Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo.
Abstract N-nitroso compounds are alkylating agents, which are widespread in our diet and the environment. They induce DNA alkylation adducts such as O6-methylguanine (O6-MeG), which is repaired by O6-methylguanine-DNA methyltransferase (MGMT). Persistent O6-MeG lesions have detrimental biological consequences like mutagenicity and cytotoxicity. Due to its pivotal role in the etiology of cancer and in cytotoxic cancer therapy, it is important to detect and quantify O6-MeG in biological specimens in a sensitive and accurate manner. Here, we used immunological approaches and established an ultra performance liquid ch...
Source: Archives of Toxicology - November 16, 2018 Category: Toxicology Authors: Kraus A, McKeague M, Seiwert N, Nagel G, Geisen SM, Ziegler N, Trantakis IA, Kaina B, Thomas AD, Sturla SJ, Fahrer J Tags: Arch Toxicol Source Type: research

Highlight report: spheroids from stem cell-derived hepatocyte-like cells.
Abstract PMID: 30446774 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - November 16, 2018 Category: Toxicology Authors: Nell P Tags: Arch Toxicol Source Type: research

Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders.
Abstract Male reproductive development is intricately dependent on fetal androgen action. Consequently, disrupted androgen action during fetal life can interfere with the development of the reproductive system resulting in adverse effects on reproductive function later in life. One biomarker used to evaluate fetal androgen action is the anogenital distance (AGD), the distance between the anus and the external genitalia. A short male AGD is strongly associated with genital malformations at birth and reproductive disorders in adulthood. AGD is therefore used as an effect readout in rodent toxicity studies aimed at t...
Source: Archives of Toxicology - November 14, 2018 Category: Toxicology Authors: Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T Tags: Arch Toxicol Source Type: research

Highlight report: the need of 'fit-for-purpose' controls for cell lines used in toxicity assays.
Abstract PMID: 30430188 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - November 14, 2018 Category: Toxicology Authors: Hassan R, Ghallab A, Seddek AL Tags: Arch Toxicol Source Type: research

Absorption of blue light by cigarette smoke components is highly toxic for retinal pigmented epithelial cells.
Abstract Lesion to the retinal pigment epithelium (RPE) is a crucial event in the development of age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries. Tobacco smoking and high-energy visible blue (HEV; 400-500 nm) light exposure are major environmental risk factors for AMD. Individually, they have been shown to cause damage to the RPE. Tobacco smoke contains toxic polycyclic aromatic hydrocarbons (PAH) that can accumulate in RPE and which absorb HEV light. It can thus be postulated that the interaction between both factors in RPE cells can have a synergic toxic ef...
Source: Archives of Toxicology - November 13, 2018 Category: Toxicology Authors: Zinflou C, Rochette PJ Tags: Arch Toxicol Source Type: research

Long-term and mechanistic evaluation of drug-induced liver injury in Upcyte human hepatocytes.
ón MJ, Donato MT Abstract Drug-induced liver injury (DILI) constitutes one of the most frequent reasons of restricted-use warnings as well as withdrawals of drugs in postmarketing and poses an important concern for the pharmaceutical industry. The current hepatic in vivo and in vitro models for DILI detection have shown clear limitations, mainly for studies of long-term hepatotoxicity. For this reason, we here evaluated the potential of using Upcytes human hepatocytes (UHH) for repeated-dose long-term exposure to drugs. The UHH were incubated with 15 toxic and non-toxic compounds for up to 21 days using a r...
Source: Archives of Toxicology - November 13, 2018 Category: Toxicology Authors: Tolosa L, Jiménez N, Pelechá M, Castell JV, Gómez-Lechón MJ, Donato MT Tags: Arch Toxicol Source Type: research

Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury.
Abstract The transcription factor NRF2, governed by its repressor KEAP1, protects cells against oxidative stress. There is interest in modelling the NRF2 response to improve the prediction of clinical toxicities such as drug-induced liver injury (DILI). However, very little is known about the makeup of the NRF2 transcriptional network and its response to chemical perturbation in primary human hepatocytes (PHH), which are often used as a translational model for investigating DILI. Here, microarray analysis identified 108 transcripts (including several putative novel NRF2-regulated genes) that were both downregulate...
Source: Archives of Toxicology - November 13, 2018 Category: Toxicology Authors: Copple IM, den Hollander W, Callegaro G, Mutter FE, Maggs JL, Schofield AL, Rainbow L, Fang Y, Sutherland JJ, Ellis EC, Ingelman-Sundberg M, Fenwick SW, Goldring CE, van de Water B, Stevens JL, Park BK Tags: Arch Toxicol Source Type: research

Two-photon based imaging reveals mechanisms of tissue damage.
Abstract PMID: 30406371 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - November 7, 2018 Category: Toxicology Authors: Hashem MMM Tags: Arch Toxicol Source Type: research

