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  • “Juice monsters”: sub-ohm vaping and toxic volatile aldehyde emissions
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Soha Talih, Rola Salman, Nareg Karaoghlanian, Ahmad El-Hellani, Najat Aoun Saliba, Thomas Eissenberg, Alan Shihadeh

    An emerging category of electronic cigarettes (ECIGs) are sub-Ohm devices (SODs) that operate at ten or more times the power of conventional ECIGs. Because carcinogenic volatile aldehyde (VAs) emissions increase sharply with power, SODs may expose users to greater VAs. In this study, we compared VA emissions from several SODs and found that across device, VAs and power were un-correlated unless power was normalized by coil surface area. VA emissions and liquid consumed were correlated highly. Analyzed in light of EU regulations limiting ECIG liquid nicotine concentration, these findings suggest potential regulatory levers and pitfalls for protecting public health.

    更新日期:2017-09-23
  • Investigation of Dioscorea bulbifera Rhizome-Induced Hepatotoxicity in Rats by a Multisample Integrated Metabolomics Approach
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Dong-Sheng Zhao, Li-Long Jiang, Ya-Xi Fan, Ling-Li Wang, Zhuo-Qing Li, Wei Shi, Ping Li, Hui-Jun Li
    更新日期:2017-09-23
  • Coordination and Substitution of DNA Polymerases in Response to Genomic Obstacles
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Michael A. Trakselis, Matthew T. Cranford, Aurea M. Chu
    更新日期:2017-09-23
  • Multidrug Resistance Protein 4 (MRP4/ABCC4) Protects Cells from the Toxic Effects of Halobenzoquinones
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-22
    Jinhua Li, Madlen Bauer, Birget Moe, Elaine M. Leslie, Xing-Fang Li
    更新日期:2017-09-22
  • Detoxification of atrazine by low molecular weight thiols in alfalfa (Medicago sativa)
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-21
    Jing Jing Zhang, Jiang-Yan Xu, Feng Fan Lu, She Feng Jin, Hong Yang

    Low molecular weight (LMW) thiols in higher plants are a group of sulfur-rich non-protein compounds and play primary and multiple roles in cellular redox homeostasis, enzyme activities, and xenobiotics detoxification. This study focused on identifying thiols-related protein genes from the legume alfalfa exposed to the herbicide atrazine (ATZ) residues in environment. Using high-throughput RNA-sequencing, a set of ATZ-responsive thiols-related protein genes highly up-regulated and differentially expressed in alfalfa were identified. Most of the differentially expressed genes (DEGs) were involved in regulation of biotic and abiotic stress responses. By analyzing the genes involved in thiols-mediated redox homeostasis, we found that many of them were thiols-synthetic enzymes such as γ-glutamylcysteine synthase (γECS), homoglutathione synthetase (hGSHS) and glutathione synthetase (GSHS). Using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), we further characterized a group of ATZ-thiols conjugates, which are the detoxified forms of ATZ in plants. Cysteine S-conjugate ATZ-HCl+Cys was the most important metabolite detected by the mass spectrometry. Several other ATZ-conjugates were also examined as ATZ-detoxified metabolites. Such results were validated by characterizing their analogs in rice. Our data showed that some conjugates under ATZ stress were detected in both plants, indicating that some detoxified mechanisms and pathways can be shared by the two plant species. Overall, these results indicate that LMW thiols play critical roles in detoxification of ATZ in the plants.

    更新日期:2017-09-21
  • Hemoglobin Adducts and Urinary Metabolites of Arylamines and Nitroarenes
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-21
    Gabriele Sabbioni
    更新日期:2017-09-21
  • The potential of phenylbutyrate as adjuvant chemotherapy: an overview of cellular and molecular anticancer mechanisms
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-20
    Maha Al-Keilani, Nour A. Al-Sawalha

    Despite the advancement in cancer therapy, a high number of patients fail treatment because of drug resistance. Several preclinical in vitro data suggest that phenylbutyrate has antiproliferative, antiangiogenic, antimetastatic, immunomodulatory, and differentiating properties. Moreover, phenylbutyrate administration in vivo provided an oncoprotective effect. However, the results of clinical trials indicate that the antineoplastic potential of phenylbutyrate is hindered by its pharmacokinetic and pharmacodynamic properties. Thus, understanding the exact mechanisms of the anticancer effect of phenylbutyrate could assist in the selection of patients who will best benefit from this drug. The present review discusses the proposed mechanisms of antineoplastic effect of phenylbutyrate and the preclinical and clinical evidences suggesting its potential role as anticancer in different types of cancer.

