease, with significant implications for early diagnosis and treatment of patients.
Differential effects of different time windows of postnatal perfluorooctane sulfonate exposure on cognitive development in mouse hippocampus.
Ninomiya A, Haijima A, Fujiwara Y … +3 more , Kawabata-Iwakawa R, Amano I, Koibuchi N
J Toxicol Sci · 2025 · PMID 40307013 · Publisher ↗
Perinatal perfluorooctane sulfonate (PFOS) exposure of the next generation through placenta and breast milk has been of high concern. Epidemiological and animal studies have reported that perinatal PFOS exposure is assoc...
Perinatal perfluorooctane sulfonate (PFOS) exposure of the next generation through placenta and breast milk has been of high concern. Epidemiological and animal studies have reported that perinatal PFOS exposure is associated with neurodevelopmental disorders such as learning and autism spectrum disorders in children. However, the sensitive time window of perinatal PFOS exposure for neurodevelopment has yet to be elucidated. Here we examined differential effects of different time windows of postnatal PFOS exposure (postnatal day (PD) 1-7 or 8-14) on cognitive development and gene expression profiles in the hippocampus. Pups were exposed to PFOS from PD 1 to 7 (PD 1-7 group) or from PD 8-14 (PD 8-14 group) through breastfeeding by dams who received a daily gavage of 1 mg/kg body weight PFOS per day during each period. An object location test and an object recognition test revealed the impairment in spatial memory in PD 1-7 group at PD 70. Learning ability was also retarded in a visual discrimination test. According to RNA-seq analysis and real-time PCR, Serpina3g and Tmem91 were significantly downregulated in the hippocampus of PD 1-7 group at PD 21. These results suggest that the first 7 days after birth are critically vulnerable to PFOS exposure and consequent neurodevelopmental deficits rather than the late phase of postpartum. Our work puts a strong emphasis on the importance of monitoring PFOS concentration in pregnant women and potential impact on retardation of neurodevelopment in children.
Induction of systemic inflammation by welding fume exposure in office workers as well as welders in welding factories.
Tsuji M, Koriyama C, Nakane T … +2 more , Ueno S, Ishihara Y
J Toxicol Sci · 2025 · PMID 40307012 · Publisher ↗
Welding fumes are metal particles of 1 µm or less generated during welding. Welding fumes generated in welding factories spread throughout the workplace. However, the effects of exposure have been measured primarily in w...
Welding fumes are metal particles of 1 µm or less generated during welding. Welding fumes generated in welding factories spread throughout the workplace. However, the effects of exposure have been measured primarily in welding workers, and no research has been conducted on the effects of fumes on workplace office workers. In this study, we recruited welding and office workers who worked in the same factories at ten workplaces in Japan, mainly in the Kyushu and Kanto regions, and separated their serum after blood sampling. We also obtained serum from the general subjects of Minami-Kagoshima City, which is located far from the welding factory. Cytokines and chemokines were quantified in the serum samples, and the concentration of interleukin (IL)-1β was significantly increased in office workers and welders compared with general subjects. Importantly, the serum concentrations of IL-12p70, IL-17A, IL-33, tumor necrosis factor α, and C-C motif chemokine ligand 3 in office workers were significantly higher than those in the general subjects, and there was no significant difference in the levels of these inflammatory molecules between welders and general subjects. This study suggests that office workers exposed to high fume concentrations exhibit increased systemic inflammation. Exposure assessments should be conducted not only for welders but also for office workers to reduce exposure risks.
Reported liver toxicity of food chemicals in rats extrapolated to humans using virtual human-to-rat hepatic concentration ratios generated by pharmacokinetic modeling with machine learning-derived parameters.
Adachi K, Hosoi M, Shimura Y … +2 more , Shimizu M, Yamazaki H
J Toxicol Sci · 2025 · PMID 40307011 · Publisher ↗
Pharmacokinetic data are not generally available for evaluating the toxicological potential of food chemicals. A simplified physiologically based pharmacokinetic (PBPK) model has been established to evaluate internal exp...