Calyx junction dismantlement and synaptic uncoupling precede hair cell extrusion in the vestibular sensory epithelium during sub-chronic 3,3'-iminodipropionitrile ototoxicity in the mouse.
Abstract The cellular and molecular events that precede hair cell (HC) loss in the vestibular epithelium during chronic ototoxic exposure have not been widely studied. To select a study model, we compared the effects of sub-chronic exposure to different concentrations of 3,3'-iminodipropionitrile (IDPN) in the drinking water of two strains of mice and of both sexes. In subsequent experiments, male 129S1/SvImJ mice were exposed to 30 mM IDPN for 5 or 8 weeks; animals were euthanized at the end of the exposure or after a washout period of 13 weeks. In behavioral tests, IDPN mice showed progressive vestibular dy...
Source: Archives of Toxicology - October 30, 2018 Category: Toxicology Authors: Greguske EA, Carreres-Pons M, Cutillas B, Boadas-Vaello P, Llorens J Tags: Arch Toxicol Source Type: research

Skin sensitization testing needs and data uses by US regulatory and research agencies.
Abstract United States regulatory and research agencies may rely upon skin sensitization test data to assess the sensitization hazards associated with dermal exposure to chemicals and products. These data are evaluated to ensure that such substances will not cause unreasonable adverse effects to human health when used appropriately. The US Consumer Product Safety Commission, the US Environmental Protection Agency, the US Food and Drug Administration, the Occupational Safety and Health Administration, the National Institute for Occupational Safety and Health, and the US Department of Defense are member agencies of ...
Source: Archives of Toxicology - October 30, 2018 Category: Toxicology Authors: Strickland J, Daniel AB, Allen D, Aguila C, Ahir S, Bancos S, Craig E, Germolec D, Ghosh C, Hudson NL, Jacobs A, Lehmann DM, Matheson J, Reinke EN, Sadrieh N, Vukmanovic S, Kleinstreuer N Tags: Arch Toxicol Source Type: research

sFRP1 has a biphasic effect on doxorubicin-induced cardiotoxicity in a cellular location-dependent manner in NRCMs and Rats.
Abstract Doxorubicin (Dox) is an effective anticancer drug, however, its clinical application is restricted by the life-threatening cardiotoxic effects. Secreted Frizzled-related protein 1 (sFRP1) has been reported to participate in both the cancer and cardiovascular diseases and was one of the differential expression genes in normal hearts compared with Dox-treated hearts. Thus, it is important to reveal the potential role of sFRP1 in Dox-induced cardiotoxicity. Here, we show that sFRP1 has a biphasic effect on Dox-induced cardiotoxicity in a location-dependent manner. The secretion of sFRP1 was significantly inc...
Source: Archives of Toxicology - October 30, 2018 Category: Toxicology Authors: Hu Y, Guo Z, Lu J, Wang P, Sun S, Zhang Y, Li J, Zheng Q, Guo K, Wang J, Jiang J, Liu P Tags: Arch Toxicol Source Type: research

Exposure of pregnant mice to triclosan causes hyperphagic obesity of offspring via the hypermethylation of proopiomelanocortin promoter.
This study demonstrates that TCS exposure during early/mid-gestation through the hypermethylation of the POMC promoter reduces the expression of anorexigenic neuropeptides to cause the postnatal hyperphagic obesity, leading to metabolic syndrome in adulthood. PMID: 30377736 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - October 30, 2018 Category: Toxicology Authors: Hua X, Xiong JW, Zhang YJ, Cao XY, Sun P, Wu J, Chen L Tags: Arch Toxicol Source Type: research

My experiences with the MAK Commission: a response to a recent editorial.
Abstract PMID: 30370461 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - October 29, 2018 Category: Toxicology Authors: Greim H Tags: Arch Toxicol Source Type: research

Acrylamide aggravates cognitive deficits at night period via the gut-brain axis by reprogramming the brain circadian clock.
Abstract Imbalance of the circadian rhythm leads to pathologies including obesity, neurodegenerative diseases, and even cancer. Acrylamide (ACR) is a chronic neurotoxin which can lead to carcinogenicity, reproduction toxicity, teratogenicity, and neurotoxicity. The aim of this study was to reveal a potential mechanism of ACR-triggered neurotoxicity related to circadian clock in mice brain. For this purpose, 80 3-month-old C57/BL6J mice were randomly divided into two groups (n = 40/group): the control group was fed a standard diet (AIN-93M) with pure water, and the ACR group was fed a standard diet (A...
Source: Archives of Toxicology - October 29, 2018 Category: Toxicology Authors: Tan X, Ye J, Liu W, Zhao B, Shi X, Zhang C, Liu Z, Liu X Tags: Arch Toxicol Source Type: research

