Phospholipids modifications in human hepatoma cell lines (HepG2) exposed to silver and iron oxide nanoparticles.
Abstract Metallic nanoparticles such as silver (Ag NPs) and iron oxide (Fe3O4 NPs) nanoparticles are high production volume materials due to their applications in various consumer products, and in nanomedicine. However, their inherent toxicities to human cells remain a challenge. The present study was aimed at combining lipidomics data with common phenotypically-based toxicological assays to gain better understanding into cellular response to Ag NPs and Fe3O4 NPs exposure. HepG2 cells were exposed to different concentrations (3.125, 6.25, 12.5, 25, 50 and 100 µg/ml) of the nanoparticles for 24 h, a...
Source: Archives of Toxicology - May 30, 2020 Category: Toxicology Authors: Adeyemi JA, Sorgi CA, Machado ART, Ogunjimi AT, Gardinassi LGA, Nardini V, Faccioli LH, Antunes LMG, Barbosa F Tags: Arch Toxicol Source Type: research

Human multidrug resistance protein 4 (MRP4) is a cellular efflux transporter for paracetamol glutathione and cysteine conjugates.
In this study we examined whether ATP-binding cassette (ABC) transporters play a role in the cellular efflux of APAP, APAP-GSH, and APAP-CYS. The ABC transport proteins P-gp/ABCB1, BSEP/ABCB11, BCRP/ABCG2, and MRP/ABCC1-5 were overexpressed in HEK293 cells and membrane vesicles were produced. Whereas P-gp, BSEP, MRP3, MRP5, and BCRP did not transport any of the compounds, uptake of APAP-GSH was found for MRP1, MRP2 and MRP4. APAP-CYS appeared to be a substrate of MRP4 and none of the ABC proteins transported APAP. The results suggest that the NAPQI metabolite APAP-CYS can be excreted into plasma by MRP4, where it could be ...
Source: Archives of Toxicology - May 29, 2020 Category: Toxicology Authors: Koenderink JB, van den Heuvel JJMW, Bilos A, Vredenburg G, Vermeulen NPE, Russel FGM Tags: Arch Toxicol Source Type: research

The mycotoxin deoxynivalenol activates GABAergic neurons in the reward system and inhibits feeding and maternal behaviours.
S, Világi I, Dobolyi A Abstract Deoxynivalenol (DON) or vomitoxin, is a trichothecene mycotoxin produced mainly by Fusarium graminearum and culmorum. Mycotoxins or secondary metabolic products of mold fungi are micro-pollutants, which may affect human and animal health. The neuronal and behavioural actions of DON were analysed in the present study. To address, which neurons can be affected by DON, the neuronal activation pattern following intraperitoneal injection of DON (1 mg/kg) was investigated in adult male rats and the results were confirmed in mice, too. DON-induced neuronal activation was assess...
Source: Archives of Toxicology - May 29, 2020 Category: Toxicology Authors: Csikós V, Varró P, Bódi V, Oláh S, Világi I, Dobolyi A Tags: Arch Toxicol Source Type: research

Treatments of a phthalocyanine-based green ink for tattoo removal purposes: generation of toxic fragments and potentially harmful morphologies.
Abstract Since tattoos became overwhelmingly fashionable worldwide, the demand for removal has proportionally increased, Nd:YAG Q-switch laser being the most commonly used tool for the purpose. In this framework we investigated the composition and products of laser treatment of green tattoo ink, the Green Concentrate from Eternal. The ink characterization has been carried out by IR, UV-Vis, EDX spectroscopies, and SEM imaging. It revealed the presence of the pigment PG7, rather than PG36 as reported on the bottle label, along with non-fully halogenated analogues. The morphology is an extended sheath with embedded ...
Source: Archives of Toxicology - May 29, 2020 Category: Toxicology Authors: Bauer EM, Scibetta EV, Cecchetti D, Piccirillo S, Antonaroli S, Sennato S, Cerasa M, Tagliatesta P, Carbone M Tags: Arch Toxicol Source Type: research

Toll of acute methanol poisoning for preventing COVID-19.
PMID: 32462212 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 27, 2020 Category: Toxicology Authors: Mehrpour O, Sadeghi M Tags: Arch Toxicol Source Type: research

Culprit or correlate? An application of the Bradford Hill criteria to Vitamin E acetate.
Abstract Vitamin E acetate (VEA) has come under significant scrutiny due to its association with e-cigarette, or vaping, product use-associated lung injury (EVALI). In 1965, Sir Austin Bradford Hill proposed a set of criteria used to critically assess an association for causality. In this article, we apply the Bradford Hill causation criteria to VEA and the EVALI outbreak to clarify what further areas of study are needed to strengthen the causal argument. Additionally, we highlight the need for systematized approaches to rapidly identify the cause of mass poisoning events of unknown etiology. PMID: 32451600 [...
Source: Archives of Toxicology - May 25, 2020 Category: Toxicology Authors: Feldman R, Meiman J, Stanton M, Gummin DD Tags: Arch Toxicol Source Type: research

