6,976 results match your criteria Archives of Toxicology[Journal]


Highlight report: False positives in genotoxicity testing.

Authors:
Regina Stöber

Arch Toxicol 2018 Jun 20. Epub 2018 Jun 20.

Center for Research Acceleration in Pediatrics (ZFFP), Hufelandstr. 17, 45147, Essen, Germany.

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Correction to: Polymyxin B causes DNA damage in HK-2 cells and mice.

Arch Toxicol 2018 Jun 18. Epub 2018 Jun 18.

Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.

In the original publication of the article, part of Fig. 6 is missing. The missing subpanels, Fig. Read More

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June 2018
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Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

Arch Toxicol 2018 Jun 18. Epub 2018 Jun 18.

Experimental Toxicology and Ecology, GV/TB, Z470, BASF SE, Carl-Bosch-Str. 38, 67056, Ludwigshafen, Germany.

Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. Read More

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June 2018
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Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects.

Authors:
Brian A Baldo

Arch Toxicol 2018 Jun 18. Epub 2018 Jun 18.

Molecular Immunology Unit, Department of Medicine, Kolling Institute of Medical Research, Royal North Shore Hospital of Sydney, University of Sydney, 11 Bent Street, Lindfield, Sydney, NSW, 2070, Australia.

Drugs may cause serotonin toxicity by a number of different mechanisms including inhibition of serotonin uptake and metabolism, increased serotonin synthesis and release, activation of serotonin receptors, and inhibition of cytochrome P450 oxidases. Some drug interactions involving opioids can increase intrasynaptic levels of serotonin, and opioid analgesic drugs are now recognized as being involved in some cases of serotonin toxicity especially if administered in conjunction with other serotonergic medications including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. In March 2016, the FDA issued a Drug Safety Communication concerning the association of the entire class of opioid pain medicines with serotonin toxicity. Read More

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June 2018
2 Reads

Autophagy and acetaminophen-induced hepatotoxicity.

Arch Toxicol 2018 Jun 6. Epub 2018 Jun 6.

Institute of Toxicology, Shandong University, 44 West Wenhua Road, Jinan, 250012, Shandong, People's Republic of China.

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. APAP overdose can induce acute liver injury in humans, which is responsible for approximately 50% of total cases of acute liver failure in the United States and some European countries. Currently, the metabolism of APAP in the body has been extensively investigated; however, the exact mechanisms for APAP hepatotoxicity are not well understood. Read More

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Aged rats are more vulnerable than adolescents to "ecstasy"-induced toxicity.

Arch Toxicol 2018 Jun 4. Epub 2018 Jun 4.

UCIBIO, REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a widespread drug of abuse with known neurotoxic properties. The present study aimed to evaluate the differential toxic effects of MDMA in adolescent and aged Wistar rats, using doses pharmacologically comparable to humans. Adolescent (post-natal day 40) (3 × 5 mg/kg, 2 h apart) and aged (mean 20 months old) (2 × 5 mg/kg, 2 h apart) rats received MDMA intraperitoneally. Read More

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June 2018
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Comparison of iohexol and iodixanol induced nephrotoxicity, mitochondrial damage and mitophagy in a new contrast-induced acute kidney injury rat model.

Arch Toxicol 2018 Jun 2. Epub 2018 Jun 2.

Department of Nephrology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China.

Recent progress in angiography and interventional therapy has revived interest in comparison of nephrotoxicity of low-or iso-osmolar contrast media, but detailed mechanisms and effective treatments of contrast-induced acute kidney injury (CI-AKI) remain elusive. We established a new model of CI-AKI and compared the nephrotoxicity of iohexol and iodixanol with a focus on renal oxidative stress, mitochondrial damage and mitophagy. Our results showed that 48-h dehydration plus furosemide injection before iohexol administration successfully induced CI-AKI in rats. Read More

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June 2018
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Humoral and cellular immune response in Wistar Han RCC rats fed two genetically modified maize MON810 varieties for 90 days (EU 7th Framework Programme project GRACE).