    更新日期:2017-09-20
  • Benchmark Dose Modeling Estimates of the Concentrations of Inorganic Arsenic that Induce Changes to the Neonatal Transcriptome, Proteome and Epigenome in a Pregnancy Cohort
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-19
    Julia Rager, Scott S. Auerbach, Grace A Chappell, Elizabeth Martin, Chad Thompson, Rebecca C Fry

    Prenatal inorganic arsenic (iAs) exposure influences the expression of critical genes and proteins associated with adverse outcomes in newborns, in part through epigenetic mediators. The doses at which these genomic and epigenomic changes occur have yet to be evaluated in the context of dose-response modeling. The goal of the present study was to estimate iAs doses that correspond to changes in transcriptomic, proteomic, epigenomic, and integrated multi-omic signatures in human cord blood through benchmark dose (BMD) modeling. Genome-wide DNA methylation, microRNA expression, mRNA expression, and protein expression levels in cord blood were modeled against total urinary arsenic (U-tAs) levels from pregnant women exposed to varying levels of iAs. Dose-response relationships were modeled in BMDExpress, and BMDs representing 10% response levels were estimated. Overall, DNA methylation changes were estimated to occur at lower exposure concentrations in comparison to other molecular endpoints. Multi-omic module eigengenes were derived through weighted gene co-expression network analysis, representing co-modulated signatures across transcriptomic, proteomic, and epigenomic profiles. One module eigengene was associated with decreased gestational age occurring alongside increased iAs exposure. Genes/proteins within this module eigengene showed enrichment for organismal development, including potassium voltage-gated channel subfamily Q member 1 (KCNQ1), an imprinted gene showing differential methylation and expression in response to iAs. Modeling of this prioritized multi-omic module eigengene resulted in a BMD(BMDL) of 58(45) µg/L U-tAs, which was estimated to correspond to drinking water arsenic concentrations of 51(40) µg/L. Results are in line with epidemiological evidence supporting effects of prenatal iAs occurring at levels <100 µg As/L urine. Together, findings present a variety of BMD measures to estimate doses at which prenatal iAs exposure influences neonatal outcome-relevant transcriptomic, proteomic and epigenomic profiles.

    更新日期:2017-09-20
  • Copper Inhibits the AlkB Family DNA Repair Enzymes under Wilson’s Disease Condition
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-19
    Ke Bian, Fangyi Chen, Zachary T. Humulock, Qi Tang, Deyu Li

    Disturbed metabolism of copper ions can cause diseases, such as Wilson’s disease (WD). In this work, we investigated the inhibi-tory effect of Cu(II) ion on the AlkB family DNA repair enzymes in vitro, which are members of the Fe(II)/alpha-ketoglutarate-dependent dioxygenase and include human ALKBH2, ALKBH3, and E. coli AlkB proteins. None of the three proteins were significantly inhibited under normal cellular copper concentrations. But under WD related condition, we observed the activities of all three enzymes were strongly suppressed (from 95.2 to 100.0%). We also noted the repair efficiency under ds-DNA condition is less susceptible than ss-DNA to the inhibition.

    更新日期:2017-09-20
  • Dose-dependent response to 3-nitrobenzanthrone exposure in human urothelial cancer cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-18
    Mario Pink, Nisha Verma, Anna Zerries, Simone Schmitz-Spanke

    A product of incomplete combustion of diesel fuel, 3-nitrobenzanthrone (3-NBA), has been classified as a cancer-causing substance. It first gained attention as a potential urinary bladder carcinogen due to the presence of its metabolite in urine and formation of DNA adducts. The aim of the present study was to characterise the dose-response relationship of 3-NBA in human urothelial cancer cell line (RT4) exposed to concentrations ranging from 0.0003 µM (environmentally relevant) to 80 µM by utilising toxicological and metabolomic approaches. We observed that the RT4 cells were capable of bioactivation of 3-NBA within 30 minutes of exposure. Activity measurements of various enzymes involved in the conversion of 3-NBA in RT4 cells demonstrated NAD(P)H:quinone oxidoreductase (NQO1) as the main contributor for its bioactivation. Moreover, cytotoxicity assessment exhibited an initiation of adaptive mechanisms at low dosages, which diminished at higher doses, indicating that the capacity of these mechanisms no longer suffices - resulting in increased levels of intracellular reactive oxygen species, reduced proliferation and hyperpolarisation of the mitochondrial membrane. To characterise the underlying mechanisms of this cellular response, the metabolism of 3-NBA and metabolomic changes in the cells were analysed. The metabolomic analysis of the cells (0.0003, 0.01, 0.08, 10, and 80 µM 3-NBA) showed elevated levels of various antioxidants at low concentrations of 3-NBA. Whereas, at higher exposure concentrations, it appeared that the cells reprogrammed their metabolism to maintain the cell homeostasis via activation of pentose phosphate pathway (PPP).