Xenobiotica-metabolizing enzyme induction potential of chemicals in animal studies: NanoString nCounter gene expression and peptide group-specific immunoaffinity as accelerated and economical substitutions for enzyme activity determinations?
In this study, changes of XME activity by the known standard XME inducers phenobarbital, beta-naphthoflavone and Aroclor 1254 were demonstrated by these two methods. To investigate the applicability of these methods to demonstrate XME-inducing activity of an unknown, TS was also examined and found to be an XME inducer. More specifically, TS was found to be a phenobarbital-type inducer (likely mediated by CAR rather than PXR as nuclear receptor), but not due to Ah receptor-mediated or antioxidant response element-mediated beta-naphthoflavone-type induction. The results for TS were confirmed via enzymatic activity measuremen...
Source: Archives of Toxicology - May 25, 2020 Category: Toxicology Authors: Riffle B, Oesch F, Heckmanns A, Fabian E, Wang M, Samuga A, Ren P, Hammer H, Schmidt F, Pötz O, van Ravenzwaay B, Landsiedel R Tags: Arch Toxicol Source Type: research

Potentials and pitfalls of transient in vitro reporter bioassays: interference by vector geometry and cytotoxicity in recombinant zebrafish cell lines.
We describe how varying vector geometry and different regulatory gene elements on plasmids used for transfection in zebrafish hepatocytes and embryonic fibroblasts may lead up to a tenfold difference in potency. Cells were transiently co-transfected with an Nrf2-responsive Firefly luciferase reporter plasmid and eight different Renilla luciferase normalization plasmids. Transfected cells were exposed to two different regimes (0.1-100 µM and 7.8-250 µM) of the oxidative stress-inducing compounds, sulforaphane, tertbutylhydroquinone, and metazachlor. Nrf2 activity was measured in dual-luciferase assays. In parall...
Source: Archives of Toxicology - May 23, 2020 Category: Toxicology Authors: Lungu-Mitea S, Lundqvist J Tags: Arch Toxicol Source Type: research

Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines.
Abstract The COVID-19-inducing virus, SARS-CoV2, is likely to remain a threat to human health unless efficient drugs or vaccines become available. Given the extent of the current pandemic (people in over one hundred countries infected) and its disastrous effect on world economy (associated with limitations of human rights), speedy drug discovery is critical. In this situation, past investments into the development of new (animal-free) approach methods (NAM) for drug safety, efficacy, and quality evaluation can be leveraged. For this, we provide an overview of repurposing ideas to shortcut drug development times. A...
Source: Archives of Toxicology - May 23, 2020 Category: Toxicology Authors: Busquet F, Hartung T, Pallocca G, Rovida C, Leist M Tags: Arch Toxicol Source Type: research

Hypersensitivity of bladder low threshold, wide dynamic range, afferent fibres following treatment with the chemotherapeutic drugs cyclophosphamide and ifosfamide.
This study aimed to identify changes in the bladder afferent system following treatment with these drugs that might explain reported urological adverse effects. Intravesical pressure and afferent nerve activity were recorded during bladder distension and drug administration in isolated bladders from mice, 24 h after intraperitoneal treatment with cyclophosphamide (100 mg/kg), ifosphamide (200 mg/kg) or saline (control). In isolated bladders, total afferent nerve activity at maximum bladder distension was increased from 182 ± 13 imp/s in control animals, to 230 ± 14 i...
Source: Archives of Toxicology - May 22, 2020 Category: Toxicology Authors: Mills KA, West EJ, Grundy L, McDermott C, Sellers DJ, Rose'Myer RB, Chess-Williams R Tags: Arch Toxicol Source Type: research

Electronic cigarettes and vaping: toxicological awareness is increasing.
PMID: 32440856 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 21, 2020 Category: Toxicology Authors: Bolt HM Tags: Arch Toxicol Source Type: research

The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) targets the olfactory bulb region.
The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) targets the olfactory bulb region. Arch Toxicol. 2020 May 20;: Authors: Pierozan P, Piras E, Brittebo E, Karlsson O Abstract Olfactory dysfunction is implicated in neurodegenerative disorders and typically manifests years before other symptoms. The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) is suggested as a risk factor for neurodegenerative disease. Detection of BMAA in air filters has increased the concern that aerosolization may lead to human BMAA exposure through the air. The aim of this study was to determine...
Source: Archives of Toxicology - May 20, 2020 Category: Toxicology Authors: Pierozan P, Piras E, Brittebo E, Karlsson O Tags: Arch Toxicol Source Type: research