Arch Toxicol 2018 May 31. Epub 2018 May 31.

Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173, Hannover, Germany.

The genetically modified maize event MON810 expresses a Bacillus thuringiensis-derived gene, which encodes the insecticidal protein Cry1Ab to control some lepidopteran insect pests such as the European corn borer. It has been claimed that the immune system may be affected following the oral/intragastric administration of the MON810 maize in various different animal species. In the frame of the EU-funded project GRACE, two 90-day feeding trials, the so-called studies D and E, were performed to analyze the humoral and cellular immune responses of male and female Wistar Han RCC rats fed the MON810 maize. Read More

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Ethanol addictively enhances the in vitro cardiotoxicity of cocaine through oxidative damage, energetic deregulation, and apoptosis.

Arch Toxicol 2018 May 30. Epub 2018 May 30.

UCIBIO/REQUIMTE, Laboratory of Toxicology, Biological Sciences Department, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, Porto, 4050-313, Portugal.

Cocaine (COC) is frequently consumed in polydrug abuse settings, and ethanol (EtOH) is the most prominent co-abused substance. Clinical data and experimental evidence suggest that the co-administration of COC with EtOH can be more cardiotoxic than EtOH or COC alone, but information on the molecular pathways involved is scarce. Since these data are crucial to potentiate the identification of therapeutic targets to treat intoxications, we sought to (i) elucidate the type of interaction that occurs between both substances, and (ii) assess the mechanisms implicated in the cardiotoxic effects elicited by COC combined with EtOH. Read More

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The histone deacetylases HDAC1 and HDAC2 are required for the growth and survival of renal carcinoma cells.

Arch Toxicol 2018 May 29. Epub 2018 May 29.

Department of Toxicology, University Medical Center Mainz, 55131, Mainz, Germany.

Novel therapies are required for the treatment of metastatic renal cell carcinoma (RCC), which is associated with inoperable disease and patient death. Histone deacetylases (HDACs) are epigenetic modifiers and potential drug targets. Additional information on molecular pathways that are altered by histone deacetylase inhibitors (HDACi) in RCC cells is warranted. Read More

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Galunisertib modifies the liver fibrotic composition in the Abcb4Ko mouse model.

Arch Toxicol 2018 May 28. Epub 2018 May 28.

National Institute of Gastroenterology, "S. de Bellis" Research Hospital, Castellana Grotte, Bari, Italy.

Transforming growth factor (TGF)-β stimulates extracellular matrix (ECM) deposition during development of liver fibrosis and cirrhosis, the most important risk factor for the onset of hepatocellular carcinoma. In liver cancer, TGF-β is responsible for a more aggressive and invasive phenotype, orchestrating remodeling of the tumor microenvironment and triggering epithelial-mesenchymal transition of cancer cells. This is the scientific rationale for targeting the TGF-β pathway via a small molecule, galunisertib (intracellular inhibitor of ALK5) in clinical trials to treat liver cancer patients at an advanced disease stage. Read More

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Chronic ingestion of deoxynivalenol at human dietary levels impairs intestinal homeostasis and gut microbiota in mice.

Arch Toxicol 2018 May 26. Epub 2018 May 26.

Univ. Lille, Inserm, CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, 59000, Lille, France.

The mycotoxin deoxynivalenol (DON) is a frequent contaminant of cereals and their by-products in areas with a moderate climate. Produced by Fusarium species, it is one of the most prevalent mycotoxins in cereal crops worldwide, and the most frequently occurring type B trichothecene in Europe. Due to its toxic properties, high stability and prevalence, the presence of DON in the food chain could represent a major public health risk. Read More

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Revisiting the stress paradigm for silica nanoparticles: decoupling of the anti-oxidative defense, pro-inflammatory response and cytotoxicity.

Arch Toxicol 2018 May 24. Epub 2018 May 24.

Karlsruhe Institute of Technology, Campus North, Institute of Toxicology and Genetics, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.

