Specificity of transaminase activities in the prediction of drug-induced hepatotoxicity.
Authors: Kobayashi A, Suzuki Y, Sugai S Abstract The activities of the transaminases (aminotransferases) alanine aminotransferase and aspartate aminotransferase in the blood (serum or plasma) are widely used as sensitive markers of possible tissue damage and, in particular for liver toxicity. On the other hand, an increase in transaminase activities is not always accompanied by findings suggestive of hepatotoxicity. Transaminases are some of the key enzymes in the gluconeogenesis and glycolysis pathways and exist in many organs and tissues which have high activities of the gluconeogenesis and glycolysis. The activi...
Source: Journal of Toxicological Sciences - September 5, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Involvement of metal transporters in the intestinal uptake of cadmium.
Authors: Ohta H, Ohba K Abstract We investigated the mechanism underlying intestinal cadmium (Cd) uptake based on the mediators (metal transporters) of essential elements, such as Fe, Zn, Cu, and Ca, under normal conditions in female rats. These elements interact with Cd uptake from the intestinal tract. Cd concentration at each site of the small intestine (duodenum, jejunum, and ileum) increased as Cd exposure increased. However, Cd concentration was the highest in the duodenum. The gene expression of ZIP14, DMT1, and ATP7A increased with increase in Cd concentration. Further, Cu concentration decreased as Cd conc...
Source: Journal of Toxicological Sciences - September 5, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Mechanism in bradycardia induced by Trimethyltin chloride: Inhibition activity and expression of Na+/K+-ATPase and apoptosis in myocardia.
This study explored the mechanism of TMT resulting in bradycardia of C57BL/6 mice. TMT was administered to mice to measure heart rate, serum succinate dehydrogenase (SDH) level, and myocardial Na+/K+-ATPase activity and expression. The effects of TMT on myocardial apoptosis were observed by changing the expressions of caspase-3, Bax and Bcl-2 in myocardium. It was found that the heart rate and SDH activity in serum of mice gradually decreased with the increase of TMT dose compared with the control group. The activity and the expression of Na+/K+-ATPase in the heart tissue of mice exposed to TMT was measured and gradually d...
Source: Journal of Toxicological Sciences - September 5, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Lead exposure induces cell autophagy via blocking the Akt/mTOR signaling in rat astrocytes.
Authors: Huang Y, Liao Y, Zhang H, Li S Abstract Lead is a main threat to human health due to its neurotoxicity and the astrocyte is known to be a common deposit site of lead in vivo. However, the detailed mechanisms related to lead exposure in the astrocytes were unclear. In order to deeply investigate this issue, we used Sprague-Dawley (SD) rats and astrocytes isolated from the hippocampus of SD rats to establish the lead-exposed animal and cell models through treating with lead acetate. The expression levels of GFAP, LC3, and p62 in the rat hippocampus were detected by immunofluorescence and Western blot after l...
Source: Journal of Toxicological Sciences - September 5, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Effects of indole and indoxyl on the intracellular oxidation level and phagocytic activity of differentiated HL-60 human macrophage cells.
Authors: Tsutsumi S, Tokunaga Y, Shimizu S, Kinoshita H, Ono M, Kurogi K, Sakakibara Y, Suiko M, Liu MC, Yasuda S Abstract Indoxyl, a derivative of indole originating from tryptophan, may undergo phase-II sulfate-conjugation pathway, thereby forming indoxyl sulfate (IS) in vivo. We previously reported that IS, a well-known uremic toxin, can increase the intracellular oxidation level and decrease the phagocytic activity in a differentiated HL-60 human macrophage cell model. Using the same cell model, the current study aimed to investigate whether indole and indoxyl (the metabolic precursors of indoxyl and IS, respec...
Source: Journal of Toxicological Sciences - September 5, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Tri-substituted organotin compounds, but not retinoic acid, are potent ligands of complement component 8 γ.
Tri-substituted organotin compounds, but not retinoic acid, are potent ligands of complement component 8 γ. J Toxicol Sci. 2020;45(9):581-587 Authors: Yamamoto K, Hiromori Y, Matsumaru D, Ishii Y, Takeshita Y, Tsubakihara I, Kimura T, Nagase H, Nakanishi T Abstract Complement component 8 γ (C8γ) is a subunit of complement protein 8 (C8), which itself is a subunit of the complement cytolytic membrane attack complex. However, C8γ is also suggested to be a carrier protein for the general clearance of endogenous and exogenous compounds because it belongs to the lipocalin family of s...