Biotransformation of arsenic and toxicological implication of arsenic metabolites.
Abstract Arsenic is a well-known environmental carcinogen and chronic exposure to arsenic through drinking water has been reported to cause skin, bladder and lung cancers, with arsenic metabolites being implicated in the pathogenesis. In contrast, arsenic trioxide (As2O3) is an effective therapeutic agent for the treatment of acute promyelocytic leukemia, in which the binding of arsenite (iAsIII) to promyelocytic leukemia (PML) protein is the proposed initial step. These findings on the two-edged sword characteristics of arsenic suggest that after entry into cells, arsenic reaches the nucleus and triggers various ...
Source: Archives of Toxicology - May 20, 2020 Category: Toxicology Authors: Hirano S Tags: Arch Toxicol Source Type: research

Proteomic analysis of liver proteins of mice exposed to 1,2-dichloropropane.
Abstract 1,2-Dichloropropane (1,2-DCP) is recognized as the causative agent for cholangiocarcinoma among offset color proof-printing workers in Japan. The aim of the present study was to characterize the molecular mechanisms of 1,2-DCP-induced hepatotoxic effects by proteomic analysis. We analyzed quantitatively the differential expression of proteins in the mouse liver and investigated the role of P450 in mediating the effects of 1,2-DCP. Male C57BL/6JJcl mice were exposed to 0, 50, 250, or 1250 ppm 1,2-DCP and treated with either 1-aminobenzotriazole (1-ABT), a nonselective P450 inhibitor, or saline, for 8&...
Source: Archives of Toxicology - May 20, 2020 Category: Toxicology Authors: Zhang X, Morikawa K, Mori Y, Zong C, Zhang L, Garner E, Huang C, Wu W, Chang J, Nagashima D, Sakurai T, Ichihara S, Oikawa S, Ichihara G Tags: Arch Toxicol Source Type: research

Constitutive androstane receptor (CAR) mediates dieldrin-induced liver tumorigenesis in mouse.
Abstract Dieldrin has been shown to induce liver tumors selectively in mice. Although the exact mechanism is not fully understood, previous studies from our laboratory and others have shown that dieldrin induced liver tumors in mice through a non-genotoxic mechanism acting on tumor promotion stage. Two studies were performed to examine the role of nuclear receptor activation as a possible mode of action (MOA) for dieldrin-induced mouse liver tumors. In the initial study, male C57BL/6 mice (6- to 8-week old) were treated with dieldrin in diet (10 ppm) for 7, 14, and 28 days. Phenobarbital (PB), beta-napht...
Source: Archives of Toxicology - May 20, 2020 Category: Toxicology Authors: Wang Z, Wu Q, Li X, Klaunig JE Tags: Arch Toxicol Source Type: research

Dermal exposure to the UV filter benzophenone-3 during early pregnancy affects fetal growth and sex ratio of the progeny in mice.
Abstract The aim of this study was to analyze whether dermal exposure to benzophenone 3 (BP-3) during pregnancy affects critical parameters of pregnancy, and whether this exposure may affect the outcome of a second pregnancy in mice. Pregnant mice were exposed to 50-mg BP-3/kg body weight/day or olive oil (vehicle) from gestation day (gd) 0 to gd6 by dermal exposure. High-frequency ultrasound imaging was used to follow up fetal and placental growth in vivo. Blood flow parameters in uterine and umbilical arteries were analyzed by Doppler measurements. Mice were killed at gd5, gd10, and gd14 on the first pregnancy, ...
Source: Archives of Toxicology - May 19, 2020 Category: Toxicology Authors: Santamaria CG, Meyer N, Schumacher A, Zenclussen ML, Teglia CM, Culzoni MJ, Zenclussen AC, Rodriguez HA Tags: Arch Toxicol Source Type: research

Quantitative adverse outcome pathway (qAOP) models for toxicity prediction.
Abstract The quantitative adverse outcome pathway (qAOP) concept is gaining interest due to its potential regulatory applications in chemical risk assessment. Even though an increasing number of qAOP models are being proposed as computational predictive tools, there is no framework to guide their development and assessment. As such, the objectives of this review were to: (i) analyse the definitions of qAOPs published in the scientific literature, (ii) define a set of common features of existing qAOP models derived from the published definitions, and (iii) identify and assess the existing published qAOP models and ...
Source: Archives of Toxicology - May 18, 2020 Category: Toxicology Authors: Spinu N, Cronin MTD, Enoch SJ, Madden JC, Worth AP Tags: Arch Toxicol Source Type: research