    更新日期:2017-09-19
  • 更新日期:2017-09-15
  • Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-15
    Alice R. Walker, G. Andrés Cisneros
    更新日期:2017-09-15
  • Occupational Respiratory Exposure to Platinum Group Metals: A Review and Recommendations
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-15
    Stephanus J. L. Linde, Anja Franken, Johannes L. du Plessis
    更新日期:2017-09-15
  • Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-13
    Jarno E. J. Wolters, Simone G. J. van Breda, Florian Caiment, Sandra M. Claessen, Theo M. C. M. de Kok, Jos C. S. Kleinjans
    更新日期:2017-09-14
  • Investigation of Dioscorea bulbifera rhizome-induced hepatotoxicity in rats by a multi-sample integrated metabolomics approach
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-13
    Dong-Sheng Zhao, Li-Long Jiang, Ya-Xi Fan, Ling-Li Wang, Zhuo-Qing Li, Wei Shi, Ping Li, Hui-Jun Li

    The use of herbal medicines continues to expand globally, meanwhile, herb-associated hepatotoxicity is becoming a safety issue. Dioscorea bulbifera rhizome (DBR), a traditionally used medicinal plant in China, is reported to induce hepatotoxicity. However, the precise molecular mechanism involved has not been comprehensively explored. The objectives of the present study were to profile entire endogenous metabolites in a biological system and provide additional insight into the molecular mechanism of the hepatotoxicity induced by DBR using a multi-sample integrated metabolomics strategy. Gas chromatography-mass spectrometry coupled with multivariate analysis was employed to discover differentiating metabolites in metabolomics data of rat plasma, urine, and feces. In total, 55 metabolites distributed in 33 metabolic pathways were identified as being significantly altered in DBR-treated rats. Correlation network analysis revealed that the hub metabolites of hepatotoxicity were mainly associated with amino acid, bile acid, purine, pyrimidine, lipid, and energy metabolism. As such, DBR affected the physiological and biological functions of liver via the regulation of multiple metabolic pathways to an abnormal state. Notably, our findings also demonstrated that the multi-sample integrated metabolomics strategy has a great potential for identifying more biomarkers and pathways to unravel the mechanistic complexity of toxicity of traditional Chinese medicine.

    更新日期:2017-09-13
  • Transcriptomic analysis of thalidomide challenged chick embryo suggests possible link between impaired vasculogenesis and defective organogenesis
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-11
    Vimal Veeriah, Pavitra Kumar, Lakshmikirupa Sundaresan, Zeenath Mafitha, Ravi Gupta, Uttara Saran, Jeganathan Manivannan, Suvro Chatterjee

    Since the conception of thalidomide as a teratogen approximately 30 hypotheses have been put forward to explain the developmental toxicity of the molecule. However, no systems biology approach has been taken to understand the phenomena yet. The proposed work was aimed to explore the mechanism of thalidomide toxicity in developing chick embryo in the context of transcriptomics by using genome wide RNA sequencing data. In this study, we challenged the developing embryo at the stage of blood island formations (HH8) which is the most vulnerable stage for thalidomide-induced deformities. We observed that thalidomide affects the early vasculogenesis through interfering with the blood island formation and extends its effect to organogenesis. The transcriptome analyses of the embryos collected on 6th day of incubation have shown that eye, liver and blood tissue associated genes are down regulated due to thalidomide treatment. The conserved gene co-expression module also indicated that the genes involved in lens development are heavily affected. Further, the Gene Ontology (GO) analysis explored that the pathways of eye development, retinol metabolism, and cartilage development are dampened in consistent with the observed deformities of eye (absence of lens formations) and other organs. The study concludes that thalidomide exerts its toxic teratogenic effects through interfering with early extra-embryonic vasculogenesis and ultimately gives an erroneous transcriptomic pattern to organogenesis.