Source: Journal of Toxicological Sciences - September 5, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

The role of endoplasmic reticulum stress in renal damage caused by acute mercury chloride poisoning.
In this study, we examined the kidney injury and the corresponding ER stress in the mouse model of different doses of acute HgCl2 poisoning. To further confirm the role of ER stress, we tested the effects of its chemical chaperone [4-phenylbutyric acid (4-PBA)]. The results revealed that acute HgCl2 poisoning caused more severe kidney injury with dose on and activated ER stress, as indicated by increased expression of GRP78 and CHOP. Inhibition of ER stress restored the functional and morphological changes of kidneys, and partly attenuated renal tubular epithelial cell apoptosis. In summary, ER stress contributes to the ac...
Source: Journal of Toxicological Sciences - September 5, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Effects of intragastric administration of La2O3 nanoparticles on mouse testes.
This study provided useful information for risk analysis and regulation of La2O3 NPs by administrative agencies. PMID: 32741894 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - August 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Analysis of microRNA expression profiling during paraquat-induced injury of murine lung alveolar epithelial cells.
Authors: Zhao HW, Liu H, Liu LY, Liu Z, Dong XS Abstract Paraquat (PQ) as a non-selective heterocyclic herbicide, has been applied worldwide for over a few decades. But PQ is very harmful to humans and rodents. The lung is the main target organ of PQ poisoning. It is an important event that lung epithelial cells are injured during PQ-induced acute lung injury and pulmonary fibrosis. As a regulator of mRNA expression, microRNA (miRNA) may play an important role in the progress. Our study was to investigate the mechanisms of PQ-induced injury of pulmonary epithelial cells through analyzing the profiling of miRNAs and...
Source: Journal of Toxicological Sciences - August 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Gene expression profiling in dorsolateral prostates of prepubertal and adult Sprague-Dawley rats dosed with estradiol benzoate, estradiol, and testosterone.
In this study, microarray analysis was used for gene expression profiling in rat prostate tissue after exposure to EDCs and sex hormones over multiple time points (prepubertal through adulthood). We used dorsolateral prostate tissues from Sprague-Dawley rats (male offspring) and postnatally administered estradiol benzoate (EB) on postnatal days (PNDs) 1, 3, and 5, followed by treatment with additional hormones [estradiol (E) and testosterone (T)] on PNDs 90-200, as described by Ho et al. Microarray analysis was performed for gene expression profiling in the dorsolateral prostate, and the results were validated via qRT-PCR....
Source: Journal of Toxicological Sciences - August 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Extraction of peroxisome proliferator-activated receptor α agonist-induced lipid metabolism-related and unrelated genes in rat liver and analysis of their genomic location.
Extraction of peroxisome proliferator-activated receptor α agonist-induced lipid metabolism-related and unrelated genes in rat liver and analysis of their genomic location. J Toxicol Sci. 2020;45(8):449-473 Authors: Mizukawa Y, Amagase Y, Urushidani T Abstract Although peroxisome proliferator-activated receptor α (PPARα) agonists are obviously hepatocarcinogenic in rodents, they have been widely used for dyslipidemia and proven to be safe for clinical use without respect to the species difference. It is established that PPARα acts as a part of the transcription factor complex, b...
Source: Journal of Toxicological Sciences - August 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Peroxisome proliferator-activated receptor α agonist-induced histidine decarboxylase gene expression in the rat and mouse liver.
Peroxisome proliferator-activated receptor α agonist-induced histidine decarboxylase gene expression in the rat and mouse liver. J Toxicol Sci. 2020;45(8):475-492 Authors: Amagase Y, Mizukawa Y, Urushidani T Abstract By analysis of the data from the Toxicogenomics Database (TG-GATEs), histidine decarboxylase gene (Hdc) was identified as largely and commonly upregulated by three fibrates, clofibrate, fenofibrate, and WY-14,643, which are known to induce hepatocellular hypertrophy and proliferation via stimulation of peroxisome proliferator-activated receptor α (PPARα) in rodents. As hi...
