The amino acid derivative reactivity assay with fluorescence detection and its application to multi-constituent substances.
In this study, we demonstrate the efficacy of ADRA-FL by testing 82 test chemicals used in the development of both DPRA and the conventional ADRA (ADRA-UV) as well as establish a threshold value for distinguishing sensitizers and non-sensitizers. Our results show that not only are depletion values obtained using ADRA-FL virtually identical to those obtained using ADRA-UV, the threshold value for either test is 4.9%. Additionally, in order to demonstrate the applicability of ADRA-FL to multi-constituent substances, we prepared test samples that consisted of a set of 10 non-sensitizers combined with one of 10 different sensi...
Source: Journal of Toxicological Sciences - December 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Functional modulation of liver mitochondria in lipopolysaccharide/drug co-treated rat liver injury model.
In conclusion, LPS-induced transient ischemia disrupts respiratory chain complex activities, enhances reactive oxygen species production, especially in mitochondria, and sensitizes mitochondria to permeability transition pore opening when testing a potentially hepatotoxic drug in vivo. PMID: 31813902 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - December 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Intracellular accumulation-independent cytotoxicity of pentavalent organoantimony compounds in cultured vascular endothelial cells.
In this study, we investigated the cytotoxicity of pentavalent organoantimony compounds with three phenyl groups on cultured vascular endothelial cells. The results indicated that the cytotoxicity of pentavalent organoantimony compounds was not correlated with the hydrophobicity and intracellular accumulation of these compounds. Therefore, we suggest that hydrophobicity and intracellular accumulation are not necessarily predictive of cytotoxicity in organic-inorganic hybrid molecules. PMID: 31813903 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - December 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Simultaneous profiling of organic and inorganic impurities in α-pyrrolidinopentiophenone (α-PVP).
Simultaneous profiling of organic and inorganic impurities in α-pyrrolidinopentiophenone (α-PVP). J Toxicol Sci. 2019;44(12):849-857 Authors: Hattori N, Kaizaki-Mitsumoto A, Hataoka K, Numazawa S Abstract Abuse of recreational drugs (i.e., synthetic chemicals with the structure or expected neurotropic effects, or both, similar to those of controlled substances) is a serious and continuous social harm. Designer drugs are often manufactured or synthesized in small-scale clandestine laboratories with impure starting materials, poor handling skills and inferior storage conditions. Therefore, in...
Source: Journal of Toxicological Sciences - December 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Cardiac safety assessment with motion field imaging analysis of human iPS cell-derived cardiomyocytes is improved by an integrated evaluation with cardiac ion channel profiling.
In conclusion, the MFI assay with hiPS-CMs would be useful for evaluating multiple cardiac liabilities. The ion channel profile helps to interpret the results of MFI assay and correctly evaluate cardiac risks. Therefore, an integrated cardiac safety assessment with MFI and ion channel profiling is recommended. PMID: 31813905 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - December 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

In vitro genotoxicity analyses of colibactin-producing E. coli isolated from a Japanese colorectal cancer patient.
Authors: Kawanishi M, Hisatomi Y, Oda Y, Shimohara C, Tsunematsu Y, Sato M, Hirayama Y, Miyoshi N, Iwashita Y, Yoshikawa Y, Sugimura H, Mutoh M, Ishikawa H, Wakabayashi K, Yagi T, Watanabe K Abstract Colibactin is a polyketide-peptide genotoxin produced by enteric bacteria such as E. coli, and is considered to contribute to the development of colorectal cancer. We previously isolated E. coli strains from Japanese colorectal cancer patients, and in the present study we investigated the genotoxic potency of the colibactin-producing (clb+) E. coli strains that carry the polyketide synthases "pks" gene cluste...
Source: Journal of Toxicological Sciences - December 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Current status and future perspective of computational toxicology in drug safety assessment under ontological intellection.
Authors: Yamagata Y, Yamada H, Horii I Abstract For the safety assessment of pharmaceuticals, initial data management requires accurate toxicological data acquisition, which is based on regulatory safety studies according to guidelines, and computational systems have been developed under the application of Good Laboratory Practice (GLP). In addition to these regulatory toxicology studies, investigative toxicological study data for the selection of lead compound and candidate compound for clinical trials are directed to estimation by computational systems such as Quantitative Structure-Activity Relationship (QSAR) a...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

A comparative study of nickel nanoparticle and ionic nickel toxicities in zebrafish: histopathological changes and oxidative stress.