Correlations between metabolism and structural elements of the alicyclic fentanyl analogs cyclopropyl fentanyl, cyclobutyl fentanyl, cyclopentyl fentanyl, cyclohexyl fentanyl and 2,2,3,3-tetramethylcyclopropyl fentanyl studied by human hepatocytes and LC-QTOF-MS.
In this study, reference standards of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 2,2,3,3-tetramethylcyclopropyl fentanyl (TMCPF) at a final concentration of 5 µM were incubated with cryopreserved human hepatocytes (1 × 106 cells/mL) for 0, 1, 3 and 5 h. The metabolites formed were identified by liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. The most abundant biotransformation found was N-dealkylation (formation of normetabolites) and oxidation of the alicyclic rings. As ring size increased, the significance of N-dealkylation decreased in favor of a...
Source: Archives of Toxicology - October 25, 2018 Category: Toxicology Authors: Åstrand A, Töreskog A, Watanabe S, Kronstrand R, Gréen H, Vikingsson S Tags: Arch Toxicol Source Type: research

Gut microbiome disruption altered the biotransformation and liver toxicity of arsenic in mice.
Abstract The mammalian gut microbiome (GM) plays a critical role in xenobiotic biotransformation and can profoundly affect the toxic effects of xenobiotics. Previous in vitro studies have demonstrated that gut bacteria have the capability to metabolize arsenic (As); however, the specific roles of the gut microbiota in As metabolism in vivo and the toxic effects of As are largely unknown. Here, we administered sodium arsenite to conventionally raised mice (with normal microbiomes) and GM-disrupted mice with antibiotics to investigate the role of the gut microbiota in As biotransformation and its toxicity. We found ...
Source: Archives of Toxicology - October 24, 2018 Category: Toxicology Authors: Chi L, Xue J, Tu P, Lai Y, Ru H, Lu K Tags: Arch Toxicol Source Type: research

A realistic human skin model to study benzo[a]pyrene cutaneous absorption in order to determine the most relevant biomarker for carcinogenic exposure.
tre A Abstract Polycyclic aromatic hydrocarbons (PAH) are ubiquitous pollutants, among which benzo[a]pyrene (B[a]P) is the only compound classified carcinogenic to humans. Besides pulmonary uptake, skin is the major route of PAH absorption during occupational exposure. Health risk due to PAH exposure is commonly assessed among workers using biomonitoring. A realistic human ex vivo skin model was developed to explore B[a]P diffusion and metabolism to determine the most relevant biomarker following dermal exposure. Three realistic doses (0.88, 8.85 and 22.11 nmol/cm2) were topically applied for 8, 24, and 48&nb...
Source: Archives of Toxicology - October 22, 2018 Category: Toxicology Authors: Bourgart E, Barbeau D, Marques M, von Koschembahr A, Béal D, Persoons R, Leccia MT, Douki T, Maitre A Tags: Arch Toxicol Source Type: research

Peroxisome proliferator-activated receptor α attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice.
Peroxisome proliferator-activated receptor α attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice. Arch Toxicol. 2018 Oct 19;: Authors: Lu Y, Harada M, Kamijo Y, Nakajima T, Tanaka N, Sugiyama E, Kyogashima M, Gonzalez FJ, Aoyama T Abstract Peroxisome proliferator-activated receptor α (PPARα) is involved in the regulation of fatty acid and cholesterol metabolism. A high-cholesterol (HC) diet increases the risk of developing cardiovascular diseases (CVD); however, it is unclear whether the toxic effects of cholesterol involve changes in thrombotic facto...
Source: Archives of Toxicology - October 19, 2018 Category: Toxicology Authors: Lu Y, Harada M, Kamijo Y, Nakajima T, Tanaka N, Sugiyama E, Kyogashima M, Gonzalez FJ, Aoyama T Tags: Arch Toxicol Source Type: research

Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells.
asmüller S Abstract Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are consumed in increasing amounts worldwide in cannabis extracts, as they prevent epilepsy, anxiety, and seizures. It was claimed that they may be useful in cancer therapy and have anti-inflammatory properties. Adverse long-term effects of these drugs (induction of cancer and infertility) which are related to damage of the genetic material have not been investigated. Therefore, we studied their DNA-damaging properties in human-derived cell lines under conditions which reflect the exposure of consumers. Both compoun...
Source: Archives of Toxicology - October 19, 2018 Category: Toxicology Authors: Russo C, Ferk F, Mišík M, Ropek N, Nersesyan A, Mejri D, Holzmann K, Lavorgna M, Isidori M, Knasmüller S Tags: Arch Toxicol Source Type: research