Source: Journal of Toxicological Sciences - August 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice.
In this study, we investigated whether GSH depletion can sensitize mice to liver injury caused by GEF. Male C57BL/6J mice were intraperitoneally pretreated with L-buthionine (S,R)-sulfoximine (BSO) at 700 mg/kg to inhibit GSH synthesis and then orally administered GEF at 500 mg/kg every 24 hr for 4 consecutive days. The coadministration of BSO and GEF increased plasma alanine aminotransferase (ALT) levels to approximately 700 U/L and 1600 U/L at 72 and 96 hr after the first administration, respectively, whereas the increase in plasma ALT levels in mice receiving GEF at 500 mg/kg alone was limited, suggesting that GSH plays...
Source: Journal of Toxicological Sciences - August 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Serum miR-206 as a biomarker for drug-induced skeletal muscle injury in rats.
Authors: Yamaura Y, Kanki M, Sasaki D, Nakajima M, Unami A Abstract Creatine kinase (CK) and lactate dehydrogenase (LDH) serve as biomarkers for skeletal muscle injury in preclinical toxicity studies, but have a limitation regarding tissue specificity. Circulating miR-206 was recently reported to be a useful biomarker for skeletal muscle disorders in humans. Here, we sought to determine whether serum miR-206 can be used as a biomarker in preclinical toxicity studies to detect drug-induced skeletal muscle injury with higher sensitivity and specificity than the biomarkers CK, LDH, skeletal troponin I (sTnI), and myos...
Source: Journal of Toxicological Sciences - August 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Non-clinical combination toxicology studies: strategy, examples and future perspective.
Authors: Sacaan A, Hashida SN, Khan NK Abstract Over the last decade, combination of drugs in all stages of pharmaceutical development has accelerated availability of promising new therapies for difficult to treat diseases. Safety assessment of combined drugs to be tested in humans can occur at a critical path prior to proceeding in clinical testing. A recent survey by The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ DruSafe) summarized member companies' approaches to combination safety strategies. In addition, feedback from Health Authorities (HAs) support a case-by-case sc...
Source: Journal of Toxicological Sciences - July 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Rosmarinic acid alleviates di-2-ethylhexyl phthalate (DEHP) -induced thyroid dysfunction via multiple inflammasomes activation.
Authors: Wu H, Ma K, Na X Abstract DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Spra...
Source: Journal of Toxicological Sciences - July 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Toxicological effects of propofol abuse on the dopaminergic neurons in ventral tegmental area and corpus striatum and its potential mechanisms.
This study was aimed at examining propofol- (a known anesthetic) induced emotion-related behavioral disorders in mice, and exploring the possible molecular mechanisms. A total of 60 mice were divided into two groups: control and propofol group. Mice were injected with propofol (150 mg/kg, ip) at 8:00 a.m. (once a day, lasting for 30 days). During the 30 days, loss of righting reflex (LORR) and return of righting reflex (RORR) of mice were recorded every day. At the 1st (T1) and 30th (T2) day of drug discontinuance (T2), 15 mice of each group were selected to perform the open field test; then the mice underwent perfusion fi...
Source: Journal of Toxicological Sciences - July 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

The effect of dihydropyrazines on lipopolysaccharide-stimulated human hepatoma HepG2 cells via regulating the TLR4-MyD88-mediated NF- κB signaling pathway.
The effect of dihydropyrazines on lipopolysaccharide-stimulated human hepatoma HepG2 cells via regulating the TLR4-MyD88-mediated NF-κB signaling pathway. J Toxicol Sci. 2020;45(7):401-409 Authors: Esaki M, Ishida T, Miyauchi Y, Takechi S Abstract Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products that are spontaneously generated in vivo and ingested via food. DHPs generate various radicals and reactive oxygen species (ROS), which can induce the expression of several antioxidant genes in HepG2 cells. However, detailed information on DHP-response...
Source: Journal of Toxicological Sciences - July 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Endoplasmic reticulum stress mediated apoptosis via JNK in MWCNT-exposed in vitro systems: size, surface functionalization and cell type specificity.