Authors: Yokota S, Nakamura K, Kamata R Abstract Industry demand for nanomaterials is growing, but metal nanoparticle toxicity is not fully understood. For example, nickel nanoparticles (NiNPs) are used in electric capacitors, and their consumption is increasing, but there have been few reports of their toxicity and environmental effects. To elucidate the toxicological characteristics of NiNPs, we investigated their effects on the histopathology and oxidative states of zebrafish (Danio rerio) and compared the results with those of ionic nickel. Zebrafish exposed to four different concentrations of NiNPs or NiCl2 fo...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Magnolol protects PC12 cells from hydrogen peroxide or 6-hydroxydopamine induced cytotoxicity.
In this study, we investigated whether honokiol and magnolol, which are known to be active components of Magnoliae Cortex, induce drug-metabolizing enzymes and antioxidant enzymes in PC12 cells. We also examined the cytoprotective effect of honokiol and magnolol against H2O2 or 6-OHDA induced cell death in PC12 cells. Our results revealed that honokiol and magnolol induced both NAD(P)H:quinone oxidoreductase 1 (NQO1) and catalase enzyme activities in a concentration-dependent manner. Pretreatment of PC12 cells with magnolol suppressed toxicity induced by H2O2 or 6-OHDA. However, pretreatment of PC12 cells with honokiol sho...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Estimation of potential risk of allyl alcohol induced liver injury in diabetic patients using type 2 diabetes spontaneously diabetic Torii-Leprfa (SDT fatty) rats.
Authors: Takahashi T, Matsuura C, Toyoda K, Suzuki Y, Yamada N, Kobayashi A, Sugai S, Shimoi K Abstract In order to estimate the potential risk of chemicals including drug in patients with type 2 diabetes mellitus (T2DM), we investigated allyl alcohol induced liver injury using SD rats and Spontaneously Diabetic Torii-Leprfa (SDT fatty) rats as a model for human T2DM. The diabetic state is one of the risk factors for chemically induced liver injury because of lower levels of glutathione for detoxification by conjugation with chemicals and environmental pollutants and their reactive metabolites. Allyl alcohol is met...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Alterations of NMDA and AMPA receptors and their signaling apparatus in the hippocampus of mouse offspring induced by developmental arsenite exposure.
Authors: Zhao F, Wang Z, Liao Y, Wang G, Jin Y Abstract Loss of cognitive function due to arsenic exposure is a serious health concern in many parts of the world, including China. The present study aims to determine the molecular mechanism of arsenic-induced neurotoxicity and its consequent effect on downstream signaling pathways of mouse N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Drinking water containing 0, 25, 50 or 100 mg/L arsenite was provided each day to mother mice throughout gestation period until postnatal day (PND) 35 to expo...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Human induced pluripotent stem cell-derived mast cells useful for in vitro mast cell activation assay exhibiting phenotypes and morphological characteristics of human mast cells.
Authors: Ikuno T, Ito S, Inoue T Abstract Mast cells are key players in the inflammatory response with an important role in allergic reactions and are therefore useful for assessing the risk of anaphylaxis. However, they are difficult to isolate due to their low abundance and wide distribution. To overcome this, we generated and characterized mast cell-like cells derived from human induced pluripotent stem (hiPS) cells. These hiPS cell-derived mast cells (hiPS-MCs) were generated using recombinant human bone morphogenetic protein 4 (BMP4), vascular endothelial growth factor 165 (VEGF), stem cell factor (SCF), inter...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Effects of ascorbic acid treatment on developmental alterations in calcium-binding proteins and gamma-aminobutyric acid transporter 1 in the cerebellum of lead-exposed rats during pregnancy and lactation.