Comparative pulmonary toxicity of a DWCNT and MWCNT-7 in rats.
Abstract Very little is known about the in vivo toxicity of inhaled double-walled carbon nanotubes (DWCNTs). In the present study, we compared the pulmonary toxicity of DWCNT to MWCNT-7, a well-known multi-walled carbon nanotube. Rats were divided into six groups: untreated, vehicle, low-dose DWCNT, high-dose DWCNT, low-dose MWCNT-7, and high-dose MWCNT-7. The test materials were administered by intra-tracheal intra-pulmonary spraying (TIPS) every other day for 15 days: the low-dose and high-dose groups were administered final total doses of 0.25 and 0.50 mg/rat of the test material. The animals were sac...
Source: Archives of Toxicology - October 19, 2018 Category: Toxicology Authors: El-Gazzar AM, Abdelgied M, Alexander DB, Alexander WT, Numano T, Iigo M, Naiki A, Takahashi S, Takase H, Hirose A, Kannno J, Elokle OS, Nazem AM, Tsuda H Tags: Arch Toxicol Source Type: research

Novel neurotoxic peptides from Protopalythoa variabilis virtually interact with voltage-gated sodium channel and display anti-epilepsy and neuroprotective activities in zebrafish.
This study indicates that the single S-S bond folded PpVα peptide arises as a new structural template to develop sodium channel blockers and provides an insight on the peptide discovery from cnidarian transcriptome to potentially manage epilepsy and neurodegenerative disorders. PMID: 30334080 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - October 17, 2018 Category: Toxicology Authors: Liao Q, Li S, Siu SWI, Morlighem JRL, Wong CTT, Wang X, Rádis-Baptista G, Lee SM Tags: Arch Toxicol Source Type: research

Comment on Sj ögren et al. (2018) A novel multi-parametric high-content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity in drug discovery. Arch Toxicol 92(10):3175-3190.
Comment on Sjögren et al. (2018) A novel multi-parametric high-content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity in drug discovery. Arch Toxicol 92(10):3175-3190. Arch Toxicol. 2018 Oct 17;: Authors: Zink D Abstract Rapid progress is made in the development of high-content screening assays for the prediction of nephrotoxicity. The findings from different laboratories are consistent with respect to endpoints and concentration ranges screened. Discrepancies regarding compound annotation and the predictive performance analysis are discussed. PMID: 30328497 [PubMed - ...
Source: Archives of Toxicology - October 17, 2018 Category: Toxicology Authors: Zink D Tags: Arch Toxicol Source Type: research

Whole genome sequencing analysis of small and large colony mutants from the mouse lymphoma assay.
Abstract The Thymidine kinase (Tk) gene forward mutation assay, known as the mouse lymphoma assay (MLA), has been widely used for evaluating the genotoxicity of chemical agents. A striking morphological feature of Tk mutant colonies is the bimodal distribution of their sizes, with cells from the large colonies growing at a normal rate and cells from the small colonies growing at a slower rate than normal. To understand the molecular distinction for the different growth rates, we performed whole genome sequencing (WGS) analysis of the large and small colony mutants generated from the MLA. Three large colony and thr...
Source: Archives of Toxicology - October 17, 2018 Category: Toxicology Authors: Guo X, Pan B, Seo JE, Chen Y, Yan J, Mei N, Chen T Tags: Arch Toxicol Source Type: research

Benzene metabolite 1,2,4-benzenetriol changes DNA methylation and histone acetylation of erythroid-specific genes in K562 cells.
Abstract 1,2,4-Benzenetriol (BT) is one of the phenolic metabolites of benzene, a general occupational hazard and ubiquitous environmental air pollutant with leukemogenic potential in humans. Previous studies have revealed that the benzene metabolites phenol and hydroquinone can inhibit hemin-induced erythroid differentiation in K562 cells. We investigated the roles of DNA methylation and histone acetylation in BT-inhibited erythroid differentiation in K562 cells. When K562 cells were treated with 0, 5, 10, 15 or 20 µM BT for 72 h, hemin-induced hemoglobin synthesis decreased in a concentration-dep...
Source: Archives of Toxicology - October 16, 2018 Category: Toxicology Authors: Yu CH, Li Y, Zhao X, Yang SQ, Li L, Cui NX, Rong L, Yi ZC Tags: Arch Toxicol Source Type: research

Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity.
Abstract We previously reported that delayed treatment with Mito-tempo (MT), a mitochondria-targeted superoxide dismutase mimetic, protects against the early phase of acetaminophen (APAP) hepatotoxicity by inhibiting peroxynitrite formation. However, whether this protection is sustained to the late phase of toxicity is unknown. To investigate the late protection, C57Bl/6J mice were treated with 300 mg/kg APAP followed by 20 mg/kg MT 1.5 h or 3 h later. We found that both MT treatments protected against the late phase of APAP hepatotoxicity at 12 and 24 h. Surprisingly, MT-treated mice demo...
Source: Archives of Toxicology - October 15, 2018 Category: Toxicology Authors: Du K, Ramachandran A, Weemhoff JL, Woolbright BL, Jaeschke AH, Chao X, Ding WX, Jaeschke H Tags: Arch Toxicol Source Type: research