Authors: Chatterjee N, Choi J Abstract The aim of the present study was to evaluate the underlying mechanism of multi-walled carbon nanotubes (MWCNT) induced cellular response and their potential cross-talk, specifically, between endoplasmic reticulum (ER) stress, MAPK activation and apoptosis and how these nano-bio interactions depend on the physico-chemical properties of MWCNT. For this purpose, human bronchial epithelial (Beas2B) and human hepatoma (HepG2) cell lines, were exposed to five kinds of MWCNTs which differ in functionalization and aspect ratios. Tissue-specific sensitivity was evident for calcium home...
Source: Journal of Toxicological Sciences - June 6, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Lack of toxicological influences by microsampling (50 µL) from jugular vein of rats in a collaborative 28-day study.
Lack of toxicological influences by microsampling (50 µL) from jugular vein of rats in a collaborative 28-day study. J Toxicol Sci. 2020;45(6):319-325 Authors: Yokoyama H, Hattori N, Ohtsuka H, Murata E, Kobayashi A, Muta K, Takumi A, Kitaura H, Jinno F, Iwai A, Nakai K, Mori K, Saito K, Saito Y Abstract Due to finalization of the ICH S3A Q&A focusing on microsampling, application of microsampling technique to regular non-clinical animal studies is expected for non-clinical safety assessment of pharmaceuticals. In Europe, microsampling from the tail vein or saphenous vein has often been used,...
Source: Journal of Toxicological Sciences - June 6, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

An acid-hydrolyzed wheat protein activates the inflammatory and NF- κB pathways leading to long TSLP transcription in human keratinocytes.
An acid-hydrolyzed wheat protein activates the inflammatory and NF-κB pathways leading to long TSLP transcription in human keratinocytes. J Toxicol Sci. 2020;45(6):327-337 Authors: Kuroda Y, Yuki T, Takahashi Y, Sakaguchi H, Matsunaga K, Itagaki H Abstract Hydrolyzed wheat proteins (HWPs) contained in cosmetics have occasionally caused immediate-type hypersensitivity following repeated skin exposure. Although the Cosmetic Ingredient Review Expert Panel concluded that
Source: Journal of Toxicological Sciences - June 6, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Biochemical profiles of rat primary cultured hepatocytes following treatment with rotenone, FCCP, or (+)-usnic acid.
In conclusion, these biochemical profiles could provide new insights into the mechanism(s) of mitochondrial toxicity. PMID: 32493876 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - June 6, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Redox cycling of 9,10-phenanthrenequinone activates epidermal growth factor receptor signaling through S-oxidation of protein tyrosine phosphatase 1B.
Authors: Luong NC, Abiko Y, Shibata T, Uchida K, Warabi E, Suzuki M, Noguchi T, Matsuzawa A, Kumagai Y Abstract 9,10-Phenanthrenequinone (9,10-PQ) is a polycyclic aromatic hydrocarbon quinone contaminated in diesel exhaust particles and particulate matter 2.5. It is an efficient electron acceptor that induces redox cycling with electron donors, resulting in excessive reactive oxygen species and oxidized protein production in cells. The current study examined whether 9,10-PQ could activate epidermal growth factor receptor (EGFR) signaling in A431 cells through S-oxidation of its negative regulators such as protein t...
Source: Journal of Toxicological Sciences - June 6, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Enhancement of acetaminophen-induced chronic hepatotoxicity in spontaneously diabetic torii (SDT) rats.
In conclusion, SDT rats were more sensitive to APAP-induced chronic hepatotoxicity than SD rats and the high susceptibility of SDT rats was considered to be attributable to lowered hepatic glutathione levels induced by accelerated gluconeogenesis. PMID: 32404557 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - May 15, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Outer retinal involvement in N-methyl-D-aspartate-induced inner retinal injury in rabbits assessed by optical coherence tomography.
In conclusion, our results suggest involvement of photoreceptors in NMDA-induced inner retinal injury. Additionally, OCT revealed acute inner retinal findings suggestive of temporary edema. PMID: 32404558 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - May 15, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Secretogranin III upregulation is involved in parkinsonian toxin-mediated astroglia activation.