    更新日期:2017-09-11
  • Immunopurification of acetylcholinesterase from red blood cells for detection of nerve agent exposure
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-11
    Alicia J. Dafferner, Lawrence M. Schopfer, Gaoping Xiao, John R. Cashman, Udaya Yerramalla, Rudolph C Johnson, Thomas A. Blake, Oksana Lockridge

    Nerve agents and organophosphorus pesticides make a covalent bond with the active site serine of acetylcholinesterase (AChE), resulting in inhibition of AChE activity and toxic symptoms. AChE in red blood cells (RBC) serves as a surrogate for AChE in the nervous system. Mass spectrometry analysis of adducts on RBC AChE could provide evidence of exposure. Our goal was to develop a method of immunopurifying human RBC AChE in quantities adequate for detecting exposure by mass spectrometry. For this purpose we immobilized 3 commercially available anti-human acetylcholinesterase monoclonals (AE-1, AE-2, and HR2) plus 3 new monoclonals. The monoclonals were characterized for binding affinity, epitope mapping by pairing analysis, and nucleotide and amino acid sequences. AChE was solubilized from frozen RBC with 1% Triton X-100. A 16 mL sample containing 5.8 µg RBC AChE was treated with a quantity of soman model compound that inhibited 50% of the AChE activity. Native and soman-inhibited RBC AChE were immunopurified on antibody-Sepharose beads. The immunopurified RBC AChE was digested with pepsin and analyzed by liquid chromatography tandem mass spectrometry on a 6600 Triple-TOF mass spectrometer. The aged soman-modified FGESAGAAS peptide was detected using a targeted analysis method. It was concluded that all 6 monoclonals could be used to immunopurify RBC AChE and that exposure to nerve agents could be detected as adducts on the active site serine of RBC AChE.

    更新日期:2017-09-11
  • Effect of Subcellular Translocation of Protein Disulfide Isomerase on Tetrachlorobenzoquinone-Induced Signaling Shift from Endoplasmic Reticulum Stress to Apoptosis
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-11
    Zixuan Liu, Yawen Wang, Yuxin Wang, Wenjing Dong, Xiaomin Xia, Erqun Song, Yang Song
    更新日期:2017-09-11
  • 更新日期:2017-09-08
  • Multidrug resistance protein 4 (MRP4/ABCC4) protects cells from the toxic effects of halobenzoquinones
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-08
    Jinhua Li, Madlen Bauer, Birget Moe, Elaine M. Leslie, Xing-Fang Li

    Halobenzoquinones (HBQs) are frequently detected disinfection byproducts (DBPs) in treated water. Recent studies have demonstrated that HBQs are highly cytotoxic and capable of inducing the generation of reactive oxygen species (ROS) and depleting cellular glutathione (GSH). Multidrug resistance proteins (MRPs/ABCCs) are known to play a critical role in the elimination of numerous drugs, carcinogens, toxicants, and their conjugated metabolites. In general, little is known about the roles of transporters in DBP toxicity. Here, we hypothesize that MRPs may play roles in detoxication of HBQs. To test this hypothesis, we used human embryonic kidney 293 (HEK293) cells stably expressing MRPs (MRP1, 3, 4, and 5) and HEK293 cells with empty vector (HEK-V) to examine the comparative cytotoxicity of four HBQs: 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ), 2,6-dichloro-3-methyl-1,4-benzoquinone (DCMBQ), and 2,3,6-trichloro-1,4-benzoquinone (TriCBQ). The cytotoxicity (IC50) of the four HBQs in HEK-MRP1, -MRP3, -MRP4, and -MRP5 cells and the control HEK-V cells clearly showed that MRP4 had the most significant effect on reducing the toxicity of the four HBQs. To further support MRP4-mediated detoxication of HBQs, we examined the HBQ-induced ROS levels in HEK-MRP4 and HEK-V cells. ROS levels were significantly reduced in HEK-MRP4 cells compared with HEK-V cells after HBQ treatment. Furthermore, it was found that MRP4-mediated detoxication of the HBQs was GSH dependent, as the cytotoxicity of the HBQs was increased in GSH-depleted HEK-MRP4 cells in comparison to HEK-MRP4 cells. The GSH-dependent protection of cells from HBQs supports the possibility of HBQ-GSH conjugate effluxed by MRP4. This study demonstrates a role for MRP4 in cellular protection against HBQ DBP-induced toxicity and oxidative stress.