Authors: Nam SM, Seo JS, Nahm SS, Chang BJ Abstract In the present study, we investigated the effects of lead (Pb) and ascorbic acid co-administration on rat cerebellar development. Female rats were randomly divided into the following groups: control, Pb, and Pb plus ascorbic acid (PA) groups. From one week prior to mating, female rats were administered Pb (0.3% Pb acetate in drinking water) and ascorbic acid (100 mg/kg, oral intubation). The chemical administration was stopped on postnatal day 21 when the morphology of the offspring's cerebellum is similar to that of the adult brain. The blood Pb level was signifi...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Mild depolarization is involved in troglitazone-induced liver mitochondrial membrane permeability transition via mitochondrial iPLA2 activation.
Authors: Sato T, Segawa M, Sekine S, Ito K Abstract Troglitazone, the first peroxisome proliferator-associated receptor γ agonist developed as an antidiabetic drug, was withdrawn from the market due to idiosyncratic severe liver toxicity. One proposed mechanism by which troglitazone causes liver injury is induction of mitochondrial membrane permeability transition (MPT), which occurs in a calcium-independent phospholipase A2 (iPLA2)-dependent manner at a concentration of 10 µM. MPT, induced by opening of the MPT pore, leads to the release of cytochrome c and consequent apoptosis or necrosis. In the pres...
Source: Journal of Toxicological Sciences - November 13, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Central nervous system tumors in 2-year rat carcinogenicity studies: perspectives on human risk assessment.
Authors: Sacaan A, Thibault S, Khan KN Abstract Rodent in vivo carcinogenicity bioassays are required for human risk assessment and have been utilized in this capacity for decades. Accordingly, there is an abundance of data that could be accessed and analyzed to better understand the translatability of xenobiotic-induced rodent tumors to human risk assessment. In the past decade, various groups have published assessments of the value garnered by these life-time rodent studies. Results and recommendations from the International Council for Harmonization Expert Working Group (ICH-S1 EWG) on the predictability of the ...
Source: Journal of Toxicological Sciences - October 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Per fluorooctane sulfonate induces apoptosis via activation of FoxO3a and upregulation of proapoptotic Bcl-2 proteins in PC12 cells.
In this study, PC12 cells were used to investigate the changes of the expression of apoptosis-related proteins, forkhead box O3 (FoxO3a) and pro-apoptotic Bcl-2 proteins. We detected that the levels of cleaved caspase-3 and cleaved PARP were up-regulated obviously in PFOS-treated PC12 cells by using Western blotting, and that the apoptotic rate of PC12 cells was increased significantly by using flow cytometry, verifying that PFOS could induce neuronal apoptosis. Western blot analysis and immunofluorescence revealed obvious up-regulation of the expression of FoxO3a and proapoptotic Bcl-2 proteins. In addition, knockdown of ...
Source: Journal of Toxicological Sciences - October 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Gene expression profiling of cultured mouse testis fragments treated with ethinylestradiol.
Authors: Nakamura N, Sloper DT, Del Valle PL Abstract The assessment of xenobiotic-induced testicular toxicity is important in drug development. Nonetheless, in vitro models to test drugs and chemicals that may cause testicular toxicity are lacking, requiring the continued use of animal models for those studies. We previously evaluated an in vitro mouse testis organ culture system using ethinylestradiol (EE), a well-studied testicular toxicant, and demonstrated a dose-dependent relationship between adverse effects to germ cell differentiation and increasing EE concentrations. However, we terminated that study after...
Source: Journal of Toxicological Sciences - October 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Long-term administration of excess zinc impairs learning and memory in aged mice.
Authors: Yoshida K, Gi M, Fujioka M, Teramoto I, Wanibuchi H Abstract Zinc (Zn) is an essential element, but excess amounts are known to cause neurotoxic effects. The risk of excessive Zn intake is increased by supplementing food intake with dietary supplements. Ageing affects many cellular processes that predispose individuals to neurodegeneration. Indeed, the prevalence of senile dementia such as Alzheimer's disease, Parkinson's disease, and vascular-type dementia increases with age. As such, we investigated the effects of long-term exposure to excess Zn on learning and memory in aged mice. ICR-JCL female mice (a...
Source: Journal of Toxicological Sciences - October 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide has the potential to form 2'-deoxyguanosine and N-acetylcysteine adducts.