Pharmacokinetic data are not generally available for evaluating the toxicological potential of food chemicals. A simplified physiologically based pharmacokinetic (PBPK) model has been established to evaluate internal exposures to chemicals in rats or humans with no reference to in vitro or in vivo experimental data. In this study, reported liver toxicity levels in rats were extrapolated to humans using virtual hepatic concentration-time curves (AUC) as the interspecies factor. Virtual liver exposures to 27 lipophilic food chemicals (octanol-water partition coefficient logP >1) with reported rat hepatic lowest-observed-effect levels (LOELs) of ≤1000 mg/kg/day were generated using PBPK models with input parameters obtained entirely in silico via machine learning algorithms. The resulting virtual rat and human liver AUCs were correlated (n = 27, r = 0.52, p < 0.01). However, AUCs for the phenolic compounds emodin, isoeugenol, and tert-butylhydroquinone, which have reported rat LOEL values of ≤300 mg/kg/day, were located outside the relatively wide 95% confidence interval, indicating more extensive hepatic elimination in rats than in humans. In vitro depletion of tert-butylhydroquinone in rat liver fractions via sulfation was confirmed to be faster than that in humans. For emodin, isoeugenol, and tert-butylhydroquinone, human-to-rat AUC ratios ranged from 10- to 13-fold; consequently, their extrapolated human hepatic LOEL values were estimated as ≤30 mg/kg/day, i.e., one order of magnitude smaller than the rat LOELs. Despite the small number of lipophilic food chemicals considered here, the PBPK modeling approach using in silico-generated input parameters for rats and humans has the potential to facilitate toxicological studies.
Induction of VEGF-A expression by methylmercury is mediated by the EGFR-p38 MAPK-COX-2-PKA pathway in cultured human brain microvascular pericytes.
Yoshida E, Sakurai K, Hirata A … +9 more , Sasaoka T, Hirooka T, Fujie T, Hara T, Yamamoto C, Fujiwara Y, Shinoda Y, Eto K, Kaji T
J Toxicol Sci · 2025 · PMID 40175113 · Publisher ↗
Methylmercury is the causative organometallic compound of Minamata disease. Pathological changes in the cerebrum of patients are localized along the deep sulci and fissures of the cerebral cortex such as the calcarine fi...
Methylmercury is the causative organometallic compound of Minamata disease. Pathological changes in the cerebrum of patients are localized along the deep sulci and fissures of the cerebral cortex such as the calcarine fissure. It has been suggested that the occurrence of brain edema is important for the cerebral damage caused by methylmercury. Previously, we found that methylmercury induces vascular endothelial growth factor-A in cultured human brain microvascular pericytes, which may increase permeability of the brain microvasculature. In the present study, our findings suggest that this induction is mediated via the epidermal growth factor receptor-p38 mitogen-activated protein kinase-cyclooxygenase-2-protein kinase A pathway in cultured human brain microvascular pericytes. These results partly support our hypothesis that methylmercury causes neurotoxicity by activation of intracellular signaling pathways in various cell types, including neurons, macrophages, vascular endothelial cells, and pericytes.
Effect of the barrier function of stratum corneum and viable epidermis and dermis on the skin concentration of topically applied chemicals.
Todo H, Oshizaka T, Komatsu S … +1 more , Sugibayashi K
J Toxicol Sci · 2025 · PMID 40175112 · Publisher ↗
Three-dimensional cultured skin (3D skin) models have been utilized for in vitro skin permeation tests to evaluate the skin permeation rate and local effects (efficacy and toxicity) of applied chemicals, particularly fro...
Three-dimensional cultured skin (3D skin) models have been utilized for in vitro skin permeation tests to evaluate the skin permeation rate and local effects (efficacy and toxicity) of applied chemicals, particularly from the perspective of the 3Rs (reduction, replacement, refinement) approach. The steady-state concentration of applied chemicals at different depths in the viable epidermis and dermis (VED) is affected by their skin permeation parameters, such as permeability coefficient (K) and partition coefficient (K) from the donor solution to the skin of the chemicals. In the present study, the steady-state concentration of chemicals in the VED of EpiDerm 606X (EpiDerm) as representative of a 3D skin model were compared with hairless rat skin. The VED concentrations of chemicals in EpiDerm were higher than those in hairless rat skin when a model hydrophilic compound, antipyrine, and a model lipophilic compound, flurbiprofen, were applied, suggesting that the barrier functions of the VED against the whole skin were higher in EpiDerm than in hairless rat skin. When an ester compound, ethyl nicotinate, was applied, the VED concentration of nicotinic acid, a metabolite of ethyl nicotinate, was lower in EpiDerm than in hairless rat skin. These differences in the VED concentrations of applied chemicals might be related to false-positives and -negatives of topical effects evaluated with 3D skin models. It is important to pay particular attention to differences in VED concentration in 3D skin models and real skin when evaluating local efficacy and toxicity using 3D skin models.
