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    1 OF 139

    The German REACH Congress 2016: a workshop report.
    Arch Toxicol 2018 Feb 17. Epub 2018 Feb 17.
    Department Chemicals and Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn Strasse 8-10, 10589, Berlin, Germany.
    In October 2016, the German REACH Congress was held at the German Federal Institute for Risk Assessment (BfR) in Berlin. Here, the associated improvement made in the fields of consumer protection and the progress in and experiences gained from the implementation of the authorisation procedure were discussed. Several speakers from EU institutions, German authorities, industry, and civil society organisations were invited to present their views. Read More

    Tissue distribution of gold and silver after subacute intravenous injection of co-administered gold and silver nanoparticles of similar sizes.
    Arch Toxicol 2018 Feb 15. Epub 2018 Feb 15.
    HCTm CO., LTD, 74 Seoicheon-ro 578 beon-gil, Majang-myeon, Icheon, Republic of Korea.
    Gold (AuNPs, 12.8 nm) and silver nanoparticles (AgNPs, 10 nm), mixed or separate, were injected into the caudal vein of male Sprague-Dawley rats for 4 weeks. The rats were allowed to recover for further 4 weeks to examine the differences in AuNP/AgNP tissue distribution and clearance. Read More

    Vocalization as a novel endpoint of atypical attachment behavior in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed infant mice.
    Arch Toxicol 2018 Feb 14. Epub 2018 Feb 14.
    Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
    Mammalian attachment behaviors, such as crying, are essential for infant survival by receiving food, protection, and warmth from caregivers. Ultrasonic vocalization (USV) of infant rodents functions to promote maternal proximity. Impaired USV emission has been reported in mouse models of autism spectrum disorder, suggesting that USV is associated with higher brain function. Read More

    The role of unfolded protein response and ER-phagy in quantum dots-induced nephrotoxicity: an in vitro and in vivo study.
    Arch Toxicol 2018 Feb 12. Epub 2018 Feb 12.
    State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, People's Republic of China.
    Unfolded protein response (UPR) and endoplasmic reticulum (ER)-phagy are essential for cell homeostasis. Quantum dots (QDs), which have been widely used for biomedical applications, can accumulate in the kidney tissues and may cause renal dysfunction. However, the molecular mechanism of QDs-induced nephrotoxicity is still obscure. Read More

    Maternal NOexposure induces cardiac hypertrophy in male offspring via ROS-HIF-1α transcriptional regulation and aberrant DNA methylation modification of Csx/Nkx2.5.
    Arch Toxicol 2018 Feb 7. Epub 2018 Feb 7.
    College of Environment and Resource, Research Center of Environment and Health, Shanxi University, Taiyuan, 030006, Shanxi, People's Republic of China.
    Maternal exposure to nitrogen dioxide (NO) poses a risk for morbidity and mortality in infantile congenital heart diseases and even adult cardiovascular diseases. However, the experimental evidence supporting these effects is insufficient, and the related regulatory mechanisms are unknown. In the present study, we aimed to determine whether maternal NOexposure causes cardiac hypertrophy-related consequences in offspring, and if so, how these adverse effects occur in the postnatal heart. Read More

    A novel genotoxin-specific qPCR array based on the metabolically competent human HepaRGcell line as a rapid and reliable tool for improved in vitro hazard assessment.
    Arch Toxicol 2018 Feb 6. Epub 2018 Feb 6.
    Department of Food, Medicines and Consumer Safety, Unit of Toxicology, Scientific Institute of Public Health (WIV-ISP), Juliette Wytsmanstraat 14, 1050, Brussels, Belgium.
    Although the value of the regulatory accepted batteries for in vitro genotoxicity testing is recognized, they result in a high number of false positives. This has a major impact on society and industries developing novel compounds for pharmaceutical, chemical, and consumer products, as afflicted compounds have to be (prematurely) abandoned or further tested on animals. Using the metabolically competent human HepaRGcell line and toxicogenomics approaches, we have developed an upgraded, innovative, and proprietary gene classifier. Read More