Hepatotoxic pyrrolizidine alkaloids induce DNA damage response in rat liver in a 28-day feeding study.
In conclusion, 1,2-unsaturated hepatotoxic PA induced cell cycle regulation processes associated with DNA damage response. Similar effects were observed for all hepatotoxic PA. Effects were observed in a dose range inducing no histopathological alterations and no increase in liver enzymes. Therefore, transcriptomics studies identified changes in expression of genes known to be involved in response to genotoxic compounds at PA doses relevant to humans under worst case exposure scenarios. PMID: 32419051 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 17, 2020 Category: Toxicology Authors: Ebmeyer J, Rasinger JD, Hengstler JG, Schaudien D, Creutzenberg O, Lampen A, Braeuning A, Hessel-Pras S Tags: Arch Toxicol Source Type: research

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors.
Abstract UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposur...
Source: Archives of Toxicology - May 15, 2020 Category: Toxicology Authors: Kasteel EEJ, Darney K, Kramer NI, Dorne JLCM, Lautz LS Tags: Arch Toxicol Source Type: research

E-vapor aerosols do not compromise bone integrity relative to cigarette smoke after 6-month inhalation in an ApoE-/- mouse model.
In conclusion, because of the bone-preserving effect of e-vapor aerosols relative to CS exposure, e-vapor products could potentially constitute less harmful alternatives to cigarettes in situations in which bone health is of importance. PMID: 32409933 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 14, 2020 Category: Toxicology Authors: Reumann MK, Schaefer J, Titz B, Aspera-Werz RH, Wong ET, Szostak J, Häussling V, Ehnert S, Leroy P, Tan WT, Kuczaj A, Audretsch C, Springer F, Badke A, Augat P, Quentanilla-Fend L, Martella M, Lee KM, Peitsch MC, Hoeng J, Nussler AK Tags: Arch Toxicol Source Type: research

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast.
Abstract Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key ev...
Source: Archives of Toxicology - May 13, 2020 Category: Toxicology Authors: Helm JS, Rudel RA Tags: Arch Toxicol Source Type: research

Recent aspects of the effects of zinc on human health.
Abstract Zinc (Zn) is one of the most important essential nutrients of great public health significance. It is involved in numerous biological functions and it is considered as a multipurpose trace element, due to its capacity to bind to more than 300 enzymes and more than 2000 transcriptional factors. Its role in biochemical pathways and cellular functions, such as the response to oxidative stress, homeostasis, immune responses, DNA replication, DNA damage repair, cell cycle progression, apoptosis and aging is significant. Zn is required for the synthesis of protein and collagen, thus contributing to wound healin...
Source: Archives of Toxicology - May 12, 2020 Category: Toxicology Authors: Chasapis CT, Ntoupa PA, Spiliopoulou CA, Stefanidou ME Tags: Arch Toxicol Source Type: research

In vitro study of carbon black nanoparticles on human pulmonary artery endothelial cells: effects on calcium signaling and mitochondrial alterations.
This study provides evidence that FW2 NPs exposure impairs calcium signaling and mitochondria triggered by oxidative stress, and, thus, could act as a cardiovascular disease risk owing to the key role of calcium homeostasis in the control of vascular tone. PMID: 32394085 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 11, 2020 Category: Toxicology Authors: Deweirdt J, Quignard JF, Lacomme S, Gontier E, Mornet S, Savineau JP, Marthan R, Guibert C, Baudrimont I Tags: Arch Toxicol Source Type: research

Arsenic intoxication: general aspects and chelating agents.
ana M Abstract Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator-metal complexes with their further excretion from the bo...
Source: Archives of Toxicology - May 9, 2020 Category: Toxicology Authors: Bjørklund G, Oliinyk P, Lysiuk R, Rahaman MS, Antonyak H, Lozynska I, Lenchyk L, Peana M Tags: Arch Toxicol Source Type: research

Functional characterization of a low-frequency V1937I variant in FASN associated with susceptibility to esophageal squamous cell carcinoma.
In conclusion, our results suggested that the FASN V1937I variant influenced ESCC cell proliferation and susceptibility by altering the catabolic activity of FASN on palmitate. These findings may highlight an important role of palmitate metabolism in the development of ESCC and may contribute to the personalized medicine of this disease. PMID: 32388819 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 9, 2020 Category: Toxicology Authors: Wang X, Tian J, Zhao Q, Yang N, Ying P, Peng X, Zou D, Zhu Y, Zhong R, Gao Y, Chang J, Miao X Tags: Arch Toxicol Source Type: research