Authors: Nishiyama T, Hayashi N, Yanagita H, Ohnuma T, Ogura K, Hiratsuka A Abstract Cigarette smoking is a risk factor for the development of various cancers, such as lung, nasal, liver and bladder cancers. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, is implicated in human lung cancer. NNK-induced DNA adducts are found in target tissues for NNK carcinogenesis. NNK is activated by cytochrome P450 dependent α-hydroxylation at either the methylene carbon or methyl carbon adjacent to the N-nitroso group. The former leads to the formation of the methylating agent, and the...
Source: Journal of Toxicological Sciences - October 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Species differences in micronucleus induction of the clastogenic compounds associated with drug metabolic profile.
In conclusion, the species difference in micronucleus induction by BaP and CPA was attributable to the differences in the metabolic profiles of these drugs among species. Our results indicate that it is crucial to understand the effect of species differences in the metabolic profile of drug candidates on genotoxicity and carcinogenicity potential and to predict their risk in human. PMID: 31588061 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - October 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

β-Naphthoflavone, an exogenous ligand of aryl hydrocarbon receptor, disrupts zinc homeostasis in human hepatoma HepG2 cells.
β-Naphthoflavone, an exogenous ligand of aryl hydrocarbon receptor, disrupts zinc homeostasis in human hepatoma HepG2 cells. J Toxicol Sci. 2019;44(10):711-720 Authors: Ishida T, Takechi S Abstract Recent studies have demonstrated a relationship between the disruption of zinc homeostasis and the onset of diseases. However, little is known about the factors that disrupt zinc homeostasis. Here, we investigated the effects of β-naphthoflavone, an exogenous ligand of aryl hydrocarbon receptor (AHR), on intracellular zinc levels. Human hepatoma HepG2 cells were treated with β-naphthoflavone f...
Source: Journal of Toxicological Sciences - October 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Physiological and drug-induced changes in blood levels of adrenal steroids and their precursors in cynomolgus monkeys: An application of steroid profiling by LC-MS/MS for evaluation of the adrenal toxicity.
In conclusion, this study showed that in cynomolgus monkeys, simultaneous measurement of blood levels of adrenal steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms. PMID: 31474739 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - September 4, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Applicability of amino acid derivative reactivity assay for prediction of skin sensitization by combining multiple alternative methods to evaluate key events.
Authors: Yamamoto Y, Fujita M, Wanibuchi S, Sato A, Akimoto M, Katsuoka Y, Ono A, Kasahara T Abstract Amino acid derivative reactivity assay (ADRA) has previously been developed as an alternative method to direct peptide reactivity assay (DPRA) to evaluate key event 1 in skin sensitization mechanisms. However, when using alternative methods for skin sensitization, integrated approaches to testing and assessment (IATA) that combine the results of multiple tests evaluating different key events are generally required. To verify whether ADRA can be used in IATA, we replaced DPRA with ADRA in five IATA methods combining...
Source: Journal of Toxicological Sciences - September 4, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Dose- and time-dependent changes in blood and adrenal levels of multiple steroids in rats after administration of ketoconazole with or without ACTH.
Authors: Tochitani T, Yamashita A, Matsumoto I, Kouchi M, Fujii Y, Miyawaki I Abstract To verify simultaneous measurement of blood levels of adrenal steroids as a tool to evaluate drug effects on adrenal steroidogenesis, dose- and time-dependent changes in blood levels of corticosterone and its precursors (pregnenolone, progesterone and deoxycorticosterone), as well as their relationship with the pathological changes in the adrenal gland, were examined in rats dosed with ketoconazole (KET). Also examined were whether effects on adrenal steroidogenesis that were not obvious in the blood steroid levels after sole adm...
Source: Journal of Toxicological Sciences - September 4, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Segment-specific and direction-dependent transport of cadmium and manganese in immortalized S1, S2, and S3 cells derived from mouse kidney proximal tubules.