In silico model to predict dermal absorption of chemicals in finite dose conditions.
Narita I, Todo H, Fujiwara C … +6 more , Teramae H, Oshizaka T, Itakura S, Komatsu S, Takayama K, Sugibayashi K
J Toxicol Sci · 2025 · PMID 40175111 · Publisher ↗
The development of in silico approaches that can estimate the dermal absorption of chemicals exposed in practical conditions is highly anticipated. In the present study, an in silico model to estimate both the dermal abs...
The development of in silico approaches that can estimate the dermal absorption of chemicals exposed in practical conditions is highly anticipated. In the present study, an in silico model to estimate both the dermal absorption rate and dermal permeation profile was developed for the application of chemicals in finite dose conditions. Forty-three chemicals with molecular weights in the range 116-362 and logK in the range 1.1-4.5 were used to develop an in silico model. A gradient boosting tree approach was applied to estimate permeation parameters for diffusion and partition coefficients of the chemicals in skin using physicochemical parameters of the chemicals such as molecular weight, lipophilicity, and the highest and lowest occupied molecular orbitals as the descriptor. In addition, 11 chemicals with different molecular weights and lipophilicities were applied on excised human skin in a finite dose condition, and dermal absorption profiles were obtained. Consideration of donor-solvent evaporation time, saturated concentrations of the chemicals, and donor-solvent coverage area on the skin surface, in addition to estimated skin permeation parameters of the chemicals, showed comparatively good dermal absorption profiles, although some cases of underestimation of dermal absorption were identified. It will be necessary to verify the accuracy of this model through experiments using more chemicals. However, the obtained results suggested that the established model may be valid to estimate the dermal absorption of chemicals in practical conditions.
Activation of the arylhydrocarbon receptor through maternal beta-naphthoflavone exposure in the neonatal kidney.
Yoshioka W, Kikutake K
J Toxicol Sci · 2025 · PMID 40175110 · Publisher ↗
The kidneys of neonates are vulnerable to stressors due to their immature structure and function. Excess activation of the transcription factor arylhydrocarbon receptor (AhR) in the kidneys of neonates can cause severe h...
The kidneys of neonates are vulnerable to stressors due to their immature structure and function. Excess activation of the transcription factor arylhydrocarbon receptor (AhR) in the kidneys of neonates can cause severe hydronephrosis, as shown previously using 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR agonist. In this study, we aimed to clarify the conditions under which AhR activation leads to hydronephrosis using beta-naphthoflavone (BNF), another potent agonist of AhR. Mouse dams were fed a BNF-containing diet, and the kidneys of their pups were examined. Maternal BNF exposure on postnatal day 1 (PND 1) significantly activated AhR, as evidenced by the increased mRNA levels of the target genes. However, AhR activation was hardly detectable on PND 2 or subsequent days although the mice were continually fed the BNF-containing diet. Further, no hydronephrosis or a related alteration was observed. Similarly, maternal BNF exposure from PND 6 induced significant AhR activation on PND 6 but not on PND 14. The overproduction of prostaglandin E (PGE), which is a pivotal mechanism in the development of neonatal hydronephrosis, was not observed, and no hydronephrosis was observed. These results suggested that the intense activation of AhR on PND 1 or 6 is insufficient to induce overproduction of PGE or hydronephrosis. Together with findings from previous studies, we conclude that the development of neonatal hydronephrosis depends on the duration and intensity of AhR activation.
Per- and polyfluoroalkyl substances: toxicokinetics, exposure and health risks.
Fujii Y, Harada KH
J Toxicol Sci · 2025 · PMID 40024759 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) are a group of chemicals containing stable per- or polyfluoroalkyl groups. Recent epidemiological studies have shown that PFAS cause health risks even at low concentrations. Thi...