Identification of compound causing yellow bone discoloration following alpha-glycosyl isoquercitrin exposure in Sprague-Dawley rats.
Abstract Previous rat toxicity studies of alpha-glycosyl isoquercitrin (AGIQ), a water-soluble flavonol glycoside derived from rutin, revealed systemic yellow bone discoloration. This investigative study was conducted to determine the AGIQ metabolite(s) responsible for the discoloration. Female Sprague-Dawley rats were administered dietary AGIQ at doses of 0%, 1.5%, 3.0%, or 5.0% (0, 1735.0, 3480.8, and 5873.7 mg/kg/day, respectively) for 14 days, followed by a 14- or 28-day recovery period. Measurements of quercetin in urine and quercetin, quercetin 3-O-glucuronide, kaempferol, and 3-o-methylquercetin m...
Source: Archives of Toxicology - May 9, 2020 Category: Toxicology Authors: Davis JP, Koyanagi M, Maronpot RR, Recio L, Hayashi SM Tags: Arch Toxicol Source Type: research

Critical evaluation of human health risks due to hydraulic fracturing in natural gas and petroleum production.
In conclusion, (1) strong evidence supports the conclusion that frac fluids can lead to local environmental contamination; (2) while changes in the chemical composition of soil, water and air are likely to occur, the increased levels are still often below threshold values for safety; (3) point source pollution due to poor maintenance of wells and pipelines can be monitored and remedied; (4) risk assessment should be based on both hazard and exposure evaluation; (5) while the concentrations of frac fluid chemicals are low, some are known carcinogens; therefore, thorough, well-designed studies are needed to assess the risk t...
Source: Archives of Toxicology - May 9, 2020 Category: Toxicology Authors: Wollin KM, Damm G, Foth H, Freyberger A, Gebel T, Mangerich A, Gundert-Remy U, Partosch F, Röhl C, Schupp T, Hengstler JG Tags: Arch Toxicol Source Type: research

Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses.
In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe. PMID: 32382957 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 8, 2020 Category: Toxicology Authors: Guth S, Hüser S, Roth A, Degen G, Diel P, Edlund K, Eisenbrand G, Engel KH, Epe B, Grune T, Heinz V, Henle T, Humpf HU, Jäger H, Joost HG, Kulling SE, Lampen A, Mally A, Marchan R, Marko D, Mühle E, Nitsche MA, Röhrdanz E, Stadler R, van Thriel C, Vie Tags: Arch Toxicol Source Type: research

The rapid development of computational toxicology.
PMID: 32382955 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 7, 2020 Category: Toxicology Authors: Bolt HM, Hengstler JG Tags: Arch Toxicol Source Type: research

Adverse outcome pathways induced by 3,4-dimethylmethcathinone and 4-methylmethcathinone in differentiated human SH-SY5Y neuronal cells.
In conclusion, the mitochondrial impairment and oxidative stress observed for the tested cathinones may be key factors for their neurotoxicity, but different outcome pathways seem to be involved in the adverse effects, when compared to METH. PMID: 32382956 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 7, 2020 Category: Toxicology Authors: Soares J, Costa VM, Gaspar H, Santos S, Bastos ML, Carvalho F, Capela JP Tags: Arch Toxicol Source Type: research

MTH1 is involved in the toxic and carcinogenic long-term effects induced by zinc oxide and cobalt nanoparticles.
This study is the first to give a mechanistic explanation for long-term NPs exposure-derived effects. We propose MTH1 as a candidate biomarker to unravel NPs potential genotoxic and carcinogenic effects, as its expression is expected to be elevated only under exposure conditions able to induce DNA damage and the acquisition of an oncogenic phenotype. PMID: 32377776 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - May 6, 2020 Category: Toxicology Authors: Barguilla I, Barszczewska G, Annangi B, Domenech J, Velázquez A, Marcos R, Hernández A Tags: Arch Toxicol Source Type: research

The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development.
Abstract Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human h...
Source: Archives of Toxicology - May 6, 2020 Category: Toxicology Authors: Walker PA, Ryder S, Lavado A, Dilworth C, Riley RJ Tags: Arch Toxicol Source Type: research

Long-term simulation of lead concentrations in agricultural soils in relation to human adverse health effects.
KM Abstract Lead (Pb) exposure of consumers and the environment has been reduced over the past decades. Despite all measures taken, immission of Pb onto agricultural soils still occurs, with fertilizer application, lead shot from hunting activities, and Pb from air deposition representing major sources. Little is known about the intermediate and long-term consequences of these emissions. To gain more insight, we established a mathematical model that considers input from fertilizer, ammunition, deposition from air, uptake of Pb by crops, and wash-out to simulate the resulting Pb concentrations in soil over extende...
Source: Archives of Toxicology - May 5, 2020 Category: Toxicology Authors: Schupp T, Damm G, Foth H, Freyberger A, Gebel T, Gundert-Remy U, Hengstler JG, Mangerich A, Partosch F, Röhl C, Wollin KM Tags: Arch Toxicol Source Type: research