Authors: Fujishiro H, Hamao S, Isawa M, Himeno S Abstract The kidney proximal tubule is a target of many renal toxicants, including cadmium (Cd), and also a place of reabsorption of essential metals in glomerular filtrate to systemic circulation. Although the mechanisms of metal transport in the convoluted proximal tubule (S1 and S2 segments) and the straight proximal tubule (S3 segment) may differ, little is known about the segment-specific modes of metal transport. Here, we utilized immortalized cell lines derived from the S1, S2, and S3 segments of mouse kidney proximal tubules, and examined the segment-specific...
Source: Journal of Toxicological Sciences - September 4, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Acute hepatotoxicity of multimodal targeted imaging contrast agent NaLuF4:Gd,Yb,Er-PEG/PEI-FA in mice.
In conclusion, NaLuF4:Gd,Yb,Er-PEG/PEI-FA nanoprobes are safe and reliable, and have potential applications in the field of tumor targeted multimodal imaging. PMID: 31474743 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - September 4, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Effect of exposure to Asian sand dust-Particulate matter on liver Tenascin-C expression in human cancer cell and mouse hepatic tissue.
In this study, we examined the expression of Tn-C and Fibronectin in human cancer-cell lines and in liver tissue of mice treated with ASD-PM to investigate the inflammatory and cell-damage effects of ASD-PM. In our in vivo study, mice were intratracheally instilled with saline suspensions of ASD-PM particles. Instillation of these particles was repeated twice a week for 12 weeks and the liver tissues were stained with hematoxylin, eosin, and Masson's trichrome, and we carried out an IF. Tn-C expression in liver tissues was detected by RT-PCR and western blot analysis. In the results, the expression of Tn-C increased in a d...
Source: Journal of Toxicological Sciences - September 4, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Effective dispersal of titanium dioxide nanoparticles for toxicity testing.
Authors: Kobayashi K, Kubota H, Hojo R, Miyagawa M Abstract Currently, protocols for the dispersal of titanium dioxide (TiO2) nanoparticles are not standardized and often yield non-uniform particles and/or insufficient dispersal in liquid medium. Our study aimed to improve dispersal so that TiO2 nanoparticles are of uniform size, making nanotoxicity testing more reliable. Various combinations of vehicles, sonication durations, and sonication volumes were assessed for optimizing preparations of TiO2 nanoparticles. We tested each of five vehicles: ultrapure water (UPW), 0.2% disodium hydrogen phosphate (DSP), Dulbecc...
Source: Journal of Toxicological Sciences - August 7, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Stephanthraniline A suppresses proliferation of HCT116 human colon cancer cells through induction of caspase-dependent apoptosis, dysregulation of mitochondrial function, cell cycle arrest and regulation of Akt/p38 signaling pathways.
In this study, we found that STA significantly inhibits the growth of HCT116 colon cancer cells in a time- and concentration-dependent manner. The inhibitory effect of STA on cell growth was related to the induction of apoptosis. Activated caspase-3, caspase-8 and caspase-9, along with a decreased Bcl-2/Bcl-x ratio and loss of mitochondrial membrane potential (Δψm), were observed in response to STA treatment. Furthermore, treatment of HCT116 cells with STA resulted in G0/G1 phase cell cycle arrest accompanied by decreased mRNA levels of cyclin-dependent kinase 4 (CDK4), p21 and c-myc. Additionally, the inhibition...
Source: Journal of Toxicological Sciences - August 7, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3.
This study also represents an important example of determining novel side effects in pre-existing drugs. This study suggests that caution may be warranted when this compound is used to treat alcohol abuse or cancer in patients carrying a SCA3-causing mutation. PMID: 31378764 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - August 7, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Human plasma and liver concentrations of styrene estimated by combining a simple physiologically based pharmacokinetic model with rodent data.
Authors: Miura T, Uehara S, Nakazato M, Kusama T, Toda A, Kamiya Y, Murayama N, Shimizu M, Suemizu H, Yamazaki H Abstract Long-term exposure to certain volatile organic compounds is a significant public health concern. A variety of food containers and drinking cups prepared from polystyrene or polystyrene-related plastics could contain styrene monomer. In the current study, the concentrations of styrene in plasma and liver were surveyed and determined after oral doses of 25 mg/kg to rats and 200 mg/kg to control and humanized-liver mice. Plasma concentrations of styrene in rats were still detected 2 hr after 10-25 ...