Per- and polyfluoroalkyl substances (PFAS) are a group of chemicals containing stable per- or polyfluoroalkyl groups. Recent epidemiological studies have shown that PFAS cause health risks even at low concentrations. This review outlines the toxicokinetics, exposure and health risks of PFAS, with a focus on perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and long-chain perfluoroalkyl carboxylic acids (LC-PFCAs). These compounds are known to interact with various proteins in vivo, including the peroxisomal proliferator-activated receptor-α (PPARα). PFOA and PFOS have been identified as carcinogenic. It is known that PFOA and PFOS are transported by transporters such as organic anion transporter. Significant species differences in the behavior of these compounds exist, with much longer half-lives in humans than in mice and rats. One of the reasons that the half-lives of PFOA and PFOS are long in humans is that their renal clearance is low in humans. For animal toxicity experiments, it is essential that the doses in animal experiments are converted to equivalent doses in humans using pharmacokinetic models. Compared with PFOA, some LC-PFCAs have longer half-lives and accumulate more in the liver. Although tap water is a source of exposure to PFAS, the most common exposure source is food, with seafood being an important source for exposure to PFAS in Japan. PFOS and PFOA concentrations in human blood in Japan have been decreasing in recent years. However, according to clinical guidance published in 2022 by the United States National Academies, most Japanese residents are still in the medium risk group (PFAS concentration in plasma or serum is greater than 2 ng/mL and less than 20 ng/mL) or above. Further research is needed to help reduce exposure, and further risk assessments are required.
Long-term exposure to urban particulate matter exacerbates mortality after ischemic stroke in mice.
Ishihara N, Tanaka M, Namba K … +9 more , Kawano S, Nishimura S, Nezu N, Nakane T, Oguro A, Okuda T, Itoh K, Nabetani Y, Ishihara Y
J Toxicol Sci · 2025 · PMID 40024758 · Publisher ↗
Exposure to fine particulate matter (PM) has been epidemiologically reported to worsen the prognosis of ischemic stroke; however, the details have not been investigated. One of the major toxic mechanisms of PM inhalation...
Exposure to fine particulate matter (PM) has been epidemiologically reported to worsen the prognosis of ischemic stroke; however, the details have not been investigated. One of the major toxic mechanisms of PM inhalation is oxidative stress, which is mediated by reactive oxygen species generated by PM components such as metals and polycyclic aromatic hydrocarbons. In this study, we examined the effects of long-term exposure to urban particulate matter, focusing on oxidative stress, on prognosis after ischemic stroke in mice. When mice were intranasally exposed for 28 days to an urban aerosol collected in Beijing, China (CRM28), microglial activation was observed in the cerebral cortex, indicating that CRM28 induced neuroinflammation. CRM28 exposure resulted in increased serum levels of brain natriuretic peptide and troponin I, suggesting that cardiac injury was elicited by CRM28. Lung inflammation was also observed following CRM28 exposure; however, systemic inflammation was not detected. Mice exposed to CRM28 showed an exacerbation of mortality after ischemic stroke induction compared with vehicle mice. A vitamin E-rich diet suppressed CRM28-induced lipid peroxidation in the heart and lungs but not in the brain. A vitamin E-rich diet also attenuated cardiac injury and lung inflammation induced by CRM28 exposure, whereas neuroinflammation was not affected. Mortality after ischemic stroke improved with the administration of a vitamin E-rich diet. Considering that systemic inflammation did not occur, cardiac injury induced by oxidative stress under exposure to urban particulate matter may be involved in increased mortality after ischemic stroke. Antioxidation under air pollution is fundamental for protection against ischemic stroke.
Potential of connexin 32 as a predictive marker for drug-induced cholestatic liver injury in a collagen vitrigel-culture model of HepG2-NIAS cells, a new subline of HepG2 cells, with bile canaliculus-like structures.
Uzu M, Takezawa T
J Toxicol Sci · 2025 · PMID 40024757 · Publisher ↗
Cholestatic drug-induced liver injury (DILI) is caused by the aberrant excretion of bile acids (BAs) from hepatocytes via bile canaliculus-like structures (BCLSs) into the bile ducts. The precise in vitro evaluation meth...