    更新日期:2017-09-08
  • Living on the Edge: DNA Polymerase Lambda between Genome Stability and Mutagenesis
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-08
    Barbara van Loon, Ulrich Hübscher, Giovanni Maga
    更新日期:2017-09-08
  • Multi-platform approach for the discovery of novel drug-induced kidney injury biomarkers
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-08
    Liuxi Chen, James D Smith, Jaromir Mikl, Ryan Fryer, Frank Pack, Brad J. Williams, Jonathan Phillips, Vladimir Papov

    Drug-induced kidney injury (DIKI) is a common toxicity observed in pharmaceutical development. We demonstrate the use of label-free liquid chromatography – mass spectrometry (LC-MS) and multiplex liquid chromatography-single reaction monitoring (LC-SRM) as practical extensions of standard immunoassay based safety biomarker assessments for identification of new toxicity marker candidates and for improved mechanistic understanding. Two different anti-cancer drugs doxorubicin (DOX) and cisplatin (cis-diamminedichloridoplatinum, CDDP) were chosen as the toxicants due to their different modes of nephrotoxicity. Analysis of urine samples from toxicant treated and untreated rats were compared to identify biochemical analytes that changed in response to toxicant exposure. A discovery (label-free LC-MS) and targeted proteomics (multiplex LC-SRM) approach was used in combination with well established immunoassay experiments for the identification of a panel of urinary protein markers related to drug induced nephrotoxicity in rats. The initial generation of an expanded set of markers was accomplished using the label-free LC-MS discovery screen and ELISA based analysis of six nephrotoxicity biomarker proteins. Diagnostic performance of the expanded analyte set was statistically compared to conventional nephrotoxicity biomarkers. False discovery rate (FDR) analysis revealed 18 and 28 proteins from the CDDP and DOX groups, respectively, exhibiting significant differences between the vehicle and treated groups. Multiplex SRM assays were constructed to more precisely quantify candidate markers selected from the discovery screen and immunoassay experiments. To evaluate the sensitivity and specificity for each of the candidate biomarkers, histopathology severity scores were used as a benchmark for renal injury followed by receiver-operating characteristic (ROC) curve analysis on selected biomarkers. Further examination of the best performing analytes revealed relevant biological significance after consideration of anatomical localization and functional roles. In summary, the inclusion of mass spectrometry together with conventional ELISA based assays resulted in the identification of an expanded set of biomarkers with a realistic potential for providing additional beneficial information in mechanistic investigations of drug induced kidney injury and with similar responsiveness to conventionally applied indicators of renal injury.

    更新日期:2017-09-08
  • Coordination and Substitution of DNA Polymerases in Response to Genomic Obstacles
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-07
    Michael A. Trakselis, Matthew T. Cranford, Aurea M. Chu

    The ability for DNA polymerases (Pols) to overcome a variety of obstacles in its path to maintain genomic stability during replication is a complex endeavor. It requires the coordination of multiple Pols with differing specificities through molecular control and access to the replisome. Although a number of contacts directly between Pols and to accessory proteins have been identified forming the basis of a variety of holoenzyme (HE) complexes, the dynamics of Pol active site substitutions remain uncharacterized. Substitutions can occur externally by recruiting new Pols to replisome complexes through an ‘exchange’ of enzyme binding, or internally through a ‘switch’ in the engagement of DNA from preformed associated enzymes contained within supraholoenzyme (SHE) complexes. Models for how high fidelity (HiFi) replication Pols can be substituted by translesion synthesis (TLS) Pols at sites of damage during active replication will be discussed. These substitution mechanisms may be as diverse as the number of Pol families and types of damage, however, common themes can be recognized across species. Overall, Pol substitutions will be controlled by explicit protein contacts, complex multiequilibrium processes, and specific kinetic activities. Insight into how these dynamic processes take place and are regulated will be of utmost importance for our greater understanding of the specifics of TLS as well as providing for future novel chemotherapeutic and antimicrobial strategies.