Source: Journal of Toxicological Sciences - August 7, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Gene expression profiles in the dorsal root ganglia of methylmercury-exposed rats.
Authors: Shinoda Y, Tatsumi S, Yoshida E, Takahashi T, Eto K, Kaji T, Fujiwara Y Abstract Methylmercury (MeHg) exposure is known to induce neurodegeneration in both the central nervous system (CNS) and peripheral nervous system (PNS). Molecular mechanisms of MeHg-induced neurotoxicity have been well investigated in the CNS, however, it remains unclear in the PNS. In the present study, comprehensive gene expression analysis was performed by analyzing MeHg-exposed adult rat dorsal root ganglion (DRG) by DNA microarray. Methylmercuric chloride (6.7 mg/kg/day) was administered to nine-week-old male Wistar rats for five...
Source: Journal of Toxicological Sciences - August 7, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

LC-MS analyses of N-acetyl-p-benzoquinone imine-adducts of glutathione, cysteine, N-acetylcysteine, and albumin in a plasma sample: A case study from a patient with a rare acetaminophen-induced acute swelling rash.
Authors: Ozawa M, Kubo T, Lee SH, Oe T Abstract Acetaminophen (Paracetamol, APAP) has been widely used for many decades as an analgesic and antipyretic agent but APAP overdose often causes acute adverse reactions, particularly liver damage. The metabolically oxidized form of APAP, N-acetyl-p-benzoquinone imine (NAPQI), is chemically reactive and binds covalently to proteins. Therefore, NAPQI is believed to be the key metabolite that causes hepatotoxicity, especially under conditions of glutathione depletion. Other APAP-induced adverse reactions, such as skin damage, are rare and remain poorly studied. Here, we repo...
Source: Journal of Toxicological Sciences - August 7, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Immunohistochemical expression of autophagosome markers LC3 and p62 in preneoplastic liver foci in high fat diet-fed rats.
Authors: Masuda S, Mizukami S, Eguchi A, Ichikawa R, Nakamura M, Nakamura K, Okada R, Tanaka T, Shibutani M, Yoshida T Abstract Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive deposition of droplets in hepatocytes. Patients with NAFLD can be at risk for nonalcoholic steatohepatitis, which can lead to hepatocellular carcinoma. Autophagy is a cellular pathway that is crucial for survival and homeostasis, and which protects against pathophysiological changes like obesity and cancer. We determined the expression of autophagy markers in preneoplastic hepatic lesions and the effects of an autophagy...
Source: Journal of Toxicological Sciences - August 7, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Telemetered common marmosets is useful for the assessment of electrocardiogram parameters changes induced by multiple cardiac ion channel inhibitors.
The objective of this study is to assess the response of telemetered common marmosets to multiple cardiac ion channel inhibitors and to clarify the usefulness of this animal model in evaluating the effects of drug candidates on electrocardiogram (ECG). Six multiple cardiac ion channel inhibitors (sotalol, astemizole, flecainide, quinidine, verapamil and terfenadine) were orally administered to telemetered common marmosets and changes in QTc, PR interval and QRS duration were evaluated. Drugs plasma levels were determined to compare the sensitivity in common marmosets to that in humans. QTc prolongation was observed in the ...
Source: Journal of Toxicological Sciences - July 6, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

The effects on the endocrine system under hepatotoxicity induction by phenobarbital and di(2-ethylhexyl)phthalate in intact juvenile male rats.
This study investigated the effects of PB (100 mg/kg/day) or DEHP (500 mg/kg/day) on the endocrine system in intact juvenile/peripubertal male rats exposed for 31 days beginning on postnatal day 23. Slight hormone level changes, histopathological changes in thyroid gland or induction of UDP-glucuronosyltransferase in liver were observed in both the PB and DEHP groups. One of the assumed mechanisms inducing thyroid effects is predictable to be secondary changes based on the enhancement in thyroid hormone metabolism via the induction of hepatic microsomal enzymes. No reproductive system-related changes in organ weights, hist...
Source: Journal of Toxicological Sciences - July 6, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Evaluation of M1-microglial activation by neurotoxic metals using optimized organotypic cerebral slice cultures.