Cholestatic drug-induced liver injury (DILI) is caused by the aberrant excretion of bile acids (BAs) from hepatocytes via bile canaliculus-like structures (BCLSs) into the bile ducts. The precise in vitro evaluation method for cholestatic DILI has not been established due to a lack of specific markers and cell resources. We previously reported that HepG2-NIAS cells cultured on a collagen vitrigel (CV) membrane formed BCLSs with high protein expression of transporters involved in the excretion of BAs, including bile salt export pump (BSEP). In this study, the potential of connexin (Cx) 32, a component of gap junction, as a predictive marker for cholestatic DILI was investigated using a CV-culture model of HepG2-NIAS cells. The cells were treated with 7 drugs with different DILI-risk levels, and cell toxicity and Cx32 expression were evaluated. Cell toxicity was significantly increased not only by high DILI-risk drugs (troglitazone and cyclosporine A) but also by chlorpromazine with low DILI-risk. Furthermore, cell toxicity of troglitazone was not enhanced by a co-treatment with taurocholate, suggesting the low involvement of inhibition of BA excretion via BSEP in cholestatic DILI. In contrast, the total protein expression of Cx32 and co-localization of Cx32 and F-actin, which is composed of BCLSs, were significantly increased only by high DILI-risk drugs. Treatment with high DILI-risk drugs also induced the increased protein expression of zonula occludens (ZO)-1, which supports BCLSs concerted with Cx32. These results suggest that Cx32 expression in the CV-culture model of HepG2-NIAS cells may be a prominent predictive marker for cholestatic DILI.
Male rat-specific fatty change in liver by DS-1971a: Elevation in phospholipids and adenosine as early responses to the fatty change in male rat-derived primary hepatocytes.
Fujimoto K, Kishino H, Hirao J … +3 more , Maejima T, Mori K, Tsuchiya Y
J Toxicol Sci · 2025 · PMID 40024756 · Publisher ↗
In a 3-month repeated oral dose toxicity study of DS-1971a, a selective inhibitor of the Nav1.7 voltage-gated sodium channel, fatty change of hepatocytes was observed only in male rats at doses of 100 mg/kg and above. Ho...
In a 3-month repeated oral dose toxicity study of DS-1971a, a selective inhibitor of the Nav1.7 voltage-gated sodium channel, fatty change of hepatocytes was observed only in male rats at doses of 100 mg/kg and above. However, this change was not observed in female rats even at the highest dose of 1500 mg/kg. Furthermore, fatty change was not observed in mice and monkeys administered the highest dose of 1000 mg/kg for 6 and 9 months, respectively. To further investigate species differences of this fatty change, lipid accumulation was evaluated by staining with the LipidTOX dye in primary cultured hepatocytes derived from male and female rats, male monkeys, and male and female humans. After exposure to DS-1971a for 72 hr, the staining showed an increase in intensity specifically in male rat-derived hepatocytes in a concentration-dependent manner. Metabolomic analysis using rat-derived primary cultured hepatocytes exposed to DS-1971a for 24 and 72 hr revealed that phospholipids, not neutral lipids like triacylglycerols, and adenosine were elevated in the male-derived hepatocytes. These results suggest that the elevation of phospholipids and adenosine in the hepatocytes may contribute to the specific fatty change observed in male rats.
Prolonged QRS duration in patients with acute poisoning occurs both xenobiotics and with low level of potassium: a single-center retrospective case control study.
Katsuki H, Yamada T, Ayukawa K
J Toxicol Sci · 2025 · PMID 40024755 · Publisher ↗
Prolongation of QRS duration (prolonged QRS) is associated with severe outcomes in non-tricyclic antidepressant poisoning. However, factors other than xenobiotics affecting QRS duration have not yet been investigated. He...
Prolongation of QRS duration (prolonged QRS) is associated with severe outcomes in non-tricyclic antidepressant poisoning. However, factors other than xenobiotics affecting QRS duration have not yet been investigated. Hence, this study aimed to identify factors contributing to prolonged QRS. This study was a single-center retrospective case control study. Patients who had overdosed on drugs or orally ingested xenobiotics that they would not normally ingest orally were included in the study. Patients were divided into two groups: prolonged QRS and normal QRS. Subsequently, these groups were compared. We performed a logistic regression analysis with the factors extracted by comparison as explanatory variables and prolonged QRS as the objective variable. In total, 108 patients were analyzed; 19 belonged to the prolonged QRS group. In the prolonged QRS group, factors such as male sex, low level of potassium, and xenobiotic ingestion resulted in prolonged QRS. In a logistic regression analysis, significant differences were observed in terms of male sex (odds ratio [OR], 27.00; 95% confidence interval [CI], 5.93-123.00; p<0.001), xenobiotics ingested that resulted in prolonged QRS (OR, 8.55; 95% CI, 1.84-39.70; p<0.001), and potassium levels (OR, 0.15; 95% CI, 0.03-0.88; p=0.035). Ingestion of sodium channel blockers, male sex, and low level of potassium may contribute to prolonged QRS.