    更新日期:2017-09-08
  • Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-07
    Hideshi Ihara, Shingo Kasamatsu, Atsushi Kitamura, Akira Nishimura, Hiroyasu Tsutsuki, Tomoaki Ida, Kento Ishizaki, Takashi Toyama, Eiko Yoshida, Hisyam Abdul Hamid, Minkyung Jung, Tetsuro Matsunaga, Shigemoto Fujii, Tomohiro Sawa, Motohiro Nishida, Yoshito Kumagai, Takaaki Akaike
    更新日期:2017-09-07
  • Arsenite Binds to the Zinc Finger Motif of TIP60 Histone Acetyltransferase and Induces Its Degradation via the 26S Proteasome
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-07
    Lok Ming Tam, Ji Jiang, Pengcheng Wang, Lin Li, Weili Miao, Xuejiao Dong, Yinsheng Wang
    更新日期:2017-09-07
  • Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-06
    Alice R. Walker, G. Andres Cisneros

    Genetic information is vital in the cell cycle of DNA--based organisms. DNA Polymerases (DNA Pols) are crucial players in transactions dealing with these processes. Therefore, the detailed understanding of the structure, function, and mechanism of these proteins has been the focus of significant effort. Computational simulations have been applied to investigate various facets of DNA polymerase structure and function. These simulations have provided significant insights over the years. This perspective presents the results of various computational studies that have been employed to research different aspects of DNA polymerases including detailed reaction mechanism investigation, mutagenicity of different metal cations, possible factors for fidelity synthesis, and discovery/functional characterization of cancer--related mutations on DNA polymerases.

    更新日期:2017-09-07
  • Human Y-Family DNA Polymerase κ Is More Tolerant to Changes in Its Active Site Loop than Its Ortholog Escherichia coli DinB
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-06
    Nicole M. Antczak, Morgan R. Packer, Xueguang Lu, Ke Zhang, Penny J. Beuning
    更新日期:2017-09-06
  • Development of High Capacity Enterosorbents for Aflatoxin B1 and Other Hazardous Chemicals
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-05
    Meichen Wang, Cody R. Maki, Youjun Deng, Yanan Tian, Timothy D. Phillips
    更新日期:2017-09-06
  • New Insights into DNA Polymerase Function Revealed by Phosphonoacetic Acid-sensitive T4 DNA Polymerases
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-05
    Likui Zhang

    The bacteriophage T4 DNA polymerase (pol) and the closely related RB69 DNA pol have been developed into model enzymes to study family B DNA pols. While all family B DNA pols have similar structures and share conserved protein motifs, the molecular mechanism underlying natural drug resistance of non-herpes family B DNA pols and drug sensitivity of herpes DNA pols remains unknown. In the present study, we constructed T4 phages containing G466S, Y460F, G466S/Y460F, P469S and V475W mutations in DNA pol. These amino acid substitutions replace the residues in drug-resistant T4 DNA pol with residues found in drug-sensitive herpes family DNA pols. We investigated whether the T4 phages expressing the engineered mutant DNA pols were sensitive to the antiviral drug phosphonoacetic acid (PAA) and characterized the in vivo replication fidelity of the phage DNA pols. We found that G466S substitution marginally increased PAA sensitivity, whereas Y460F substitution conferred resistance. The phage expressing a double mutant G466S/Y460F DNA pol was more PAA-sensitive. V475W T4 DNA pol was highly sensitive to PAA, as was the case with V478W RB69 DNA pol. However, DNA replication was severely compromised, which resulted in the selection of phages expressing more robust DNA pols that have strong ability to replicate DNA and contain additional amino acid substitutions that suppress PAA sensitivity. Reduced replication fidelity was observed in all mutant phages expressing PAA-sensitive DNA pols. These observations indicate that PAA sensitivity and fidelity are balanced in DNA pols that can replicate DNA in different environments.