    New mechanistic insights on the metabolic-disruptor role of chlorpyrifos in apoE mice: a focus on insulin- and leptin-signalling pathways.
    Arch Toxicol 2018 Feb 5. Epub 2018 Feb 5.
    Research in Neurobehaviour and Health (NEUROLAB), Universitat Rovira i Virgili, Tarragona, Spain.
    Recently, we have provided evidence, suggesting that mice expressing the human apolipoprotein E3 (apoE3) are more prone to develop an obesity-like phenotype and a diabetic profile when subchronically fed a chlorpyrifos (CPF)-supplemented diet. The aim of the current study was to examine the underlying mechanisms through which CPF alters both insulin- and leptin-signalling pathways in an APOE-dependent manner. Both adult apoE3- and E4-targeted replacement and C57BL/6 mice were exposed to CPF at 0 or 2 mg/kg body weight/day through the diet for 8 consecutive weeks. Read More

    Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells.
    Arch Toxicol 2018 Feb 3. Epub 2018 Feb 3.
    Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany.
    Etoposide (ETP) and anthracyclines are applied for wide anti-cancer treatments. However, the ETP-induced cardiotoxicity remains to be a major safety issue and the underlying cardiotoxic mechanisms are not well understood. This study is aiming to unravel the cardiotoxicity profile of ETP in comparison to anthracyclines using physiologically relevant human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). Read More

    Proteomic alterations of brain subcellular organelles caused by low-dose copper exposure: implication for Alzheimer's disease.
    Arch Toxicol 2018 Jan 30. Epub 2018 Jan 30.
    Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No. 8, Longyuan Road, Nanshan District, Shenzhen, 518055, China.
    Excessive copper intake can lead to neurotoxicity, but there is a lack of comprehensive understanding on the potential impact of copper exposure especially at a low-dose on brain. We used 3xTg-AD mice to explore the potential neurotoxicity of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on behavior and the brain hippocampal mitochondrial and nuclear proteome. Read More

    Lymphocyte surface markers and cytokines are suitable for detection and potency assessment of skin-sensitizing chemicals in an in vitro model of allergic contact dermatitis: the LCSA-ly.
    Arch Toxicol 2018 Jan 30. Epub 2018 Jan 30.
    Department of Internal Medicine, Bundeswehr Hospital, Scharnhorststraße 13, 10115, Berlin, Germany.
    Allergic contact dermatitis is a widespread health disorder and occupational skin disease. Hence, screening for contact-sensitizing chemicals is highly relevant to toxicology, dermatology, and occupational medicine. The use of animal tests for this purpose is constrained by ethical considerations, need for high-throughput screening, and legislation (e. Read More

    Effects of bisphenol A on ovarian follicular development and female germline stem cells.
    Arch Toxicol 2018 Jan 29. Epub 2018 Jan 29.
    Renji Hospital, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, School of Medicine, Shanghai Jiao Tong University, No. 800. Dongchuan Road, Minhang District, Shanghai, 200240, China.
    Bisphenol A (BPA), one of the most frequently detected emerging pollutants in the environment, has been implicated in adverse effects in male and female reproduction at extremely low concentrations. This study aimed to investigate the effects and potential mechanism of BPA on mouse ovarian follicular development and female germline stem cells (FGSCs). Female CD-1 adult mice were administered gradient concentrations of BPA (12. Read More

    Cytochrome bimpacts on cytochrome P450-mediated metabolism of benzo[a]pyrene and its DNA adduct formation: studies in hepatic cytochrome b/P450 reductase null (HBRN) mice.
    Arch Toxicol 2018 Jan 24. Epub 2018 Jan 24.
    Department of Analytical, Environmental and Forensic Sciences, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
    Benzo[a]pyrene (BaP) is an environmental pollutant that, based on evidence largely from in vitro studies, exerts its genotoxic effects after metabolic activation by cytochrome P450s. In the present study, Hepatic Reductase Null (HRN) and Hepatic Cytochrome b/P450 Reductase Null (HBRN) mice have been used to study the role of P450s in the metabolic activation of BaP in vivo. In HRN mice, cytochrome P450 oxidoreductase (POR), the electron donor to P450, is deleted specifically in hepatocytes. Read More

    Irritant-induced asthma to hypochlorite in mice due to impairment of the airway barrier.
    Arch Toxicol 2018 Jan 24. Epub 2018 Jan 24.
    Centre for Environment and Health, Department of Public Health and Primary Care, University of Leuven, Herestraat 49 Mailbox 706, 3000, Leuven, Belgium.
    Inhalation of commonly present irritants, such as chlorine and chlorine derivatives, can cause adverse respiratory effects, including irritant-induced asthma (IIA). We hypothesize that due to airway barrier impairment, exposure to hypochlorite (ClO) can result in airway hypersensitivity. C57Bl/6 mice received an intra-peritoneal (i. Read More

    Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation.
    Arch Toxicol 2018 Jan 23. Epub 2018 Jan 23.
    EA 4483-IMPECS-IMPact of Environmental ChemicalS on Human Health, Faculté de Médecine/Pôle Recherche, Univ. Lille, 1, place de Verdun, 59045, Lille Cedex, France.
    Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1 mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation. Read More

    Innovative organotypic in vitro models for safety assessment: aligning with regulatory requirements and understanding models of the heart, skin, and liver as paradigms.
    Arch Toxicol 2018 Feb 23;92(2):557-569. Epub 2018 Jan 23.
    Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, L69 3GE, UK.
    The development of improved, innovative models for the detection of toxicity of drugs, chemicals, or chemicals in cosmetics is crucial to efficiently bring new products safely to market in a cost-effective and timely manner. In addition, improvement in models to detect toxicity may reduce the incidence of unexpected post-marketing toxicity and reduce or eliminate the need for animal testing. The safety of novel products of the pharmaceutical, chemical, or cosmetics industry must be assured; therefore, toxicological properties need to be assessed. Read More

    The development of an in vitro Pig-a assay in L5178Y cells.
    Arch Toxicol 2018 Jan 23. Epub 2018 Jan 23.
    Genetic Toxicology, Discovery Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
    A recent flow cytometry-based in vivo mutagenicity assay involves the hemizygous phosphatidylinositol class A (Pig-a) gene. Pig-a forms the catalytic subunit of N-acetylglucosaminyltransferase required for glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in Pig-a prevent GPI-anchor synthesis resulting in loss of cell-surface GPI-linked proteins. Read More

    Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer.
    Arch Toxicol 2018 Jan 23. Epub 2018 Jan 23.
    Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK.
    Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. Read More

    Flame retardants, hexabromocyclododecane (HCBD) and tetrabromobisphenol a (TBBPA), alter secretion of tumor necrosis factor alpha (TNFα) from human immune cells.
    Arch Toxicol 2018 Jan 22. Epub 2018 Jan 22.
    Departments of Chemistry, Tennessee State University, Nashville, TN, 37209, USA.
    Hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) are flame retardants, used in a variety of applications, which contaminate the environment and are found in human blood. HBCD and TBBPA have been shown to alter the tumor killing function of natural killer (NK) lymphocytes and the secretion of the inflammatory cytokines interferon gamma (IFNγ) and interleukin 1 beta (IL-1β). The current study examined the effects of HBCD and TBBPA on secretion of the critical pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells. Read More

    Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles.
    Arch Toxicol 2018 Jan 22. Epub 2018 Jan 22.
    Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Schnackenburgallee 114, 22525, Hamburg, Germany.
    Activation of pregnane X receptor (PXR) results in the induction of first-pass metabolism and drug efflux. Hereby, PXR may cause adverse drug reactions or therapeutic failure of drugs. PXR inhibition is thus an attractive option to minimise adverse effects or to improve therapeutic efficiencies; however, only a limited number of antagonists have been identified so far. Read More

    Anti-estrogenic activity of tris(2,3-dibromopropyl) isocyanurate through disruption of co-activator recruitment: experimental and computational studies.
    Arch Toxicol 2018 Jan 22. Epub 2018 Jan 22.
    State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, Beijing, 100085, People's Republic of China.
    As a potential endocrine disruptor, tris(2,3-dibromopropyl) isocyanurate (TBC) has previously been demonstrated to reduce expression of estrogen-dependent vitellogenin (vtg) mRNA in adult zebrafish. However, the underlying toxicity pathways and molecular mechanisms involved in TBC-induced endocrine disruption remain elusive. In the current study, E-Screen and MVLN assays were employed to explore the potential anti-estrogenic effects of TBC via the estrogen receptor α (ERα)-mediated signaling pathway. Read More

    Correction to: Selective determination of mandelic acid in urine using molecularly imprinted polymer in microextraction by packed sorbent.
    Arch Toxicol 2018 Jan;92(1):223
    Department of Occupational Health, School of Public Health, Hamadan University of Medical Sciences, PO Box 65175-4171, Hamadan, 6517838695, Iran.
    In the original publication of the article, there is an error in Fig. 2c. The authors would like to correct this error and the corrected version of Fig. Read More