A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure.
h A Abstract Despite its worldwide ban, the warfare agent sulfur mustard (SM) still represents a realistic threat, due to potential release in terroristic attacks and asymmetric conflicts. Therefore, the rigorous and quantitative detection of SM exposure is crucial for diagnosis, health risk assessment, and surveillance of international law. Alkylation adducts of nucleic acids can serve as valuable toxicologically relevant 'biomarkers of SM exposure'. Here, we developed a robust and versatile bioanalytical platform based on isotope dilution UPLC-MS/MS to quantify major SM-induced DNA and RNA adducts, as well as ad...
Source: Archives of Toxicology - October 15, 2018 Category: Toxicology Authors: Zubel T, Hochgesand S, John H, Steinritz D, Schmidt A, Bürkle A, Mangerich A Tags: Arch Toxicol Source Type: research

Mechanisms of tissue factor induction by the uremic toxin indole-3 acetic acid through aryl hydrocarbon receptor/nuclear factor-kappa B signaling pathway in human endothelial cells.
In conclusion, TF up-regulation by IAA in human endothelial cells involves a non-genomic AhR/p38 MAPK/NF-κB pathway. The understanding of signal transduction pathways related to AhR thrombotic/inflammatory pathway is of interest to find therapeutic targets to reduce TF expression and thrombotic risk in patients with CKD. PMID: 30324315 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - October 15, 2018 Category: Toxicology Authors: Addi T, Poitevin S, McKay N, El Mecherfi KE, Kheroua O, Jourde-Chiche N, de Macedo A, Gondouin B, Cerini C, Brunet P, Dignat-George F, Burtey S, Dou L Tags: Arch Toxicol Source Type: research

Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes.
In conclusion, the median cytotoxicity of the test compounds increased between 1 and 2 days of incubation, with no or only a minimal further increase until day 7. It remains to be studied whether the different results obtained for some individual compounds after longer exposure periods would correspond better to human-repeated dose toxicity. PMID: 30317417 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - October 13, 2018 Category: Toxicology Authors: Gu X, Albrecht W, Edlund K, Kappenberg F, Rahnenführer J, Leist M, Moritz W, Godoy P, Cadenas C, Marchan R, Brecklinghaus T, Pardo LT, Castell JV, Gardner I, Han B, Hengstler JG, Stoeber R Tags: Arch Toxicol Source Type: research

Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats.
i B Abstract Knowledge of dose linearity, plasma clearance, rate and extent of subcutaneous (SC) and intramuscular (IM) absorption of soluble aluminium (Al) citrate is considered a prerequisite for evaluation of toxicokinetic data obtained from SC or IM administration of Al adjuvants in medicinal products. Therefore, total Al plasma kinetics was investigated after SC, IM, and IV administration of single Al doses (36 and 360 µg/kg IM or SC; 30 and 300 µg/kg IV) given as citrate solution in rats. Control groups receiving vehicle (saline) were run in parallel to monitor background plasma Al leve...
Source: Archives of Toxicology - October 9, 2018 Category: Toxicology Authors: Weisser K, Göen T, Oduro JD, Wangorsch G, Hanschmann KO, Keller-Stanislawski B Tags: Arch Toxicol Source Type: research

The Yin-Yang of CYP3A4: a Bayesian meta-analysis to quantify inhibition and induction of CYP3A4 metabolism in humans and refine uncertainty factors for mixture risk assessment.
Abstract Quantifying differences in pharmacokinetics (PK) and toxicokinetics (TK) provides a science-based approach to refine uncertainty factors (UFs) for chemical risk assessment. Cytochrome P450 (CYP) 3A4-the major hepatic and intestinal human CYP-and the P-glycoprotein (Pgp) transporter share a vast range of common substrates for which PK may be modulated through inhibition or induction in the presence of grapefruit juice (GFJ) or St. John's wort (SJW), respectively. Here, an extensive literature search was performed on PK interactions for CYP3A4 and Pgp substrates after oral co-exposure to GFJ and SJW. Releva...
Source: Archives of Toxicology - October 8, 2018 Category: Toxicology Authors: Quignot N, Wiecek W, Amzal B, Dorne JL Tags: Arch Toxicol Source Type: research

Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift.
Abstract Genomic drift affects the functional properties of cell lines, and the reproducibility of data from in vitro studies. While chromosomal aberrations and mutations in single pivotal genes are well explored, little is known about effects of minor, possibly pleiotropic, genome changes. We addressed this question for the human dopaminergic neuronal precursor cell line LUHMES by comparing two subpopulations (SP) maintained either at the American-Type-Culture-Collection (ATCC) or by the original provider (UKN). Drastic differences in susceptibility towards the specific dopaminergic toxicant 1-methyl-4-phenylpyri...
Source: Archives of Toxicology - October 8, 2018 Category: Toxicology Authors: Gutbier S, May P, Berthelot S, Krishna A, Trefzer T, Behbehani M, Efremova L, Delp J, Gstraunthaler G, Waldmann T, Leist M Tags: Arch Toxicol Source Type: research

Propiconazole is an activator of AHR and causes concentration additive effects with an established AHR ligand.
In conclusion, our results demonstrate that the triazole Pi is an activator of AHR in silico, in vitro and in vivo and causes additive effects with an established AHR ligand. PMID: 30293151 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - October 6, 2018 Category: Toxicology Authors: Knebel C, Kebben J, Eberini I, Palazzolo L, Hammer HS, Süssmuth RD, Heise T, Hessel-Pras S, Lampen A, Braeuning A, Marx-Stoelting P Tags: Arch Toxicol Source Type: research

Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds.
Abstract The EU-EuroMix project adopted the strategy of the European Food Safety Authority (EFSA) for cumulative risk assessment, which limits the number of chemicals to consider in a mixture to those that induce a specific toxicological phenotype. These so-called cumulative assessment groups (CAGs) are refined at several levels, including the target organ and specific phenotype. Here, we explore the zebrafish embryo as a test model for quantitative evaluation in one such CAG, skeletal malformations, through exposure to test compounds 0-120 hpf and alcian blue cartilage staining at 120 hpf, focusing on t...
Source: Archives of Toxicology - October 4, 2018 Category: Toxicology Authors: Staal YCM, Meijer J, van der Kris RJC, de Bruijn AC, Boersma AY, Gremmer ER, Zwart EP, Beekhof PK, Slob W, van der Ven LTM Tags: Arch Toxicol Source Type: research

Hepatic zonation of toxic metabolite formation: perspectives of matrix-assisted laser desorption mass spectrometry imaging.
PMID: 30284600 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - October 4, 2018 Category: Toxicology Authors: Murad W, Abbass T, Seddek AL Tags: Arch Toxicol Source Type: research

Functional impairment triggered by altertoxin II (ATXII) in intestinal cells in vitro: cross-talk between cytotoxicity and mechanotransduction.
Abstract Intestinal cells are able to continuously integrate response to multiple stimuli/stressors; these include the concomitant activation of "chemically driven" pathways, of paramount importance in the response to toxicants, as well as physical stimulation derived from motility. Altertoxin II (ATXII, 0.1, 1 and 10 µM), a mycotoxin produced by the food contaminant fungus Alternaria alternata was studied in HT-29 intestinal adenocarcinoma cells and in non-transformed intestinal epithelial cells, HCEC. One-hour incubation with ATXII was sufficient to trigger irreversible cytotoxicity in both ...
Source: Archives of Toxicology - October 1, 2018 Category: Toxicology Authors: Del Favero G, Zaharescu R, Marko D Tags: Arch Toxicol Source Type: research

Retraction Note to: Mouse models of intestinal inflammation and cancer.
Abstract The original article can be found online. PMID: 30267108 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - September 28, 2018 Category: Toxicology Authors: Westbrook AM, Szakmary A, Schiestl RH Tags: Arch Toxicol Source Type: research

Discovery of rubiarbonone C as a selective inhibitor of cytochrome P450 4F enzymes.
Abstract Cytochrome P450 (CYP) enzymes, particularly CYP4A/4F, are the major ω-hydroxylases of arachidonic acid (AA) that can produce 20-hydroxyeicosatetraenoic acid (20-HETE). Although there are dissimilarities in substrate specificity, tissue distribution, and gene regulation between CYP4A and CYP4F, selective CYP4A or 4F inhibitors are currently unavailable. Therefore, this study was designed to develop CYP4F selective inhibitors using a novel inhibitory assay of 20-HETE formation. The assay was established using pooled human kidney microsomes (HKMs) and human recombinant CYP4 enzymes incubated with 1,2,3...
Source: Archives of Toxicology - September 27, 2018 Category: Toxicology Authors: Choi YJ, Quan KT, Park I, Lee SJ, Kang KW, Na M, Kim SK Tags: Arch Toxicol Source Type: research