Engineered amorphous silica nanoparticles (nanosilica) are widely used in industry yet can induce adverse effects, which might be classified according to the oxidative stress model. However, the underlying mechanisms as well as the potential interactions of the three postulated different tiers of toxicity-i.e. Read More

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The impact of desorption kinetics from albumin on hepatic extraction efficiency and hepatic clearance: a model study.

Arch Toxicol 2018 May 23. Epub 2018 May 23.

Department of Analytical Environmental Chemistry, Helmholtz Centre for Environmental Research UFZ, Permoserstr. 15, 04318, Leipzig, Germany.

Until now, the question whether slow desorption of compounds from transport proteins like the plasma protein albumin can affect hepatic uptake and thereby hepatic metabolism of these compounds has not yet been answered conclusively. This work now combines recently published experimental desorption rate constants with a liver model to address this question. For doing so, the used liver model differentiates the bound compound in blood, the unbound compound in blood and the compound within the hepatocytes as three well-stirred compartments. Read More

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Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity.

Arch Toxicol 2018 May 22. Epub 2018 May 22.

MedGenesis Therapeutix Inc., Victoria, BC, Canada.

Glial cell line-derived neurotrophic factor (GDNF) has demonstrated neurorestorative and neuroprotective effects in rodent and nonhuman primate models of Parkinson's disease. However, continuous intraputamenal infusion of GDNF (100 µg/day) resulted in multifocal cerebellar Purkinje cell loss in a 6-month toxicity study in rhesus monkeys. It was hypothesized that continuous leakage of GDNF into the cerebrospinal fluid compartment during the infusions led to down-regulation of GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF then mediated the observed cerebellar lesions. Read More

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FRZB1 rs2242070 polymorphisms is associated with brick tea type skeletal fluorosis in Kazakhs, but not in Tibetans, China.

Arch Toxicol 2018 May 21. Epub 2018 May 21.

Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, Heilongjiang, China.

Skeletal fluorosis is a metabolic bone and joint disease caused by excessive accumulation of fluoride in the bones. Compared with Kazakhs, Tibetans are more likely to develop moderate and severe brick tea type skeletal fluorosis, although they have similar fluoride exposure. Single nucleotide polymorphisms (SNPs) in frizzled-related protein (FRZB) have been associated with osteoarthritis, but their association with the risk of skeletal fluorosis has not been reported. Read More

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Computational identification of structural factors affecting the mutagenic potential of aromatic amines: study design and experimental validation.

Arch Toxicol 2018 May 19. Epub 2018 May 19.

Federal Food Safety and Veterinary Office FSVO/BLV, Risk Assessment Division, Schwarzenburgstrasse 155, Berne, 3003, Switzerland.

A grid-based, alignment-independent 3D-SDAR (three-dimensional spectral data-activity relationship) approach based on simulated C and N NMR chemical shifts augmented with through-space interatomic distances was used to model the mutagenicity of 554 primary and 419 secondary aromatic amines. A robust modeling strategy supported by extensive validation including randomized training/hold-out test set pairs, validation sets, "blind" external test sets as well as experimental validation was applied to avoid over-parameterization and build Organization for Economic Cooperation and Development (OECD 2004) compliant models. Based on an experimental validation set of 23 chemicals tested in a two-strain Salmonella typhimurium Ames assay, 3D-SDAR was able to achieve performance comparable to 5-strain (Ames) predictions by Lhasa Limited's Derek and Sarah Nexus for the same set. Read More

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Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data.

Arch Toxicol 2018 May 17. Epub 2018 May 17.

Chemistry Section, Norwegian Veterinary Institute, Oslo, Norway.

Deoxynivalenol (DON) is the most prevalent mycotoxin in cereals worldwide. It can cause adverse health effects in humans and animals, and maximum levels in food and feed have been implemented by food authorities based on risk assessments derived from estimated intake levels. The lack of human toxicokinetic data such as absorption, distribution, and elimination characteristics hinders the direct calculation of DON plasma levels and exposure. Read More

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Association study of genetic variants in estrogen metabolic pathway genes and colorectal cancer risk and survival.