    Exposure assessment of process-related contaminants in food by biomarker monitoring.
    Arch Toxicol 2018 Jan 4;92(1):15-40. Epub 2018 Jan 4.
    Division of Food Chemistry and Toxicology, Department of Chemistry, University of Kaiserslautern, P.O. Box 3049, 67653, Kaiserslautern, Germany.
    Exposure assessment is a fundamental part of the risk assessment paradigm, but can often present a number of challenges and uncertainties. This is especially the case for process contaminants formed during the processing, e.g. Read More

    The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.
    Arch Toxicol 2017 Dec 28. Epub 2017 Dec 28.
    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376, Stuttgart, Germany.
    Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. Read More

    Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts.
    Arch Toxicol 2017 Dec 23. Epub 2017 Dec 23.
    Departments of Biology and Chemistry, Institute of Biochemistry, Carleton University, Ottawa, ON, Canada.
    Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction. Read More

    Nanomaterials: certain aspects of application, risk assessment and risk communication.
    Arch Toxicol 2018 Jan 22;92(1):121-141. Epub 2017 Dec 22.
    Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany.
    Development and market introduction of new nanomaterials trigger the need for an adequate risk assessment of such products alongside suitable risk communication measures. Current application of classical and new nanomaterials is analyzed in context of regulatory requirements and standardization for chemicals, food and consumer products. The challenges of nanomaterial characterization as the main bottleneck of risk assessment and regulation are presented. Read More

    A methodology for the assessment of inhalation exposure to aluminium from antiperspirant sprays.
    Arch Toxicol 2017 Dec 21. Epub 2017 Dec 21.
    Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Nikolai-Fuchs-Strasse 1, 30625, Hanover, Germany.
    Inhalative exposure can occur accidentally when using cosmetic spray products. Usually, a tiered approach is applied for exposure assessment, starting with rather conservative, simplistic calculation models that may be improved with measured data and more refined modelling. Here we report on an advanced methodology to mimic in-use conditions for antiperspirant spray products to provide a more accurate estimate of the amount of aluminium possibly inhaled and taken up systemically, thus contributing to the overall body burden. Read More

    Mesenchyme-derived factors enhance preneoplastic growth by non-genotoxic carcinogens in rat liver.
    Arch Toxicol 2018 Feb 21;92(2):953-966. Epub 2017 Dec 21.
    Department of Medicine I, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
    Many frequently prescribed drugs are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action and health risks for humans remain to be elucidated. Here, we investigated the impact of two model NGC, the anti-epileptic drug phenobarbital (PB) and the contraceptive cyproterone acetate (CPA), on intrahepatic epithelial-mesenchymal crosstalk and on growth of first stages of hepatocarcinogenesis. Read More

    Combination of etoposide and fisetin results in anti-cancer efficiency against osteosarcoma cell models.
    Arch Toxicol 2017 Dec 21. Epub 2017 Dec 21.
    Department of Biology, Faculty of Sciences, University of Porto, 4150-171, Porto, Portugal.
    Osteosarcoma chemotherapy is often limited by chemoresistance, resulting in poor prognosis. Combined chemotherapy could, therefore, be used to prevent resistance to chemotherapeutics. Here, the effects of fisetin on osteosarcoma cells were investigated, as well as cytostatic potential in combination with the anti-cancer drug etoposide. Read More

    Resveratrol protects primary cilia integrity of human mesenchymal stem cells from cigarette smoke to improve osteogenic differentiation in vitro.
    Arch Toxicol 2017 Dec 20. Epub 2017 Dec 20.
    Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany.
    Several studies have explored the negative effects of cigarette smoke on bone healing; however, the complex pathogenesis still remains unclear. One crucial and primary factor determining effective fracture repair is the recruitment and differentiation of mesenchymal stem cells (MSCs) into bone-forming cells. Recently, primary cilia, microtubule-based sensory organelles, have been shown to be critical in lineage commitment and differentiation of MSCs. Read More

    Lanthanum chloride reduces lactate production in primary culture rat cortical astrocytes and suppresses primary co-culture rat cortical astrocyte-neuron lactate transport.
    Arch Toxicol 2017 Dec 20. Epub 2017 Dec 20.
    Department of Toxicology, School of Public Health, China Medical University, No.77Puhe road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People's Republic of China.
    Lanthanum (La) can impair learning memory and induce behavioral abnormalities in animals. However, the mechanism underlying these adverse effects of La is still elusive. It has been demonstrated that lactate derived from astrocytes is the major energy source for neurons during long-term memory (LTM) formation and the deficiency of lactate supply can result in LTM damage. Read More

    Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data.
    Arch Toxicol 2017 Dec 12. Epub 2017 Dec 12.
    Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
    Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration-response data. In the present study, the potential of this approach to predict the dose-dependent increase of uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration-response data of 17β-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALUX assay and the yeast estrogen screen (YES) assay, were translated into in vivo dose-response data in rat, using a PBK model with a minimum number of in vitro and in silico determined parameter values. Read More

    Cadmium favors F-actin depolymerization in rat renal mesangial cells by site-specific, disulfide-based dimerization of the CAP1 protein.
    Arch Toxicol 2017 Dec 8. Epub 2017 Dec 8.
    Laboratory Medicine and Pathobiology 1 King's College Circle, University of Toronto, Toronto, ON, M5S 1A8, Canada.
    Cadmium is a toxic metal that produces oxidative stress and has been shown to disrupt the actin cytoskeleton in rat renal mesangial cells (RMC). In a survey of proteins that might undergo Cd-dependent disulfide crosslinking, we identified the adenylyl cyclase-associated protein, CAP1, as undergoing a dimerization in response to Cd(5-40 µM) that was sensitive to disulfide reducing agents, was reproduced by the disulfide crosslinking agent diamide, and was shown by site-directed mutagenesis to involve the Cysresidue of the protein. Reactive oxygen species are not involved in the thiol oxidation, and glutathione modulates background levels of dimer. Read More

    MiR-26a functions as a tumor suppressor in ambient particulate matter-bound metal-triggered lung cancer cell metastasis by targeting LIN28B-IL6-STAT3 axis.
    Arch Toxicol 2017 Dec 8. Epub 2017 Dec 8.
    Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, China.
    Exposure to ambient particulate matter (PM) has been linked to the increasing incidence and mortality of lung cancer, but the principal toxic components and molecular mechanism remain to be further elucidated. In this study, human lung adenocarcinoma A549 cells were treated with serial concentrations of water-extracted PM(WE-PM) collected from Beijing, China. Our results showed that exposure to 25 and 50 μg/ml of WE-PMfor 48 h significantly suppressed miR-26a to upregulate lin-28 homolog B (LIN28B), and in turn activated interleukin 6 (IL6) and signal transducer and activator of transcription 3 (STAT3) in A549 cells, subsequently contributing to enhanced epithelial-mesenchymal transition and accelerated migration and invasion. Read More

    Activation of intestinal GR-FXR and PPARα-UGT signaling exacerbates ibuprofen-induced enteropathy in mice.
    Arch Toxicol 2017 Dec 8. Epub 2017 Dec 8.
    School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai Disctrict, Tianjin, 300072, People's Republic of China.
    Nonsteroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury (enteropathy) occurs in about two-thirds of regular NSAID users. To date, there is no proven-effective treatment for NSAID enteropathy, and its underlying mechanism remains obscure. The present study showed that glucocorticoids are an important determinant of NSAID enteropathy. Read More

    Protective effect of cadmium-induced autophagy in rat renal mesangial cells.
    Arch Toxicol 2018 Feb 7;92(2):619-631. Epub 2017 Dec 7.
    Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M5S 1A8, Canada.
    Cadmium damages renal cells, and in particular may cause mesangial cell death by necrosis or apoptosis, depending on exposure conditions in cultured cells. However, there is an uncertainty as to whether Cd-induced autophagy can protect mesangial cells against these other mechanisms of cell death. We have used autophagy-incompetent mouse embryonic fibroblast (MEF) cells lacking the Atg16 gene, as well as cultured rat mesangial cells (RMC) in which Atg16 has been silenced, to examine this issue. Read More

    Use of HuH6 and other human-derived hepatoma lines for the detection of genotoxins: a new hope for laboratory animals?
    Arch Toxicol 2018 Feb 7;92(2):921-934. Epub 2017 Dec 7.
    Department of Internal Medicine I, Institute of Cancer Research, Medical University Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
    Cell lines which are currently used in genotoxicity tests lack enzymes which activate/detoxify mutagens. Therefore, rodent-derived liver preparations are used which reflect their metabolism in humans only partly; as a consequence misleading results are often obtained. Previous findings suggest that certain liver cell lines express phase I/II enzymes and detect promutagens without activation; however, their use is hampered by different shortcomings. Read More