Authors: Hoshi T, Toyama T, Shinozaki Y, Koizumi S, Lee JY, Naganuma A, Hwang GW Abstract M1-microglia (neurotoxic microglia) regulate neuronal development and cell death and are involved in many pathologies in the brain. Although organotypic brain slice cultures are widely used to study the crosstalk between neurons and microglia, little is known about the properties of microglia in the mouse cerebral cortex slices. Here, we aimed to optimize the mouse cerebral slice cultures that reflect microglial functions and evaluate the effects of neurotoxic metals on M1-microglial activation. Most microglia in the cerebral ...
Source: Journal of Toxicological Sciences - July 6, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Bisphenol A induces cholesterol biosynthesis in HepG2 cells via SREBP-2/HMGCR signaling pathway.
This study provides important implications for understanding the potential lipotoxicity of BPA exposure, and it also indicates that low-dose BPA induces hepatic cholesterol biosynthesis through upregulating the SREBP-2/HMGCR signaling pathway. PMID: 31270304 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - July 6, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Methamphetamine exposure upregulates the amyloid precursor protein and hyperphosphorylated tau expression: The roles of insulin signaling in SH-SY5Y cell line.
Authors: Chen L, Zhou L, Yu P, Fang F, Jiang L, Fei J, Xiao H, Wang J Abstract Methamphetamine (METH) is a potent and highly addictive central nervous system stimulant. The association between METH exposure and Alzheimer's disease (AD) has gained more attention, but, the mechanisms behind METH-induced neuron-related adverse outcomes remain poorly understood. With the western blot assay, our results revealed that METH exposure significantly increased the expression of AD-associated pathological proteins, including the amyloid precursor protein (APP) and the phosphorylated tau protein (p-tau). Meanwhile, the insulin ...
Source: Journal of Toxicological Sciences - July 6, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Cardiotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure through lactation in mice.
Authors: Fujisawa N, Tohyama C, Yoshioka W Abstract Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after ...
Source: Journal of Toxicological Sciences - July 6, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Predicting the results of a 24-hr human patch test for surfactants: utility of margin-setting in a reconstructed human epidermis model.
Authors: Sugiyama M, Ueki T, Ogata S, Itagaki H Abstract To predict the results of a 24-hr closed human patch test, we previously recommended the use of in vitro test with a reconstructed human epidermis (RhE) model adopted in OECD TG 439, and proposed the margin method, which includes evaluation of twice the concentration to avoid a false positive for surfactants. Therefore, in this study, we used LabCyte EPI-MODEL as a RhE model, and confirmed the reproducibility of this method using five surfactants, including benzalkonium chloride (BC), sodium lauryl sulfate (SLS), and lauryl betaine (LB), for which false negat...
Source: Journal of Toxicological Sciences - June 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Cardio-renal safety of non-steroidal anti-inflammatory drugs.
Authors: Radi ZA, Khan KN Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutic class in clinical medicine. These are sub-divided based on their selectivity for inhibition of cyclooxygenase (COX) isoforms (COX-1 and COX-2) into: (1) non-selective (ns-NSAIDs), and (2) selective NSAIDs (s-NSAIDs) with preferential inhibition of COX-2 isozyme. The safety and pathophysiology of NSAIDs on the renal and cardiovascular systems have continued to evolve over the years following short- and long-term treatment in both preclinical models and humans. This review summarizes major lear...
Source: Journal of Toxicological Sciences - June 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Ketoconazole pretreatment ameliorates carbon tetrachloride-induced acute liver injury in rats by suppressing inflammation and oxidative stress.
Authors: Zhou Y, Peng C, Zhou Z, Huang K Abstract Several studies have demonstrated the chemopreventive role of ketoconazole in animal models of liver injury. However, the underlying molecular mechanisms of this hepatoprotective effect are poorly understood. The present study assessed the potential of ketoconazole to enhance resistance to carbon tetrachloride-induced hepatotoxicity in vivo in a rat model. Ketoconazole pretreatment adult male rats were intraperitoneally injected with carbon tetrachloride for 24 hr and various hepatic parameters were analyzed. We observed decreased serum transaminases activity, reduc...