Arch Toxicol 2018 May 16. Epub 2018 May 16.

Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, People's Republic of China.

Although studies have investigated the association of genetic variants and the abnormal expression of estrogen-related genes with colorectal cancer risk, the evidence remains inconsistent. We clarified the relationship of genetic variants in estrogen metabolic pathway genes with colorectal cancer risk and survival. A case-control study was performed to assess the association of single-nucleotide polymorphisms (SNPs) in ten candidate genes with colorectal cancer risk in a Chinese population. Read More

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Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures.

Arch Toxicol 2018 May 14. Epub 2018 May 14.

Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.

Bosentan is well known to induce cholestatic liver toxicity in humans. The present study was set up to characterize the hepatotoxic effects of this drug at the transcriptomic, proteomic, and metabolomic levels. For this purpose, human hepatoma-derived HepaRG cells were exposed to a number of concentrations of bosentan during different periods of time. Read More

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Validity of different biomonitoring parameters for the assessment of occupational exposure to N,N-dimethylformamide (DMF).

Arch Toxicol 2018 May 10. Epub 2018 May 10.

Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Henkestrasse 9-11, 91054, Erlangen, Germany.

This study was performed to assess the relation between occupational exposure to N,N-dimethylformamide after an 8 h work shift in the acrylic fibre industry and its three biological markers N-methylformamide (NMF), N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC), and N-methylcarbamoyl adduct at haemoglobin (MCVal). External DMF exposure of 220 workers was determined during the whole shift. A standardised questionnaire was used to obtain information about the worker's general health status, medical treatment, smoking habits, protective measures, and possible symptoms caused by DMF exposure. Read More

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The polymorphism rs2480258 within CYP2E1 is associated with different rates of acrylamide metabolism in vivo in humans.

Arch Toxicol 2018 Jun 10;92(6):2137-2140. Epub 2018 May 10.

Department of Biology, University of Pisa, via Derna 1, 56126, Pisa, Italy.

In a recent study, we demonstrated that the variant allele of rs2480258 within intron VIII of CYP2E1 is associated with reduced levels of mRNA, protein, and enzyme activity. CYP2E1 is the most important enzyme in the metabolism of acrylamide (AA) by operating its oxidation into glycidamide (GA). AA occurs in food, is neurotoxic and classified as a probable human carcinogen. Read More

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Biological response of an in vitro human 3D lung cell model exposed to brake wear debris varies based on brake pad formulation.

Arch Toxicol 2018 May 10. Epub 2018 May 10.

BioNanomaterials Group, Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, 1700, Fribourg, Switzerland.

Wear particles from automotive friction brake pads of various sizes, morphology, and chemical composition are significant contributors towards particulate matter. Knowledge concerning the potential adverse effects following inhalation exposure to brake wear debris is limited. Our aim was, therefore, to generate brake wear particles released from commercial low-metallic and non-asbestos organic automotive brake pads used in mid-size passenger cars by a full-scale brake dynamometer with an environmental chamber simulating urban driving and to deduce their potential hazard in vitro. Read More

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Levels of selected analytes in the emissions of "heat not burn" tobacco products that are relevant to assess human health risks.

Arch Toxicol 2018 Jun 5;92(6):2145-2149. Epub 2018 May 5.

German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Berlin, Germany.

Consumers of combustible cigarettes are exposed to many different toxicologically relevant substances associated with negative health effects. Newly developed "heat not burn" (HNB) devices are able to contain lower levels of Harmful and Potentially Harmful Constituents (HPHCs) in their emissions compared to tobacco cigarettes. However, to develop toxicological risk assessment strategies, further independent and standardized investigations addressing HPHC reduction need to be done. Read More

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Activation of autophagic flux and the Nrf2/ARE signaling pathway by hydrogen sulfide protects against acrylonitrile-induced neurotoxicity in primary rat astrocytes.