Prolyl hydroxylase domain enzymes (isoforms 1-3, PHD1-3), but not factor-inhibiting HIF-1 (FIH-1), interact with the IKK complex and attenuate LPS-activated NF-kappa-B.
Tamura A, Kitayama K, Adachi M … +3 more , Hashimoto K, Oguro A, Imaoka S
J Toxicol Sci · 2025 · PMID 40024754 · Publisher ↗
Hypoxia induces the expression of nuclear factor kappa B (NF-kappa-B). NF-kappa-B functions by forming dimers from five main subunits: p65 (RelA), RelB, p52, p50, and c-Rel. In the classical pathway, NF-kappa-B activity...
Hypoxia induces the expression of nuclear factor kappa B (NF-kappa-B). NF-kappa-B functions by forming dimers from five main subunits: p65 (RelA), RelB, p52, p50, and c-Rel. In the classical pathway, NF-kappa-B activity is regulated by the degradation-inducing factor I kappa B kinase (IKK). IKK is composed of an α/β isomer and essential modulator NEMO (γ) subunits in the classical pathway, which may be the major pathway for NF-kappa-B signaling. In the present study, we focused on factor-inhibiting HIF-1 (FIH-1) and Prolyl hydroxylase domain enzyme (PHD), which have been identified as oxygen concentration-dependent regulators of HIF-1α. PHD has three isoforms: PHD1, PHD2, and PHD3, which have different affinities towards HIF-1α. We examined the interactions between IKKα/β and PHD1-3 by immunoprecipitation. PHDs efficiently interacted with IKKα/β. Furthermore, the overexpression of PHDs decreased the mRNA level of IL-1β, a downstream factor of NF-kappa-B activated by LPS. The overexpression of PHD1 and PHD2 markedly reduced IKKα/β protein levels; however, the effects of PHD3 were weaker than those of PHD1 and PHD2. Mutants of the active sites of PHD1 and PHD2 did not decrease IKKα/β protein levels, and a mutation in the active site of PHD3 did not affect IKKα/β protein levels. We also attempted to investigate the interactions of FIH-1 with IKKα/β and IκBα by immunoprecipitation, but found none. Moreover, IKKα/β and p65 protein levels were not affected by the overexpression of FIH-1. Collectively, these results suggest that PHDs directly regulated IKK protein levels, while FIH-1 did not affect the NF-kappa-B classical pathway.
The effects of anemia on the timing of pubertal onset in female rats.
Shimada M, Hosokawa Y, Ihara R … +4 more , Ogata K, Iwashita K, Matsuyama R, Asano H
J Toxicol Sci · 2025 · PMID 39894538 · Publisher ↗
Attainment of vaginal patency is an endpoint for the onset of puberty in female animals in toxicity studies. It is widely acknowledged that certain substances with endocrine-modulating effects can influence the timing of...
Attainment of vaginal patency is an endpoint for the onset of puberty in female animals in toxicity studies. It is widely acknowledged that certain substances with endocrine-modulating effects can influence the timing of puberty in female rats and that factors unrelated to endocrine mechanisms, such as malnutrition and stress, can also affect pubertal onset. Some epidemiological studies have also suggested a link between anemia and delay in pubertal onset in women, however, little is known regarding the relation between hematological changes and female pubertal onset in experimental animals. The purpose of this study was to examine the effects of anemia during the prepubertal period on pubertal onset and reproductive organs in female rats. In this study, anemia was induced by drawing a certain amount of blood from the jugular vein or by intraperitoneal administration of phenylhydrazine, a well-known inducer of hemolytic anemia. As a result, both treatment groups showed a transient anemia characterized by an approximately 20-35% decrease in hemoglobin levels compared to the control group. Anemia in these female rats produced no obvious changes in body weight on each postnatal day and had no effect on the weights and histopathology of reproductive organs after sexual differentiation, but the age at vaginal opening (VO) was delayed and the body weight at VO was higher than the same parameters in the control group. These results suggest that anemia in prepubertal females could cause a delay in pubertal onset.
Determination of putrefactive amine and ammonia concentrations around decomposed corpses.
Sato H, Umehara T, Kimura S … +2 more , Tanaka T, Kim SE
J Toxicol Sci · 2025 · PMID 39894537 · Publisher ↗
The surface of a rotting corpse is covered with liquid decomposition products that have flowed out of the body that include putrefactive amines produced via putrefaction and decarboxylation reactions of proteins. Ammonia...