    Monitoring cytochrome P450 activity in living hepatocytes by chromogenic substrates in response to drug treatment or during cell maturation.
    Arch Toxicol 2017 Dec 5. Epub 2017 Dec 5.
    Institute of Pharmacy and Molecular Biotechnology, Pharmaceutical Biology, Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
    The metabolic activity of hepatocytes is a central prerequisite for drug activity and a key element in drug-drug interaction. This central role in metabolism largely depends on the activity of the cytochrome P450 (CYP450) enzyme family, which is not only dependent on liver cell maturation but is also controlled in response to drug and chemical exposure. Here, we report the use of VividDye fluorogenic CYP450 substrates to directly measure and continuously monitor metabolic activity in living hepatocytes. Read More

    An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition.
    Arch Toxicol 2018 Jan 5;92(1):41-82. Epub 2017 Dec 5.
    In Vitro Toxicology and Biomedicine, Department of Biology, University of Konstanz, Universitätsstr. 10, PO Box M657, 78457, Konstanz, Germany.
    Epidemiological studies have observed an association between pesticide exposure and the development of Parkinson's disease, but have not established causality. The concept of an adverse outcome pathway (AOP) has been developed as a framework for the organization of available information linking the modulation of a molecular target [molecular initiating event (MIE)], via a sequence of essential biological key events (KEs), with an adverse outcome (AO). Here, we present an AOP covering the toxicological pathways that link the binding of an inhibitor to mitochondrial complex I (i. Read More

    Association between polymorphism of GSTP1, GSTT1, GSTM1 and CYP2E1 genes and susceptibility to benzene-induced hematotoxicity.
    Arch Toxicol 2017 Dec 4. Epub 2017 Dec 4.
    Department of Occupational Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
    Occupational exposure to benzene has been associated with leukemia, anemia, leukopenia, and thrombocytopenia. Genetic susceptibility to benzene toxicity in humans may be related to variations in benzene metabolizing genes. The main objective of this study was to ascertain whether polymorphism of GSTP1, GSTM1, GSTT1 and CYP2E1 genes might influence susceptibility to the adverse effects of benzene among employees of a petrochemical plant. Read More

    Gestational exposure to inorganic arsenic (iAs3+) alters glutamate disposition in the mouse hippocampus and ionotropic glutamate receptor expression leading to memory impairment.
    Arch Toxicol 2017 Dec 4. Epub 2017 Dec 4.
    Dep. de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, A.P. 70-228, Ciudad Universitaria, 04510, Mexico, Mexico.
    Early life exposure to environmental pollutants and toxic chemicals has been linked to learning and behavioral alterations in children. iAs exposure is associated with different types neurological disorders such as memory and learning impairment. iAs is methylated in the brain by the arsenic III-methyltransferase in a process that requires glutathione (GSH). Read More

    The PPARα-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions.
    Arch Toxicol 2018 Jan 2;92(1):83-119. Epub 2017 Dec 2.
    Department of Environmental Health, Indiana University, Bloomington, IN, 47402, USA.
    A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a number of consistent mechanistic changes linked to the increased incidence of liver neoplasms. The weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis is summarized here. Read More

    PARP1 protects from benzo[a]pyrene diol epoxide-induced replication stress and mutagenicity.
    Arch Toxicol 2017 Dec 1. Epub 2017 Dec 1.
    Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457, Konstanz, Germany.
    Poly(ADP-ribosyl)ation (PARylation) is a complex and reversible posttranslational modification catalyzed by poly(ADP-ribose)polymerases (PARPs), which orchestrates protein function and subcellular localization. The function of PARP1 in genotoxic stress response upon induction of oxidative DNA lesions and strand breaks is firmly established, but its role in the response to chemical-induced, bulky DNA adducts is understood incompletely. To address the role of PARP1 in the response to bulky DNA adducts, we treated human cancer cells with benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE), which represents the active metabolite of the environmental carcinogen benzo[a]pyrene [B(a)P], in nanomolar to low micromolar concentrations. Read More

    Sirt1 overexpression suppresses fluoride-induced p53 acetylation to alleviate fluoride toxicity in ameloblasts responsible for enamel formation.
    Arch Toxicol 2017 Nov 28. Epub 2017 Nov 28.
    Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, 43210, USA.
    Low-dose fluoride is an effective caries prophylactic, but high-dose fluoride is an environmental health hazard that causes skeletal and dental fluorosis. Treatments to prevent fluorosis and the molecular pathways responsive to fluoride exposure remain to be elucidated. Previously we showed that fluoride activates SIRT1 as an adaptive response to protect cells. Read More

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