Arch Toxicol 2018 Jun 3;92(6):2093-2108. Epub 2018 May 3.

Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.

Hydrogen sulfide (HS), the third gasotransmitter, has been shown to act as a neuroprotective factor in numerous pathological processes; however, its underlying mechanism(s) of action remain unclear. It is widely accepted that activation of moderate autophagy and the Nrf2/ARE signaling pathway play important roles in the biological self-defense systems. In the present study, we investigated whether exogenous HS protects against the cytotoxicity of acrylonitrile (AN), a neurotoxin, in primary rat astrocytes. Read More

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Using the lentiviral vector system to stably express chicken P-gp and BCRP in MDCK cells for screening the substrates and studying the interplay of both transporters.

Arch Toxicol 2018 Jun 3;92(6):2027-2042. Epub 2018 May 3.

Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, 1# Weigang, Nanjing, 210095, People's Republic of China.

Transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are known to influence the pharmacokinetics and toxicity of substrate drugs. However, no detailed information is as yet available about functional activity and substrate spectra of chicken P-gp and BCRP. In this study, BCRP single and BCRP/P-gp double-transfected MDCK cell lines (named MDCK-chAbcg2 and MDCK-chAbcg2/Abcb1, respectively) were generated using lentiviral vector system to develop reliable systems for screening the substrates for these two transporters and study the interplay between them. Read More

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The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice.

Arch Toxicol 2018 Jun 2;92(6):1953-1967. Epub 2018 May 2.

Evotec (UK) Ltd, Alderley Park, Nether Alderley, Cheshire, SK10 4TG, UK.

The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2. Read More

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Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner.

Arch Toxicol 2018 Jun 2;92(6):1925-1937. Epub 2018 May 2.

Curriculum in Toxicology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Inorganic arsenic (iAs) is an established environmental diabetogen. The link between iAs exposure and diabetes is supported by evidence from adult human cohorts and adult laboratory animals. The contribution of prenatal iAs exposure to the development of diabetes and underlying mechanisms are understudied. Read More

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Corticosteroid-binding globulin, induced in testicular Leydig cells by perfluorooctanoic acid, promotes steroid hormone synthesis.

Arch Toxicol 2018 Jun 2;92(6):2013-2025. Epub 2018 May 2.

Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.

Perfluorooctanoic acid (PFOA) is an abundant perfluoroalkyl substance widely applied in industrial and consumer products. It is a ubiquitous environmental pollutant and suspected endocrine disruptor. Corticosteroid-binding globulin (CBG) is a monomeric glycoprotein that can bind specifically to anti-inflammatory steroids, such as glucocorticoids and progesterone, in circulation. Read More

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June 2018
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Lon in maintaining mitochondrial and endoplasmic reticulum homeostasis.

Arch Toxicol 2018 Jun 2;92(6):1913-1923. Epub 2018 May 2.

Department of Food Quality and Safety, School of Public Health, Zunyi Medical University, University West Road No. 6, Xinpu District, Zunyi, 563000, Guizhou, People's Republic of China.

As a vital member of AAA+ (ATPase associated with diverse cellular activities) protein superfamily, Lon, a homo-hexameric ring-shaped protein complex with a serine-lysine catalytic dyad, is highly conserved throughout almost all prokaryotic and eukaryotic organisms. Lon protease (LONP) plays an important role in maintaining mitoproteostasis through selectively recognizing and degrading oxidatively modified mitoproteins within mitochondrial matrix, such as oxidized aconitase, phosphorylated mitochondrial transcription factor A, etc. Furthermore, the up-regulated LONP increased mitochondrial ROS generation to promote cell survival, cell proliferation, epithelial-mesenchymal transition, and cell migration, which was attributed to the up-regulation of NADH:ubiquinone oxidoreductase core subunit S8 via interaction with chaperone Lon under hypoxic or oxidative stress in tumorigenesis. Read More

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Building predictive in vitro pulmonary toxicity assays using high-throughput imaging and artificial intelligence.