Authors: Zhan X, Wen G, Jiang E, Li F, Wu X, Pang H Abstract Environmental neurotoxins such as paraquat (PQ), manganese, and 1-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are associated with a higher risk of Parkinson's disease (PD). These parkinsonian toxins exert certain common toxicological effects on astroglia; however, their role in the regulatory functions of astroglial secretory proteins remains unclear. In a previous study, we observed that secretogranin II (SCG2) and secretogranin III (SCG3), which are important components of the regulated secretory pathway, were elevated in PQ-activated U118 astro...
Source: Journal of Toxicological Sciences - May 15, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Pyrethroid pesticide exposure during early pregnancy and birth outcomes in southwest China: a birth cohort study.
Authors: Xu Q, Zhu B, Dong X, Li S, Song X, Xiao X, Zhang C, Lv Y, Zhang X, Li Y Abstract Despite the developmental toxicity reported in animals, few epidemiologic studies have investigated the potential effects of prenatal exposure to pyrethroid pesticides (PYRs) on fetal growth. A birth cohort study was conducted to examine the association between prenatal exposure to PYRs and birth outcomes, and a nested case-control study was conducted in this cohort to evaluate the effects of PYR on congenital defects. The assessment of PYR exposure was based on self-reported household pesticide use and urinary PYR metabolite ...
Source: Journal of Toxicological Sciences - May 15, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Involvement of claudin-5 in H2S-induced acute lung injury.
This study aims to investigate the role of the tight junction protein claudin-5 in H2S-induced ALI. In our study, Sprague-Dawley (SD) rats were exposed to H2S to establish the ALI model, and in parallel, human pulmonary microvascular endothelial cells (HPMECs) were incubated with NaHS (a H2S donor) to establish a cell model. Lung immunohistochemistry and electron microscopy assays were used to identify H2S-induced ALI, and the expression of claudin-5, p-AKT/t-AKT and p-FoxO1/t-FoxO1 was detected. Our results show that H2S promoted the formation of ALI by morphological investigation and decreased claudin-5 expression. Dexam...
Source: Journal of Toxicological Sciences - May 15, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

A novel screening test to predict the developmental toxicity of drugs using human induced pluripotent stem cells.
Authors: Aikawa N Abstract 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 d...
Source: Journal of Toxicological Sciences - April 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Drug-induced lenticular opacity and accumulation of cholesterol-related substances in the lens cortex of dogs.
Authors: Iwasaki H, Wakamatsu M, Sugihara K, Kamio K, Tsuji S, Morita J, Kurihara Y, Izumi T, Nishimoto T, Kinoshita K, Nakanishi Y, Sasaki M Abstract 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 opac...
Source: Journal of Toxicological Sciences - April 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Pro-apoptotic functions of TRAF2 in p53-mediated apoptosis induced by cisplatin.
In this study, we assessed the function of TRAF2 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that TRAF2 exerts pro-apoptotic activity through p53-dependent mechanisms at least in human fibrosarcoma cell line HT1080. TRAF2 deficient cells exhibit significant resistance to cell death induced by cisplatin, accompanied by the reduction of both p53 protein level and caspase-3 activation. Moreover, cisplatin-induced JNK activation was attenuated in TRAF2-deficient cells, and pharmacological inhibition of JNK signaling suppressed p53 stabilization. These results suggest that TRAF2 promotes p53-depe...
Source: Journal of Toxicological Sciences - April 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Cannabidiolic acid dampens the expression of cyclooxygenase-2 in MDA-MB-231 breast cancer cells: Possible implication of the peroxisome proliferator-activated receptor β/δ abrogation.
Cannabidiolic acid dampens the expression of cyclooxygenase-2 in MDA-MB-231 breast cancer cells: Possible implication of the peroxisome proliferator-activated receptor β/δ abrogation. J Toxicol Sci. 2020;45(4):227-236 Authors: Hirao-Suzuki M, Takeda S, Koga T, Takiguchi M, Toda A Abstract 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 t...
Source: Journal of Toxicological Sciences - April 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Nuclear factor erythroid 2-related factor 2 (NRF2) is a negative regulator of tissue plasminogen activator synthesis in cultured human vascular endothelial EA.hy926 cells.