The surface of a rotting corpse is covered with liquid decomposition products that have flowed out of the body that include putrefactive amines produced via putrefaction and decarboxylation reactions of proteins. Ammonia generated by deamination is also present around the corpse as a liquid or gas. As these putrefactive substances are toxic to humans, we attempted to measure the concentration of putrefactive substances in decomposed corpses in this study. Liquid putrefaction products were collected from the surface of a corpse, and the concentrations of putrefactive amines such as histamine, tyramine, phenethylamine, and tryptamine were analyzed by LC-MS/MS. Ammonia in the liquid and air around the corpse was also measured. Putrefactive amines and ammonia were present on all corpse surfaces. The highest concentrations and postmortem days in parentheses were as follows: histamine 2.26 mg/g (15 days), tyramine 1.77 mg/g (16 days), phenethylamine 4.90 mg/g (24 days), tryptamine 1.58 mg/g (17 days) and ammonia 25.6 mg/g (24 days postmortem). The highest concentration of ammonia in the air was 1310 ppm at 24 days postmortem. The ammonia level in the air around a corpse is toxic to humans. Inhalation of putrefactive amines and ammonia can cause chemical irritation to the respiratory tract and the skin and damage the mucous membrane of the eye. Oral ingestion can also cause poisoning symptoms such as blood pressure changes and headaches. Adequate protection against putrefactive substances is required when in contact with decaying corpses.
Glasgow coma scale may be a predictive factor for delayed neurological sequelae after carbon monoxide poisoning: a retrospective analysis of a nationwide multicenter observational registry in Japan.
Kaneko T, Fujita M, Tsuruta R
J Toxicol Sci · 2025 · PMID 39894536 · Publisher ↗
Acute carbon monoxide poisoning (ACOP) is a cause of accidental or deliberate deaths worldwide. Subsequent complications, particularly delayed neurological sequelae (DNS), are preventable and treatable based on their pat...
Acute carbon monoxide poisoning (ACOP) is a cause of accidental or deliberate deaths worldwide. Subsequent complications, particularly delayed neurological sequelae (DNS), are preventable and treatable based on their pathophysiology. Hyperbaric oxygenation therapy (HBO) is a potential procedure for preventing and treating DNS; however, the effects of HBO on DNS are unclear and debated. In the present study, we investigated which factors are associated with the development of DNS and the effects of HBO in patients with ACOP. We performed retrospective subanalyses of the COP-J registry, focusing on adults who underwent HBO, regardless of whether they developed DNS. The multivariable analysis showed that the Glasgow coma scale (GCS) on admission was significantly associated with DNS (odds ratio 0.736; 95% confidence interval 0.608-0.892; P = 0.002). The receiver operating characteristic curve analysis of GCS for DNS revealed a cutoff value of 12.5 according to Youden's index (sensitivity 80.8%, specificity 76.9%). This retrospective analysis of a nationwide Japanese registry of ACOP showed that low GCS scores on admission could be a predictive factor for DNS, with a possible cutoff value of ≤12, in patients who undergo HBO.
Construction and evaluation of an open-source database for inhalation-based physiologically based kinetic modeling of selected categories for industrial chemicals.
Yamamoto S, Yoshida K, Matsumoto M … +1 more , Yamada T
J Toxicol Sci · 2025 · PMID 39894535 · Publisher ↗
A physiologically based kinetic (PBK) model is used for predicting chemical concentrations of toxicological concern in target tissues. Such models are important for understanding toxicokinetics. However, it is challengin...
A physiologically based kinetic (PBK) model is used for predicting chemical concentrations of toxicological concern in target tissues. Such models are important for understanding toxicokinetics. However, it is challenging to obtain chemical-specific empirical parameter values used for PBK modeling. Thus, developing methods predicting these values is necessary. Herein, we researched PBK models of inhalation exposure to industrial chemicals and developed a database of parameters of approximately 200 chemicals in humans and rodents. Next, the chemicals in the database were classified into three categories (I, IIA, and IIB) based on the intermolecular interactions for humans and rats. Quantitative relationships between blood/air and tissue/blood partition coefficients and physicochemical parameters were derived for the chemicals in each category. Regression analyses of blood/air and fat/blood partition coefficients against Henry's law constant and log D at pH 7.4 for chemicals in category IIA for humans, in which van der Waals and dipole-dipole interactions were involved, yielded 0.88 and 0.54 coefficients of determination, respectively. Moreover, these methods worked for other categories and species. The metabolic parameters maximal velocity (Vmax) and Michaelis-Menten constant (Km) of the chemicals that are primarily metabolized by cytochrome P450 were calculated for humans and rats. Multiple regression analyses of logs Vmax and Km against the occurrence frequency of molecular fragments showed good correlations, respectively. The aforementioned models predicted values close to the reported values for test chemicals within the applicability domains. Our approach could also be applied to other chemicals within the domains that are not included in the database.