Arch Toxicol 2018 Jun 28;92(6):2055-2075. Epub 2018 Apr 28.

Bioinformatics Institute, Agency for Science, Technology, and Research, 30 Biopolis Street, #07-01 Matrix, Singapore, 138671, Singapore.

Human lungs are susceptible to the toxicity induced by soluble xenobiotics. However, the direct cellular effects of many pulmonotoxic chemicals are not always clear, and thus, a general in vitro assay for testing pulmonotoxicity applicable to a wide variety of chemicals is not currently available. Here, we report a study that uses high-throughput imaging and artificial intelligence to build an in vitro pulmonotoxicity assay by automatically comparing and selecting human lung-cell lines and their associated quantitative phenotypic features most predictive of in vivo pulmonotoxicity. Read More

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June 2018
9 Reads

From basic research to applied veterinary sciences: current status, challenges and perspectives.

Arch Toxicol 2018 Jun 26;92(6):2141-2143. Epub 2018 Apr 26.

Department of Botany, Faculty of Science, South Valley University, Qena, Egypt.

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Highlight report: Mycotoxins as food contaminants in Africa-challenges and perspectives.

Arch Toxicol 2018 Jun 13;92(6):2151-2152. Epub 2018 Apr 13.

Laboratory of Food Analysis, Department of Bio-analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.

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June 2018
1 Read

Human-relevant potency threshold (HRPT) for ERα agonism.

Arch Toxicol 2018 May 9;92(5):1685-1702. Epub 2018 Apr 9.

Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL, USA.

The European Commission has recently proposed draft criteria for the identification of endocrine disrupting chemicals (EDCs) that pose a significant hazard to humans or the environment. Identifying and characterizing toxic hazards based on the manner by which adverse effects are produced rather than on the nature of those adverse effects departs from traditional practice and requires a proper interpretation of the evidence regarding the chemical's ability to produce physiological effect(s) via a specific mode of action (MoA). The ability of any chemical to produce a physiological effect depends on its pharmacokinetics and the potency by which it acts via the various MoAs that can lead to the particular effect. Read More

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May 2018
1 Read

Membrane microdomains regulate NLRP10- and NLRP12-dependent signalling in A549 cells challenged with cigarette smoke extract.

Arch Toxicol 2018 May 6;92(5):1767-1783. Epub 2018 Apr 6.

Laboratory of Pulmonary Immuno-toxicology, Environmental Toxicology Department, Southern University and A&M College, Baton Rouge, LA, 70813, USA.

Chronic obstructive pulmonary disease (COPD) is predicted to become the third leading cause of death and disability worldwide by 2030; with cigarette smoking (active or passive) being one of the chief cause of its occurrence. Cigarette smoke exposure has been found to result in excessive inflammation and tissue injury, which might lead to COPD, although the exact pathophysiology of the disease remains elusive. While previous studies have demonstrated the role of membrane-bound Toll-like receptors (TLRs) in cigarette smoke (CS)-induced inflammation, scant information is available about the role of cytosolic NOD-like receptors (NLRs) in regulating CS-mediated inflammatory responses. Read More

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May 2018
15 Reads

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone.

Arch Toxicol 2018 Jun 3;92(6):1969-1981. Epub 2018 Apr 3.

Division of Biochemical Toxicology, HFT-110, National Center for Toxicological Research (NCTR), Food and Drug Administration (FDA), 3900 NCTR Road, Jefferson, AR, 72079, USA.

Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. Read More

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June 2018
1 Read

EPHX1 rs1051740 T>C (Tyr113His) is strongly associated with acute myeloid leukemia and KMT2A rearrangements in early age.

Arch Toxicol 2018 Jun 31;92(6):2001-2012. Epub 2018 Mar 31.

Pediatric Hematology-Oncology Research Program, Research Center, Instituto Nacional de Câncer (INCA), Rua André Cavalcanti 37, Rio de Janeiro, RJ, Brazil.

Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i-AML risk. Read More

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June 2018
5 Reads

Arsenic-containing hydrocarbons: effects on gene expression, epigenetics, and biotransformation in HepG2 cells.

Arch Toxicol 2018 May 30;92(5):1751-1765. Epub 2018 Mar 30.

Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.

Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Read More

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May 2018
1 Read

Coffee consumption, metabolic syndrome and clinical severity of psoriasis: good or bad stuff?

Arch Toxicol 2018 May 28;92(5):1831-1845. Epub 2018 Mar 28.

Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy.

Despite the wide consumption of coffee, its anti-inflammatory effect on clinical severity of psoriasis is still debatable. The aim of this study was to evaluate the association between the coffee consumption and clinical severity of psoriasis in a sample of patients stratified according to the presence of the metabolic syndrome (MetS) and smoking. This cross-sectional case-control observational study was conducted on 221 treatment-naïve psoriatic patients. Read More

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May 2018
1 Read

Dysregulation of autophagy in rat liver with mitochondrial DNA depletion induced by the nucleoside analogue zidovudine.

Arch Toxicol 2018 Jun 28;92(6):2109-2118. Epub 2018 Mar 28.

Laboratory of Experimental Hepatology and Drug Targeting, Institute of Biomedical Research of Salamanca (IBSAL), CIBERehd, University of Salamanca, 37007, Salamanca, Spain.

The nucleoside reverse transcriptase inhibitor zidovudine (AZT), used in HIV infection treatment, induces mitochondrial DNA (mtDNA) depletion. A cause-effect relationship between mtDNA status alterations and autophagy has been reported. Both events are common in several liver diseases, including hepatocellular carcinoma. Read More

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June 2018
1 Read

Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay.

Arch Toxicol 2018 Jun 29;92(6):2043-2054. Epub 2018 Mar 29.

Department of Dermatology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.

We established a luciferase reporter assay system, the Multi-ImmunoTox Assay (MITA), which can evaluate the effects of chemicals on the promoter activities of four cytokines: IL-2, IFN-γ, IL-1β, and IL-8. We previously reported that MITA correctly reflected the change in mRNA of human whole-blood cells treated with dexamethasone, cyclosporine, FK506, or several other immunosuppressive drugs. In this study, we combined MITA with the IL-8 Luc assay to detect skin sensitization chemicals (OECD 442E) (modified MITA: mMITA) and established a data set of 60 chemicals examined by mMITA. Read More

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June 2018
2 Reads

Loss of Wilms tumor 1 protein is a marker for apoptosis in response to replicative stress in leukemic cells.

Arch Toxicol 2018 Jun 27;92(6):2119-2135. Epub 2018 Mar 27.

Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131, Mainz, Germany.

A remaining expression of the transcription factor Wilms tumor 1 (WT1) after cytotoxic chemotherapy indicates remaining leukemic clones in patients. We determined the regulation and relevance of WT1 in leukemic cells exposed to replicative stress and DNA damage. To induce these conditions, we used the clinically relevant chemotherapeutics hydroxyurea and doxorubicin. Read More

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June 2018
2 Reads

Particulate matter 2.5 damages skin cells by inducing oxidative stress, subcellular organelle dysfunction, and apoptosis.

Arch Toxicol 2018 Jun 26;92(6):2077-2091. Epub 2018 Mar 26.

Jeju National University School of Medicine and Jeju Research Center for Natural Medicine, Jeju, 63243, Republic of Korea.

The skin is the largest organ of the human body and the one mostly exposed to outdoor contaminants. To evaluate the biological mechanisms underlying skin damage caused by fine particulate matter (PM), we analyzed the effects of PM on cultured human keratinocytes and the skin of experimental animals. PM was applied to human HaCaT keratinocytes at 50 µg/mL for 24 h and to mouse skin at 100 µg/mL for 7 days. Read More

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June 2018
1 Read

Atorvastatin decreases steroid production in H295R cells and in major endocrine tissues of male rats.