An adverse outcome pathway for immune-mediated and allergic hepatitis: a case study with the NSAID diclofenac.
We report AOPs specific for immune-mediated and drug hypersensitivity/allergic hepatitis by considering genomic, histo- and clinical pathology data of mice and dogs treated with diclofenac. The findings are relevant for other NSAIDs and drugs undergoing iminoquinone and quinone reactive metabolite formation. We define reactive metabolites catalyzed by CYP monooxygenase and myeloperoxidases of neutrophils and Kupffer cells as well as acyl glucuronides produced by uridine diphosphoglucuronosyl transferase as molecular initiating events (MIE). The reactive metabolites bind to proteins and act as neo-antigen and involve antige...
Source: Archives of Toxicology - May 5, 2020 Category: Toxicology Authors: Selvaraj S, Oh JH, Borlak J Tags: Arch Toxicol Source Type: research

The role of hepatic cytochrome P450s in the cytotoxicity of sertraline.
In this study, we reported that after a 24-h treatment in HepG2 cells, sertraline caused cytotoxicity, suppressed topoisomerase I and IIα, and damaged DNA in a concentration-dependent manner. We also investigated the role of cytochrome P450 (CYP)-mediated metabolism in sertraline-induced toxicity using our previously established HepG2 cell lines individually expressing 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP2D6, 2C19, 2B6, and 2C9 metabolize sertraline, and sertraline-induced cytotoxicity was significantly decreased in the cells expressing these C...
Source: Archives of Toxicology - May 5, 2020 Category: Toxicology Authors: Chen S, Wu Q, Li X, Li D, Fan M, Ren Z, Bryant M, Mei N, Ning B, Guo L Tags: Arch Toxicol Source Type: research

Electronic cigarette vapour moderately stimulates pro-inflammatory signalling pathways and interleukin-6 production by human monocyte-derived dendritic cells.
Abstract Dendritic cells (DCs) are professional antigen presenting cells that play a critical role in bridging innate and adaptive immunity. Numerous studies have shown that tobacco constituents present in conventional cigarettes affect the phenotype and function of DCs; however, no studies have examined the effects of vapour from E-cigarettes on human DCs. Here, the effects of E-cigarette vapour extract (ECVE) on the phenotype and function of DCs were investigated by creating an in vitro cell culture model using human monocyte-derived DCs (MoDCs). Immature DCs were generated from peripheral blood monocytes a...
Source: Archives of Toxicology - May 5, 2020 Category: Toxicology Authors: Chen IL, Todd I, Tighe PJ, Fairclough LC Tags: Arch Toxicol Source Type: research

Evaluation of toxicity of aerosols from flavored e-liquids in Sprague-Dawley rats in a 90-day OECD inhalation study, complemented by transcriptomics analysis.
Abstract The use of flavoring substances is an important element in the development of reduced-risk products for adult smokers to increase product acceptance and encourage switching from cigarettes. In a first step towards characterizing the sub-chronic inhalation toxicity of neat flavoring substances, a study was conducted using a mixture of the substances in a base solution of e-liquid, where the standard toxicological endpoints of the nebulized aerosols were supplemented with transcriptomics analysis. The flavor mixture was produced by grouping 178 flavors into 26 distinct chemical groups based on structural si...
Source: Archives of Toxicology - May 5, 2020 Category: Toxicology Authors: Ho J, Sciuscio D, Kogel U, Titz B, Leroy P, Vuillaume G, Talikka M, Martin E, Pospisil P, Lebrun S, Xia W, Lee T, Chng YX, Phillips BW, Veljkovic E, Guedj E, Xiang Y, Ivanov NV, Peitsch MC, Hoeng J, Vanscheeuwijck P Tags: Arch Toxicol Source Type: research

Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone.
Abstract Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evalu...
Source: Archives of Toxicology - May 4, 2020 Category: Toxicology Authors: Shi M, Bouwmeester H, Rietjens IMCM, Strikwold M Tags: Arch Toxicol Source Type: research