Authors: Takahashi T, Nakano T, Katoh G, Shinoda Y, Yamamoto C, Yoshida E, Kaji T, Fujiwara Y Abstract Blood coagulation and the fibrinolytic system contribute to vascular lesions. Fibrinolysis in normal circulating blood strongly depends on the balance between tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) secreted from vascular endothelial cells; however, the mechanisms by which endothelial fibrinolysis is regulated remain to be fully understood. In the present study, human vascular endothelial EA.hy926 cells were transfected with small interfering RNA for nuclear factor er...
Source: Journal of Toxicological Sciences - April 4, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Silica nanoparticles enhance germ cell apoptosis by inducing reactive oxygen species (ROS) formation in Caenorhabditis elegans.
In this study, we used a Caenorhabditis elegans model to clarify SiO2 NPs oral toxicity in vivo and explore their effect on the reproductive system. We exposed C. elegans to 0.25, 0.5 and 1 mg /mL SiO2 NPs for 24 hr. Our results showed that SiO2 NPs exposure for 24 hr did not affect nematode survival rates, but did affect, to varying degrees, the reproduction, development, and movement of nematodes, with nematode fecundity being the most sensitive to SiO2 NPs toxicity. The NPs exposed group showed enhanced germ cell apoptosis and increased oxidative stress as seen through an increase in ROS and malondialdehyde (MDA), and d...
Source: Journal of Toxicological Sciences - March 10, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Avian eggshell thinning caused by transovarian exposure to o,p'-DDT: changes in histology and calcium-binding protein production in the oviduct uterus.
Authors: Kamata R, Shiraishi F, Nakamura K Abstract Reproductive disorders in birds are the most characteristic effects of DDT contamination of wildlife. Experimental exposure of avian eggs to the estrogenic substance o,p'-DDT causes abnormal development of the reproductive tract (shortening of the left oviduct and aberrant development of the right oviduct) and eggshell thinning in mature birds, but it is still not known how eggshell thinning occurs in the abnormal oviduct. To fill this information gap, we examined the histology of the uterine part of the oviduct in Japanese quail treated in ovo with o,p'-DDT or a ...
Source: Journal of Toxicological Sciences - March 10, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

In silico systems for predicting chemical-induced side effects using known and potential chemical protein interactions, enabling mechanism estimation.
Authors: Amano Y, Honda H, Sawada R, Nukada Y, Yamane M, Ikeda N, Morita O, Yamanishi Y Abstract 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 versatilit...
Source: Journal of Toxicological Sciences - March 10, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Preexisting diabetes mellitus had no effect on the no-observed-adverse-effect-level of acetaminophen in rats.
In conclusion, the no-observed-adverse-effect-level of acetaminophen was 800 ppm in both diabetic and control rats. PMID: 32147638 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - March 10, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Immunosuppressive drugs to reduce the mortality rate in patients with moderate to severe paraquat poisoning: A Meta-analysis.
Authors: Gao YX, Wang YB, Wan YD, Sun TW, Li Y, Hou LL, Sun P, Yuan D, Duan GY, Sun CH, Che L, Zhang Y Abstract The benefits and adverse effects of immunosuppressive drugs (ISDs) in patients with paraquat (PQ) poisoning have not been thoroughly assessed. This meta-analysis study aims to evaluate the effect of ISDs in patients with moderate to severe PQ poisoning. We searched PubMed, Embase, Cochrane Library, Ovid Medline, CNKI and Wanfang Data from inception to January 2019. The Mantel-Haenszel method with a random-effects model was used to calculate the pooled relative risks (RRs) and 95% Confidence Intervals (CIs...
Source: Journal of Toxicological Sciences - March 10, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Overexpression of MECP2 attenuates cigarette smoke extracts induced lung epithelial cell injury by promoting CYP1B1 methylation.
Authors: Lin J, Peng J, Liu G, Deng L Abstract MECP2 (Methyl-CpG-binding protein 2) has been shown to have a critical role in regulating DNA methylation against smoke exposed lung injury. However, the biological function of MECP2 and the underlying molecular mechanism remains elusive. Human bronchial epithelial (16HBE) and alveolar type II epithelial cells (AECII) were exposed to increasing concentrations of cigarette smoke extracts (CSE) solution to establish CSE-induced lung epithelial cell injury models. Our findings revealed that MECP2 was down-regulated, while CYP1B1 was up-regulated in CSE-induced lung epithe...