Arch Toxicol 2018 May 24;92(5):1703-1715. Epub 2018 Mar 24.

Toxicology Laboratory, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Obesity is increasing worldwide, and since obesity is associated with dyslipidemia, the consumption of cholesterol-lowering pharmaceuticals has increased. The aim of this study was therefore to study potential endocrine disrupting effects of one of the world's most frequently prescribed drugs, the cholesterol-lowering drug, atorvastatin (ATO) in vitro using the H295R steroidogenesis assay and in vivo using male Sprague-Dawley rats. We analyzed all major steroids in the mammalian steroidogenesis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Read More

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May 2018
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In vitro prediction of drug-induced cholestatic liver injury: a challenge for the toxicologist.

Authors:
Mathieu Vinken

Arch Toxicol 2018 May 24;92(5):1909-1912. Epub 2018 Mar 24.

Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.

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May 2018
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Polymyxin B causes DNA damage in HK-2 cells and mice.

Arch Toxicol 2018 Mar 20. Epub 2018 Mar 20.

Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.

Increasing incidence of multidrug-resistant bacteria presents an imminent risk to global health. Polymyxins are 'last-resort' antibiotics against Gram-negative 'superbugs'; however, nephrotoxicity remains a key impediment in their clinical use. Molecular mechanisms underlying this nephrotoxicity remain poorly defined. Read More

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March 2018
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Induction of hemangiosarcoma in mice after chronic treatment with S1P-modulator siponimod and its lack of relevance to rat and human.

Arch Toxicol 2018 May 19;92(5):1877-1891. Epub 2018 Mar 19.

Preclinical Safety, Novartis, Basel, Switzerland.

A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were observed in rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) activation was observed in both species, but VEC proliferation and persistent increases in circulating placental growth factor 2 (PLGF2) were only seen in the mouse. In mice, these effects were sustained over the 9-month study duration, while in rats increased mitotic gene expression was present at day 3 only and PLGF2 was induced only during the first week of treatment. Read More

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May 2018
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Respiratory hazard of Li-ion battery components: elective toxicity of lithium cobalt oxide (LiCoO) particles in a mouse bioassay.

Arch Toxicol 2018 May 17;92(5):1673-1684. Epub 2018 Mar 17.

Louvain centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue E. Mounier 52, bte B1.52.12, 1200, Brussels, Belgium.

Rechargeable Li-ion batteries (LIB) are increasingly produced and used worldwide. LIB electrodes are made of micrometric and low solubility particles, consisting of toxicologically relevant elements. The health hazard of these materials is not known. Read More

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May 2018
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Gestational bisphenol S impairs placental endocrine function and the fusogenic trophoblast signaling pathway.

Arch Toxicol 2018 May 17;92(5):1861-1876. Epub 2018 Mar 17.

Department of Animal Science, College of Agriculture and Natural Resources, Michigan State University, 474 S. Shaw Lane, Rm 1230F, East Lansing, MI, 48824, USA.

Exposure to bisphenolic chemicals during pregnancy occurs in > 90% of pregnancies. Bisphenolic compounds can cross the placental barrier reaching fetal circulation. However, the effects of emerging bisphenolic compounds, such as bisphenol S (BPS), on placental function remain untested. Read More

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May 2018
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Adipose tissue stem cell-derived hepatic progenies as an in vitro model for genotoxicity testing.

Arch Toxicol 2018 May 16;92(5):1893-1903. Epub 2018 Mar 16.

Department for Genetic Toxicology and Cancer Biology, National Institute of Biology, Vecna pot 111, Ljubljana, Slovenia.

The problem of the currently used routine genotoxicity tests is relatively low predictivity of in vitro tests for in vivo genotoxicity and carcinogenicity. An important reason is considered to be inadequate expression of xenobiotic-metabolizing enzymes in indicator cell lines. The aim of our study was to generate metabolically active differentiated hepatic progenies (hDHP) from human adipose tissue-derived mesenchymal stem cells (hASC) for genotoxicity testing. Read More

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May 2018
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