Perfluorooctane sulfonate induces hepatotoxicity through promoting inflammation, cell death and autophagy in a rat model.
Tang L, Zhu J, Zhuge S … +2 more , Yu J, Jiang G
J Toxicol Sci · 2025 · PMID 39894534 · Publisher ↗
Perfluorooctane sulfonate (PFOS) is reported to cause hepatotoxicity in animals and humans. However, the underlying mechanism by which it affects organelle toxicity in the liver are not well elucidated yet. This study ai...
Perfluorooctane sulfonate (PFOS) is reported to cause hepatotoxicity in animals and humans. However, the underlying mechanism by which it affects organelle toxicity in the liver are not well elucidated yet. This study aimed to investigate the mechanisms underlying PFOS-induced hepatic toxicity, focusing on inflammation, cell death, and autophagy. We established a PFOS-exposed Sprague-Dawley (SD) rat liver injury model by intraperitoneal injection of PFOS (1 mg/kg and 10 mg/kg body weight) every alternate day for 15 days. Our findings indicated that PFOS increased liver weight, caused lipid disorder and hepatic steatosis in rats. Meanwhile, PFOS disrupted the structure of mitochondria, increased accumulation of reactive oxygen species (ROS), repressed superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels, and elevated malondialdehyde (MDA) and nitric oxide synthase (NOS) amounts. We found PFOS induced inflammation as evidenced by activation of NOD-like receptor protein 3 (NLRP3), Cleaved cysteine-aspartic acid protease (caspase)1, tumor necrosis factor (TNF)α and interleukin (IL)-1β levels. Moreover, PFOS exposure significantly decreased B-cell lymphoma2 (Bcl2)/Bcl2 associated X (Bax) ratio and increased the protein expression of Cleaved caspase-3. Compared with the control group, PFOS upregulated the protein expression of necroptotic markers and autophagy-related proteins. In conclusion, PFOS induced inflammation, cell death, and autophagy through oxidative stress by ROS overload, thereby providing a mechanistic explanation for PFOS-induced hepatotoxicity.
Evaluation of rewarding effects of nitazene analogs: results from conditioned place preference tests and in vivo microdialysis experiments in mice.
Hataoka K, Hojo M, Nomura S … +8 more , Nakagawa Y, Kawai A, Nakamura M, Ikushima K, Alexander DB, Suzuki J, Suzuki T, Inomata A
J Toxicol Sci · 2025 · PMID 39779230 · Publisher ↗
In illicit drug markets, the most recently expanding new synthetic opioid subclass is benzimidazoles, also known as nitazenes, which were originally developed as analgesics in the 1950s. The emergence of this classical,...
In illicit drug markets, the most recently expanding new synthetic opioid subclass is benzimidazoles, also known as nitazenes, which were originally developed as analgesics in the 1950s. The emergence of this classical, potent drug family has attracted extensive research interest in the field of forensic toxicology; however, information on their psychological and physical dependence is very limited. Herein, we evaluated the rewarding effects of four nitazene analogs using a battery of in vivo experiments, with a positive control drug (isotonitazene). The four test materials, metonitazene, etodesnitazene, metodesnitazene, and flunitazene, were administered to male C57BL/6J mice by i.p. administration at 0.5, 2, 20, and 20 mg/kg, respectively. In comprehensive behavioral observation tests, representative opioid-related physiological and behavioral states, including analgesia, stereotypic circling behavior, hyperlocomotion, and Straub tail response, were observed. A set of conditioned place preference tests revealed that all the four analogs induced palatability in mice. Furthermore, measurements of dopamine levels in the nucleus accumbens shell by in vivo microdialysis resulted in significant elevations in all test material-treated groups, suggesting that the nitazenes elicit the rewarding effect through a neural circuit originating from the μ-opioid receptor activation at the ventral tegmental area. Our findings add important data regarding the psychological dependence of nitazenes and highlight the abuse potential of these four materials and other prevailing nitazene analogs.
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