Source: Journal of Toxicological Sciences - March 10, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Cell density-dependent modulation of perlecan synthesis by dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) in vascular endothelial cells.
Authors: Hara T, Sakamaki S, Ikeda A, Nakamura T, Yamamoto C, Kaji T Abstract Proteoglycans that are synthesized by vascular endothelial cells contribute to the proliferation, migration, and blood coagulation-fibrinolytic system in vascular endothelial cells. Clarification of the molecular mechanisms for proteoglycan synthesis allows understanding of the regulation of endothelial functions. The research strategy of bioorganometallics analyzes biological systems using organic-inorganic hybrid molecules as tools. The present study found dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) and its ligand-modulated perle...
Source: Journal of Toxicological Sciences - February 19, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Isoflurane-induced expression of miR-140-5p aggravates neurotoxicity in diabetic rats by targeting SNX12.
Authors: Fan D, Yang S, Han Y, Zhang R, Yang L Abstract MicroRNAs (miRNAs) are widely known as critical regulators in isoflurane-induced neurotoxicity during the development of brain. Moreover, isoflurane could aggravate cognitive impairment in diabetic rats. The present study was designed to investigate the role and mechanism of miR-140-5p on isoflurane-induced neurotoxicity in diabetic rats. Firstly, a diabetic rat model was established by injection of streptozotocin (STZ) and identified by Morris water maze test. The result indicated that isoflurane treatment exacerbated STZ-induced cognitive impairment, as demo...
Source: Journal of Toxicological Sciences - February 19, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

High expression of miR-483-5p aggravates sepsis-induced acute lung injury.
Authors: Leng C, Sun J, Xin K, Ge J, Liu P, Feng X Abstract Sepsis-induced acute lung injury (ALI) has high morbidity and mortality rates, and there remains a need for therapeutic methods to improve the outcome of ALI patients. miR-483-5p is an important regulator for the development of various diseases such as sepsis. Nevertheless, it is not known whether miR-483-5p has an effect on sepsis-induced ALI. To explore this issue, this study used cecal ligation and puncture (CLP)-treated mice and lipopolysaccharide (LPS)-treated pulmonary microvascular endothelial cells (PMVECs) cells to simulate the models of sepsis-in...
Source: Journal of Toxicological Sciences - February 19, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Taurine attenuates hepatic steatosis in a genetic model of fatty liver disease.
Authors: Miyata M, Funaki A, Fukuhara C, Sumiya Y, Sugiura Y Abstract Mice lacking the farnesoid X receptor (FXR) are used as a genetic model for nonalcoholic fatty liver disease because their livers exhibit hepatic steatosis and inflammation. The influence of taurine drinking on disrupted hepatic function was investigated using female Fxr-null mice. Significant decreases in the levels of hepatic damage-associated diagnostic markers, hepatic triglycerides, non-esterified fatty acids, and total bile acids were found in Fxr-null mice that had drunk water containing 0.5% taurine for four weeks. Hepatic but not serum t...
Source: Journal of Toxicological Sciences - February 19, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Integration of read-across and artificial neural network-based QSAR models for predicting systemic toxicity: A case study for valproic acid.
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 betw...
Source: Journal of Toxicological Sciences - February 19, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Carcinogenicity of butyl 2,3-epoxypropyl ether in rats and mice by whole body inhalation for two years.
Authors: Matsumoto M, Kasai T, Saito A, Takanobu K, Senoh H, Umeda Y, Kanno J Abstract Butyl 2,3-epoxypropyl ether (CAS No. 2426-08-6, synonym: n-butylglycidyl ether, BGE) was exposed by whole body inhalation to F344 rats and BDF1 mice of both sexes (50 animals per group) 6 hours per day, 5 days per week for 104 weeks at targeted concentrations of 0, 10, 30 or 90 ppm (v/v) for rats and 0, 5, 15 or 45 ppm for mice. In rats, 90 ppm of BGE increased the incidences of nasal squamous cell carcinomas in both sexes. Nasal adenomas and splenic mononuclear cell leukemia were increased in male rats exposed to 30 ppm. Splenic...
