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Archives of Toxicology

Xiaolong Gu, Wiebke Albrecht, Karolina Edlund, Franziska Kappenberg, Jörg Rahnenführer, Marcel Leist, Wolfgang Moritz, Patricio Godoy, Cristina Cadenas, Rosemarie Marchan, Tim Brecklinghaus, Laia Tolosa Pardo, José V Castell, Iain Gardner, Bo Han, Jan G Hengstler, Regina Stoeber
Primary human hepatocytes (PHHs) remain the gold standard for in vitro testing in the field of pharmacology and toxicology. One crucial parameter influencing the results of in vitro tests is the incubation period with test compounds. It has been suggested that longer incubation periods may be critical for the prediction of repeated dose toxicity. However, a study that systematically analyzes the relationship between incubation period and cytotoxicity in PHHs is not available. To close this gap, 30 compounds were tested in a concentration-dependent manner for cytotoxicity in cultivated cryopreserved PHHs (three donors per compound) for 1, 2 and 7 days...
October 13, 2018: Archives of Toxicology
Karin Weisser, Thomas Göen, Jennifer D Oduro, Gaby Wangorsch, Kay-Martin O Hanschmann, Brigitte Keller-Stanislawski
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 levels over time resulting from dietary intake...
October 9, 2018: Archives of Toxicology
Simon Gutbier, Patrick May, Sylvie Berthelot, Abhimanyu Krishna, Timo Trefzer, Mehri Behbehani, Liudmila Efremova, Johannes Delp, Gerhard Gstraunthaler, Tanja Waldmann, Marcel Leist
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-phenylpyridinium (MPP+) were observed...
October 8, 2018: Archives of Toxicology
Nadia Quignot, Witold Wiecek, Billy Amzal, Jean-Lou Dorne
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...
October 8, 2018: Archives of Toxicology
Constanze Knebel, Juliane Kebben, Ivano Eberini, Luca Palazzolo, Helen S Hammer, Roderich D Süssmuth, Tanja Heise, Stefanie Hessel-Pras, Alfonso Lampen, Albert Braeuning, Philip Marx-Stoelting
Consumers are exposed to pesticide residues and other food contaminants via the diet. Both can exert adverse effects on different target organs via the activation of nuclear receptor pathways. Hepatotoxic effects of the widely used triazole fungicide propiconazole (Pi) are generally attributed to the activation of the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR). We now investigated the effects of Pi on the aryl hydrocarbon receptor (AHR) and possible mixture toxicity when Pi is present in combination with BbF, an AHR ligand...
October 6, 2018: Archives of Toxicology
Yvonne C M Staal, Jeroen Meijer, Remco J C van der Kris, Annamaria C de Bruijn, Anke Y Boersma, Eric R Gremmer, Edwin P Zwart, Piet K Beekhof, Wout Slob, Leo T M van der Ven
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 the head skeleton...
October 4, 2018: Archives of Toxicology
Walaa Murad, Tahany Abbass, Abdel-Latif Seddek
No abstract text is available yet for this article.
October 4, 2018: Archives of Toxicology
Giorgia Del Favero, Ronita Zaharescu, Doris Marko
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 cell types, as well as to modify cellular responses to concomitant pro-oxidant challenge (H2 O2 , 100-500 µM, DCF-DA assay) suggesting that even relatively short-time exposure of the intestinal cells could be sufficient to alter their functionality...
October 1, 2018: Archives of Toxicology
Aya M Westbrook, Akos Szakmary, Robert H Schiestl
The original article can be found online.
September 28, 2018: Archives of Toxicology
Yeon Jung Choi, Khong Trong Quan, InWha Park, Seung Jin Lee, Keon Wook Kang, MinKyun Na, Sang Kyum Kim
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 1,2,3,4,5-13 C AA (13 C5 AA) as a substrate to minimize interference by endogenous AA...
September 27, 2018: Archives of Toxicology
Artur Filipe Rodrigues, Leon Newman, Dhifaf A Jasim, Isabella A Vacchi, Cécilia Ménard-Moyon, Livia E Crica, Alberto Bianco, Kostas Kostarelos, Cyrill Bussy
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, < 1 µm) in terms of mesothelial damage and peritoneal inflammation, after intraperitoneal (i...
September 26, 2018: Archives of Toxicology
Rhiannon M David, Nigel J Gooderham
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)...
September 26, 2018: Archives of Toxicology
Ana Margarida Araújo, Maria de Lourdes Bastos, Eduarda Fernandes, Félix Carvalho, Márcia Carvalho, Paula Guedes de Pinho
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a well-known hepatotoxic drug. Although its toxicity has been thoroughly studied at high concentrations, there is still insufficient knowledge on possible alterations of cell function at subtoxic concentrations, which are in fact more representative concentrations of intoxication scenarios. 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...
September 25, 2018: Archives of Toxicology
Min Gi, Masaki Fujioka, Shotaro Yamano, Anna Kakehashi, Yuji Oishi, Takahiro Okuno, Nao Yukimatsu, Takashi Yamaguchi, Yoshiyuki Tago, Mistuaki Kitano, Shim-Mo Hayashi, Hideki Wanibuchi
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...
September 24, 2018: Archives of Toxicology
Jan G Hengstler
No abstract text is available yet for this article.
September 24, 2018: Archives of Toxicology
Hermann M Bolt, Jan G Hengstler
No abstract text is available yet for this article.
September 22, 2018: Archives of Toxicology
Yao Lu, Jiang Ma, Zijing Song, Yang Ye, Peter P Fu, Ge Lin
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 bound to the reactive pyrrolic metabolites forming pyrrole-ATP5B adduct...
September 22, 2018: Archives of Toxicology
Yangshun Tang, Michelle M Vanlandingham, Yuanfeng Wu, Frederick A Beland, Greg R Olson, Jia-Long Fang
Triclosan, a widely used broad spectrum anti-bacterial agent, is hepatotoxic in rodents and exhibits differential effects on mouse and human peroxisome proliferator-activated receptor alpha (PPARα) in vitro; however, the mechanism underlying triclosan-induced liver toxicity has not been elucidated. 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...
September 20, 2018: Archives of Toxicology
Bridget Hindman, Qiang Ma
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...
September 18, 2018: Archives of Toxicology
Ram Kumar Manthari, Chiranjeevi Tikka, Mohammad Mehdi Ommati, Ruiyan Niu, Zilong Sun, Jinming Wang, Jianhai Zhang, Jundong Wang
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]...
September 17, 2018: Archives of Toxicology
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