Ex vivo/in vitro protective effect of myricetin bulk and nano-forms on PhIP-induced DNA damage in lymphocytes from healthy individuals and pre-cancerous MGUS patients.
This study investigates the protective potential of a well-researched flavonoid, myricetin in its bulk and nano-forms against oxidative stress induced ex vivo/in vitro by PhIP in lymphocytes from pre-cancerous monoclonal gammopathy of undetermined significance (MGUS) patients and those from healthy individuals. The results from the Comet assay revealed that in the presence of myricetin bulk (10 µM) and myricetin nano (20 µM), the DNA damage caused by a high dose of PhIP (100 µM) was significantly (P 
Source: Archives of Toxicology - April 27, 2020 Category: Toxicology Authors: Akhtar S, Najafzadeh M, Isreb M, Newton L, Gopalan RC, Anderson D Tags: Arch Toxicol Source Type: research

Correction to: Lack of adverse effects in subchronic and chronic toxicity/carcinogenicity studies on the glyphosate-resistant genetically modified maize NK603 in Wistar Han RCC rats.
akácsová M, Mikušová ML, Krivošíková Z, Spök A, Racovita M, de Vriend H, Alison R, Alison C, Baumgärtner W, Becker K, Lempp C, Schmicke M, Schrenk D, Pöting A, Schiemann J, Wilhelm R Abstract In the original publication, the starting point in time for the three feeding trials. PMID: 32328701 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - April 24, 2020 Category: Toxicology Authors: Steinberg P, van der Voet H, Goedhart PW, Kleter G, Kok EJ, Pla M, Nadal A, Zeljenková D, Aláčová R, Babincová J, Rollerová E, Jaďuďová S, Kebis A, Szabova E, Tulinská J, Líšková A, Takácsová M, Mikušová ML, Krivošíková Z, Spök A, Rac Tags: Arch Toxicol Source Type: research

Neurofilament light chain: a specific serum biomarker of axonal damage severity in rat models of Chemotherapy-Induced Peripheral Neurotoxicity.
Abstract Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a severe and long-lasting side effect of anticancer therapy, which can severely impair patients' quality of life. It is a sensory and length-dependent neuropathy, which predominantly affects large myelinated fibers. Easy and reliable monitoring of CIPN in patients is still an unmet clinical need. Since increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of axonal injury, in this study we measured serum NfL levels in animals chronically treated with cisplatin (CDDP) and paclitaxel (PTX), two antine...
Source: Archives of Toxicology - April 24, 2020 Category: Toxicology Authors: Meregalli C, Fumagalli G, Alberti P, Canta A, Chiorazzi A, Monza L, Pozzi E, Carozzi VA, Blennow K, Zetterberg H, Cavaletti G, Marmiroli P Tags: Arch Toxicol Source Type: research

Effect of estrogen-active compounds on the expression of RACK1 and immunological implications.
Abstract We previously demonstrated the existence of a balance among steroid hormones, i.e. glucocorticoids and androgens, in RACK1 (receptor for activated C kinase 1) expression and innate immunity activation, which may offer the opportunity to use RACK1 expression as marker to evaluate immunotoxicity of hormone-active substances. Because of the existence of close interconnections between the different steroid hormone receptors with overlapping ligand specificities and signaling pathways, in this study, we wanted to investigate a possible effect of estrogenic active compounds, namely 17β-estradiol, diethylst...
Source: Archives of Toxicology - April 23, 2020 Category: Toxicology Authors: Buoso E, Masi M, Galbiati V, Maddalon A, Iulini M, Kenda M, Sollner Dolenc M, Marinovich M, Racchi M, Corsini E Tags: Arch Toxicol Source Type: research

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study.
Abstract Emerging mycotoxins produced by Alternaria spp. were previously reported to exert cytotoxic, genotoxic, but also estrogenic effects in human cells. The involved mechanisms are very complex and not fully elucidated yet. Thus, we followed an in silico target fishing approach to extend knowledge on the possible biological targets underlying the activity of alternariol, taken as the signature compound of Alternaria toxins. Combining ligand-based screening and structure-based modeling, the ubiquitous casein kinase 2 (CK2) was identified as a potential target for the compound. This result was validated in a cel...
Source: Archives of Toxicology - April 23, 2020 Category: Toxicology Authors: Aichinger G, Dellafiora L, Pantazi F, Del Favero G, Galaverna G, Dall'Asta C, Marko D Tags: Arch Toxicol Source Type: research

Performance of high-throughput CometChip assay using primary human hepatocytes: a comparison of DNA damage responses with in vitro human hepatoma cell lines.
Abstract Primary human hepatocytes (PHHs) are considered the "gold standard" for evaluating hepatic metabolism and toxicity of xenobiotics. In the present study, we evaluated the genotoxic potential of four indirect-acting (requiring metabolic activation) and six direct-acting genotoxic carcinogens, one aneugen, and five non-carcinogens that are negative or equivocal for genotoxicity in vivo in cryopreserved PHHs derived from three individual donors. DNA damage was determined over a wide range of concentrations using the CometChip technology and the resulting dose-responses were quantified using benchmar...
Source: Archives of Toxicology - April 22, 2020 Category: Toxicology Authors: Seo JE, Wu Q, Bryant M, Ren L, Shi Q, Robison TW, Mei N, Manjanatha MG, Guo X Tags: Arch Toxicol Source Type: research

Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.
Abstract Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay...
Source: Archives of Toxicology - April 21, 2020 Category: Toxicology Authors: Hsueh YM, Lin YC, Chung CJ, Huang YL, Hsieh RL, Huang PT, Wu MY, Shiue HS, Chien SN, Lee CY, Lin MI, Mu SC, Su CT Tags: Arch Toxicol Source Type: research

Toxicometabolomics of the new psychoactive substances α-PBP and α-PEP studied in HepaRG cell incubates by means of untargeted metabolomics revealed unexpected amino acid adducts.
Toxicometabolomics of the new psychoactive substances α-PBP and α-PEP studied in HepaRG cell incubates by means of untargeted metabolomics revealed unexpected amino acid adducts. Arch Toxicol. 2020 Apr 20;: Authors: Manier SK, Wagmann L, Flockerzi V, Meyer MR Abstract Toxicometabolomics, essentially applying metabolomics to toxicology of endogenous compounds such as drugs of abuse or new psychoactive substances (NPS), can be investigated by using different in vitro models and dedicated metabolomics techniques to enhance the number of relevant findings. The present study aimed to study the ...
Source: Archives of Toxicology - April 20, 2020 Category: Toxicology Authors: Manier SK, Wagmann L, Flockerzi V, Meyer MR Tags: Arch Toxicol Source Type: research

A novel 3D intestine barrier model to study the immune response upon exposure to microplastics.
Abstract The plausibility of human exposure to microplastics has increased within the last years. Microplastics have been found in different food types including seafood, salt, sugar and beverages. So far, human health effects of microplastics after ingestion are unknown. Herein, we designed a novel, three-dimensional in vitro intestinal model consisting of the human intestinal epithelial cell lines Caco-2 and HT29-MTX-E12 as well as human blood monocyte-derived macrophages and dendritic cells that is suitable to assess the possible effects of ingested microplastics. Relevant microplastic particles (in the order o...
Source: Archives of Toxicology - April 19, 2020 Category: Toxicology Authors: Lehner R, Wohlleben W, Septiadi D, Landsiedel R, Petri-Fink A, Rothen-Rutishauser B Tags: Arch Toxicol Source Type: research

The chemical convulsant diisopropylfluorophosphate (DFP) causes persistent neuropathology in adult male rats independent of seizure activity.
in PJ Abstract Organophosphate (OP) threat agents can trigger seizures that progress to status epilepticus, resulting in persistent neuropathology and cognitive deficits in humans and preclinical models. However, it remains unclear whether patients who do not show overt seizure behavior develop neurological consequences. Therefore, this study compared two subpopulations of rats with a low versus high seizure response to diisopropylfluorophosphate (DFP) to evaluate whether acute OP intoxication causes persistent neuropathology in non-seizing individuals. Adult male Sprague Dawley rats administered DFP (4 mg/kg...
Source: Archives of Toxicology - April 18, 2020 Category: Toxicology Authors: González EA, Rindy AC, Guignet MA, Calsbeek JJ, Bruun DA, Dhir A, Andrew P, Saito N, Rowland DJ, Harvey DJ, Rogawski MA, Lein PJ Tags: Arch Toxicol Source Type: research

"Don't Blast": blast-in-place (BiP) operations of dumped World War munitions in the oceans significantly increase hazards to the environment and the human seafood consumer.
"Don't Blast": blast-in-place (BiP) operations of dumped World War munitions in the oceans significantly increase hazards to the environment and the human seafood consumer. Arch Toxicol. 2020 Apr 18;: Authors: Maser E, Strehse JS Abstract The seas worldwide are threatened by a "new" source of pollution: millions of tons of all kind of warfare material have been dumped intentionally after World War I and II, in addition to mine barriers, failed detonations as well as shot down military planes and sunken ship wrecks carrying munitions. For example, in the German parts of the Nor...
Source: Archives of Toxicology - April 18, 2020 Category: Toxicology Authors: Maser E, Strehse JS Tags: Arch Toxicol Source Type: research

Electronic cigarette and vaping should be discouraged during the new coronavirus SARS-CoV-2 pandemic.
PMID: 32303807 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - April 18, 2020 Category: Toxicology Authors: Javelle E Tags: Arch Toxicol Source Type: research