Dose-dependent synergistic and antagonistic mutation responses of binary mixtures of the environmental carcinogen benzo[a]pyrene with food-derived carcinogens.
Abstract Cooking food at high temperatures produces genotoxic chemicals and there is concern about their impact on human health. DNA damage caused by individual chemicals has been investigated but few studies have examined the consequences of exposure to mixtures as found in food. The current study examined the mutagenic response to binary mixtures of benzo[a]pyrene (BaP) with glycidamide (GA), BaP with acrylamide (AC), or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with GA at human-relevant concentrations (sub-nM). The metabolically competent human MCL-5 cells were exposed to these chemicals individual...
Source: Archives of Toxicology - September 26, 2018 Category: Toxicology Authors: David RM, Gooderham NJ Tags: Arch Toxicol Source Type: research

Immunological impact of graphene oxide sheets in the abdominal cavity is governed by surface reactivity.
ssy C Abstract Graphene oxide (GO) is an oxidised form of graphene that has attracted commercial interest in multiple applications, including inks, printed electronics and spray coatings, which all raise health concerns due to potential creation of inhalable aerosols. Although a number of studies have discussed the toxicity of GO sheets, the in vivo impact of their lateral dimensions is still not clear. Here, we compared the effects of large GO sheets (l-GO, 1-20 µm) with those of small GO sheets (s-GO,
Source: Archives of Toxicology - September 26, 2018 Category: Toxicology Authors: Rodrigues AF, Newman L, Jasim DA, Vacchi IA, Ménard-Moyon C, Crica LE, Bianco A, Kostarelos K, Bussy C Tags: Arch Toxicol Source Type: research

GC-MS metabolomics reveals disturbed metabolic pathways in primary mouse hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine (MDMA).
In this study, a gas chromatography-mass spectrometry (GC-MS) metabolomics approach was used to investigate the metabolic changes in primary mouse hepatocytes (PMH) exposed to two subtoxic concentrations of MDMA (LC01 and LC10) for 24 h. Metabolomic profiling of both intracellular metabolites and volatile metabolites in the extracellular medium of PMH was performed. Multivariate analysis showed that the metabolic pattern of cells exposed to MDMA discriminates from the controls in a concentration-dependent manner. Exposure to LC10 MDMA induces a significant increase in some intracellular metabolites, including oleic ac...
Source: Archives of Toxicology - September 25, 2018 Category: Toxicology Authors: Araújo AM, Bastos ML, Fernandes E, Carvalho F, Carvalho M, Guedes de Pinho P Tags: Arch Toxicol Source Type: research

The MAK-commission: finding solutions to society's future challenges.
PMID: 30251053 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - September 24, 2018 Category: Toxicology Authors: Hengstler JG Tags: Arch Toxicol Source Type: research

Chronic dietary toxicity and carcinogenicity studies of dammar resin in F344 rats.
Abstract Dammar resin is a natural food additive and flavoring substance present in many foods and drinks. The present study evaluates the chronic toxicity and carcinogenicity of dietary dammar resin in F344 rats. Dietary concentrations in the 52-week chronic toxicity study were 0, 0.03, 0.125, 0.5, or 2%. The major treatment-related deleterious effects were body weight suppression, increased relative liver weight, and low hemoglobin levels in males and females. Foci of cellular alteration in the liver were observed in the male 2% group, but not in any other group. The no-observed-adverse-effect level for chronic ...
Source: Archives of Toxicology - September 24, 2018 Category: Toxicology Authors: Gi M, Fujioka M, Yamano S, Kakehashi A, Oishi Y, Okuno T, Yukimatsu N, Yamaguchi T, Tago Y, Kitano M, Hayashi SM, Wanibuchi H Tags: Arch Toxicol Source Type: research

The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity.
Abstract Pyrrolizidine alkaloids (PAs) are one of the most significant groups of hepatotoxic phytotoxins. It is well-studied that metabolic activation of PAs generates reactive pyrrolic metabolites that rapidly bind to cellular proteins to form pyrrole-protein adducts leading to hepatotoxicity. Pyrrole-protein adducts all contain an identical core pyrrole moiety regardless of structures of the different PAs; however, the proteins forming pyrrole-protein adducts are largely unknown. The present study revealed that ATP synthase subunit beta (ATP5B), a critical subunit of mitochondrial ATP synthase, was a protein bou...
Source: Archives of Toxicology - September 22, 2018 Category: Toxicology Authors: Lu Y, Ma J, Song Z, Ye Y, Fu PP, Lin G Tags: Arch Toxicol Source Type: research

Contemporary trends in toxicological research on arsenic.
PMID: 30244273 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - September 22, 2018 Category: Toxicology Authors: Bolt HM, Hengstler JG Tags: Arch Toxicol Source Type: research