Source: Journal of Toxicological Sciences - June 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Polyhexamethylene guanidine phosphate-induced ROS-mediated DNA damage caused cell cycle arrest and apoptosis in lung epithelial cells.
In this study, the toxic response of PHMG-p on human lung epithelial cells was evaluated, and its mechanisms associated with reactive oxygen species (ROS), DNA damage, and its relationship with p53 activation were investigated. The toxic responses of epithelial cells were assessed by flow cytometry analysis and western blot analysis. The results revealed that PHMG-p induced G1/S arrest and apoptosis in A549 cells. Interestingly, p53 was activated by PHMG-p treatment and p53 knockdown suppressed PHMG-p-induced apoptosis and cell cycle arrest. PHMG-p promoted ROS generation and consequently increased the expression of DNA da...
Source: Journal of Toxicological Sciences - June 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Ellagic acid inhibits proliferation and migration of cardiac fibroblasts by down-regulating expression of HDAC1.
This study was designed to investigate the impacts of ellagic acid on CFs and the underlying mechanisms. The expression of histone deacetylases (HDACs) and fibrosis-related genes was detected by qRT-PCR and western blot. The Masson's Trichrome Staining assay was used to evaluate the area of cardiac fibrosis. The proliferation and migration of CFs were measured by CCK8 Kit and Transwell assay, respectively. Our results showed that ellagic acid significantly reduced protein expression of HDAC1, mRNA expression of collagen I, collagen III, MMP-2 and MMP-9 and the area of cardiac fibrosis in MI rats. In Ang II-stimulated CFs, ...
Source: Journal of Toxicological Sciences - June 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells.
In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downr...
Source: Journal of Toxicological Sciences - June 8, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Oxidative stress mediates renal endothelial cell damage in trichloroethylene-sensitized mice.
In conclusion, trichloroethylene-sensitized mice renal immune injury is associated with the renal endothelial cells' oxidative stress state. PMID: 31068537 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - May 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Possible mechanisms underlying transcriptional induction of metallothionein isoforms by tris(pentafluorophenyl)stibane, tris(pentafluorophenyl)arsane, and tris(pentafluorophenyl)phosphane in cultured bovine aortic endothelial cells.
Authors: Fujie T, Takenaka F, Yoshida E, Yasuike S, Fujiwara Y, Shinkai Y, Kumagai Y, Yamamoto C, Kaji T Abstract Metallothionein (MT) is a low-molecular-weight, cysteine-rich, and metal-binding protein that protects cells from the cytotoxic effects of heavy metals and reactive oxygen species. Previously, we found that transcriptional induction of endothelial MT-1A was mediated by not only the metal-regulatory transcription factor 1 (MTF-1)-metal responsive element (MRE) pathway but also the nuclear factor-erythroid 2-related factor 2 (Nrf2)-antioxidant response element/electrophile responsive element (ARE) pathway...
Source: Journal of Toxicological Sciences - May 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Titanium dioxide nanoparticles induce COX-2 expression through ROS generation in human periodontal ligament cells.
In conclusion, ROS, concomitantly overproduced by TiO2-NPs, induce COX-2 expression through activation of NF-κB signaling, which may contribute to the inflammatory effect of PDL cells. PMID: 31068539 [PubMed - in process] (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - May 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research

Transcriptional profiling of cytochrome P450 genes in the liver of adult zebrafish, Danio rerio.
Authors: Kubota A, Kawai YK, Yamashita N, Lee JS, Kondoh D, Zhang S, Nishi Y, Suzuki K, Kitazawa T, Teraoka H Abstract Increasing use of zebrafish in biomedical, toxicological and developmental studies requires explicit knowledge of cytochrome P450 (CYP), given the central role of CYP in oxidative biotransformation of xenobiotics and many regulatory molecules. A full complement of CYP genes in zebrafish and their transcript expression during early development have already been examined. Here we established a comprehensive picture of CYP gene expression in the adult zebrafish liver using a RNA-seq technique. Transcr...
Source: Journal of Toxicological Sciences - May 10, 2019 Category: Toxicology Tags: J Toxicol Sci Source Type: research