Source: Journal of Toxicological Sciences - January 16, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Eupalinolide J induces apoptosis, cell cycle arrest, mitochondrial membrane potential disruption and DNA damage in human prostate cancer cells.
Authors: Wu Z, Xu X, Dai L, Wang Y, Yang B, Zhao H, Lou C Abstract Eupalinolide J (EJ) is a new sesquiterpene lactone isolated from Eupatorium lindleyanum DC. In the present study, we investigated the anti-cancer activity of EJ on cell proliferation in human prostate cancer cells. The MTT results indicated that EJ showed marked anti-proliferative activity in PC-3 and DU-145 cells in a dose- and time-dependent manner. DAPI staining analysis demonstrated that this effect was mediated by induction of cell apoptosis. Flow cytometric analysis indicated a significant increase in apoptotic cells, cell cycle arrest at G0/G...
Source: Journal of Toxicological Sciences - January 16, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Farnesoid X receptor and liver X receptors regulate Oct3/4 expression by multiple feedback regulating system in normal renal-derived cells and renal adenocarcinoma cells.
In this study, we found that nuclear receptors FXR and LXR (originally characterized as regulatory factors involved in cholesterol/bile acid homeostasis) regulate the expression of Oct3/4, a marker for cell differentiation, in both normal renal-derived cell line HK-2 and renal adenocarcinoma cell line ACHN. Down-regulation of Oct3/4 expression by activating FXR and LXR occurs only in normal renal cell-derived HK-2 cells. We also found that the RNA-binding protein, ELAVL2, oppositely regulates Oct3/4 expressions in HK-2 and ACHN cells. Moreover, we revealed that LXR-alpha and LXR-beta regulate each other's expression. Altho...
Source: Journal of Toxicological Sciences - January 16, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Aggregation of β-crystallin through covalent binding to 1,2-naphthoquinone is rescued by α-crystallin chaperone.
Aggregation of β-crystallin through covalent binding to 1,2-naphthoquinone is rescued by α-crystallin chaperone. J Toxicol Sci. 2020;45(1):37-43 Authors: Shinkai Y, Ding Y, Miura T, Kumagai Y Abstract Cataract induced by exposure to naphthalene is thought to mainly involve its metabolic activation, forming 1,2-naphthoquinone (1,2-NQ), which can modify proteins through chemical modifications. In the present study, we examined the effect of 1,2-NQ on aggregation of crystallins (cry) associated with cataract. Incubation of bovine β-cry with 1,2-NQ caused covalent modification of β-cry...
Source: Journal of Toxicological Sciences - January 16, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Long-term in vitro effects of exposing the human HK-2 proximal tubule cell line to 3-monochloropropane-1,2-diol.
Authors: Mossoba ME, Mapa MST, Araujo M, Zhao Y, Flannery B, Flynn T, Sprando J, Wiesenfeld P, Sprando RL Abstract 3-Monochloropropane-1,2-diol (3-MCPD) is a food processing contaminant in the U.S. food supply, detected in infant formula. In vivo rodent model studies have identified a variety of possible adverse outcomes from 3-MCPD exposure including renal effects like increased kidney weights, tubular hyperplasia, kidney tubular necrosis, and chronic progressive nephropathy. Given the lack of available in vivo toxicological assessments of 3-MCPD in humans and the limited availability of in vitro human cell studie...
Source: Journal of Toxicological Sciences - January 16, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Adjustment of a no expected sensitization induction level derived from Bayesian network integrated testing strategy for skin sensitization risk assessment.
Authors: Otsubo Y, Nishijo T, Mizumachi H, Saito K, Miyazawa M, Sakaguchi H Abstract Skin sensitization is a key adverse effect to be addressed during hazard identification and risk assessment of chemicals, because it is the first step in the development of allergic contact dermatitis. Multiple non-animal testing strategies incorporating in vitro tests and in silico tools have achieved good predictivities when compared with murine local lymph node assay (LLNA). The binary test battery of KeratinoSensTM and h-CLAT could be used to classify non-sensitizers as the first part of bottom-up approach. However, the quantit...
Source: Journal of Toxicological Sciences - January 16, 2020 Category: Toxicology Tags: J Toxicol Sci Source Type: research