Role of peroxisome proliferator-activated receptor alpha (PPAR α) and PPARα-mediated species differences in triclosan-induced liver toxicity.
This study examined the role of mouse and human PPARα in triclosan-induced liver toxicity by comparing the effects between wild-type and PPARα-humanized mice. Female mice of each genotype received dermal applications of 0, 58, or 125 mg triclosan/kg body weight daily for 13 weeks. Following the treatment, triclosan caused an increase in liver weight and relative liver weight only in wild-type mice. The expression levels of PPARα target genes cytochrome P450 4A and acyl-coenzyme A oxidase 1 were increased in livers of both wild-type and PPARα-humanized mice, indicating that triclosan activa...
Source: Archives of Toxicology - September 20, 2018 Category: Toxicology Authors: Tang Y, M Vanlandingham M, Wu Y, Beland FA, Olson GR, Fang JL Tags: Arch Toxicol Source Type: research

Carbon nanotubes and crystalline silica induce matrix remodeling and contraction by stimulating myofibroblast transformation in a three-dimensional culture of human pulmonary fibroblasts: role of dimension and rigidity.
Abstract Pulmonary fibrosis is a poorly understood pathologic condition. Carbon nanotubes (CNTs) are nanomaterials with potentials for broad applications. CNTs can induce pulmonary fibrosis in animals, a cause for concern for exposed workers and consumers. Given the large number of CNTs available on the market and the seemingly infinite number of ways these particles can be modified in ways that may affect toxicity, in vitro models that can be used to quickly and effectively investigate the relative fibrogenicity of CNTs are much needed. Here we analyzed the fibrogenic potentials of six CNTs of varying physical pr...
Source: Archives of Toxicology - September 18, 2018 Category: Toxicology Authors: Hindman B, Ma Q Tags: Arch Toxicol Source Type: research

3,3'-Dichlorobiphenyl (PCB 11) promotes dendritic arborization in primary rat cortical neurons via a CREB-dependent mechanism.
Abstract PCB 11 (3,3'-dichlorobiphenyl), a contemporary congener produced as a byproduct of current pigment production processes, has recently emerged as a prevalent worldwide pollutant. We recently demonstrated that exposure to PCB 11 increases dendritic arborization in vitro, but the mechanism(s) mediating this effect remain unknown. To address this data gap, primary cortical neuron-glia co-cultures derived from neonatal Sprague-Dawley rats were exposed for 48 h to either vehicle (0.1% DMSO) or PCB 11 at concentrations ranging from 1 fM to 1 nM in the absence or presence of pharmacologic antagonis...
Source: Archives of Toxicology - September 17, 2018 Category: Toxicology Authors: Sethi S, Keil KP, Lein PJ Tags: Arch Toxicol Source Type: research

Fluoride induces apoptosis and autophagy through the IL-17 signaling pathway in mice hepatocytes.
Abstract Previous studies have reported that excessive fluoride exposure induced liver damage. However, the underlying mechanism of fluoride-induced hepatic toxicity is still unclear. Hence, this study was aimed to evaluate the fluoride-induced apoptosis, autophagy, and IL-17 signaling pathway-related genes to explore the possible mechanisms of NaF-induced liver injury in mice. For this, 48 male mice were allotted randomly to four groups, treated with deionized water, 25, 50, 100 mg/L NaF for 150 days continuously. Our results suggested that treatment with NaF decreased the PAS staining-positive area, wi...
Source: Archives of Toxicology - September 17, 2018 Category: Toxicology Authors: Zhao Y, Li Y, Wang J, Manthari RK, Wang J Tags: Arch Toxicol Source Type: research

Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: involvement of blood-brain barrier's tight junction proteins.
Abstract For the past decade, there has been an increased concern about the health risks from arsenic (As) exposure, because of its neurotoxic effects on the developing brain. The exact mechanism underlying As-induced neurotoxicity during sensitive periods of brain development remains unclear, especially the role of blood-brain barrier's (BBB) tight junction (TJ) proteins during As-induced neurotoxicity. Here, we highlight the involvement of TJ proteins in As-induced autophagy in cerebral cortex and hippocampus during developmental periods [postnatal day (PND) 21, 28, 35 and 42]. Here, the administration of arseni...
Source: Archives of Toxicology - September 17, 2018 Category: Toxicology Authors: Manthari RK, Tikka C, Ommati MM, Niu R, Sun Z, Wang J, Zhang J, Wang J Tags: Arch Toxicol Source Type: research

Correction to: Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.
This article is published with the incorrect copyright holder name in the HTML article as "© Springer 2018". The correct copyright line should read "The Author(s) 2018" (as it appears in the article PDF). PMID: 30209590 [PubMed - as supplied by publisher] (Source: Archives of Toxicology)
Source: Archives of Toxicology - September 12, 2018 Category: Toxicology Authors: Oesch F, Fabian E, Landsiedel R Tags: Arch Toxicol Source Type: research