    更新日期:2017-09-05
  • Structures of a DNA Polymerase Inserting Therapeutic Nucleotide Analogues
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-09-01
    Matthew A. Schaich, Mallory R. Smith, Ashley S. Cloud, Sean M. Holloran, Bret D. Freudenthal
    更新日期:2017-09-04
  • 更新日期:2017-09-04
  • Occupational respiratory exposure to platinum group metals: A review and recommendations
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-31
    Stephanus Johannes Lourens Linde, Anja Franken, Johannes Lodewykus du Plessis

    Platinum Group Metals (PGMs) is a group of metals that include platinum, palladium, rhodium, ruthenium, iridium and osmium. Occupational respiratory exposure to platinum has been reported since 1945 but studies investigating occupational exposure to palladium, rhodium, ruthenium, iridium and osmium are scarce. This review provides a summation of the information available on the respiratory exposure to PGMs in various industrial settings, methods used to assess exposure and the possible adverse health effects resulting from occupational exposure to PGMs. Of these effects, respiratory sensitization caused by soluble PGMs is of most importance. Metallic PGMs have not been shown to cause allergic reactions. This review reiterates that occupational respiratory exposure to PGMs is dependent on the type of industry where exposure takes place, the chemical form (soluble or insoluble) of the PGMs present in the workplace air and the tasks performed by workers in the specific work areas. Sensitization to soluble platinum is associated with the degree of exposure to soluble platinum compounds and the highest concentrations of soluble PGMs in workplace air have been reported for precious metals refineries where personal exposures frequently exceed the occupational exposure limit for soluble platinum (2 µg/m3). Additionally, this review emphasizes that personal exposure monitoring is preferred over area monitoring when assessing workers’ exposure to PGMs. The legislation applicable to occupational exposure to PGMs is also discussed and it is highlighted that the occupational exposure limit for soluble platinum has remained unchanged, in most countries, since 1970 and that too few countries have classified PGM compounds as respiratory and/or skin sensitizers. Finally, recommendations are made to ensure that future investigations are comparable in terms of the type of exposure monitoring (personal or area) conducted, the type of tasks included in the exposure monitoring program and the format in which results are reported.

    更新日期:2017-09-04
  • Nuclear and mitochondrial DNA methylation patterns induced by valproic acid in human hepatocytes
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-30
    Jarno E.J. Wolters, Simone G.J. van Breda, Florian Caiment, Sandra M. Claessen, Theo M.C.M. de Kok, Jos C.S. Kleinjans

    Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs in the world. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunctioning. The aim of this study is to further investigate VPA-induced mechanisms of steatosis by analyzing changes in patterns of methylation in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, primary human hepatocytes (PHH) were exposed to an incubation concentration of VPA which was shown to cause steatosis without inducing overt cytotoxicity. VPA was administered daily for 5 days and this was followed by a 3 days washout (WO). Methylated DNA regions (DMRs) were identified by using the ‘Methylated DNA Immuno-Precipitation - sequencing’ (MeDIP-seq) method. The nDNA DMRs after VPA-treatment could indeed be classified into oxidative stress- and steatosis-related pathways. Especially networks of the steatosis-related gene EP300 provided novel insight in mechanisms of toxicity induced by VPA-treatment. Furthermore, we suggest that VPA induces a crosstalk between nDNA hypermethylation and mtDNA hypomethylation which plays a role in oxidative stress and steatosis development. While most VPA-induced methylation patterns appeared reversible upon terminating VPA-treatment, 31 nDNA DMRs (including 5 zinc finger protein genes) remained persistent after the WO-period. Overall, we have shown that MeDIP-seq analysis is highly informative in disclosing novel mechanisms of VPA-induced toxicity in PHH. Our results thus provide a prototype for a novel generation of interesting methylation biomarkers for repeated dose liver toxicity in vitro.

    更新日期:2017-08-31
  • Biological monitoring of inhaled nanoparticles in patients: an appealing approach to study causal link between human respiratory pathology and exposure to nanoparticles
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-30
    Valerie Forest, Jean-Michel Vergnon, Jeremie Pourchez

    Although necessary, in vitro and in vivo studies are not fully successful at predicting nanomaterials toxicity. We propose to associate such assays to the biological monitoring of nanoparticles in clinical samples to get more relevant data on the chemical and physical nature and dose of nanoparticles found in humans. The concept is to establish the load of nanoparticles in biological samples of patients. Then, by comparing samples from different patient groups, nanoparticles of interest could be identified and a potential link between a given nanoparticle type and toxicity could be suggested. It has to be confirmed by investigating the biological effects induced by these nanoparticles using in vitro or in vivo models (mechanistic or dose-response studies). This translational approach from the bedside to the bench and vice-versa could allow a better understanding of the nanoparticle effects and mechanisms of toxicity that can contribute, at least in part, to a disease.

    更新日期:2017-08-31
  • Physiological Concentrations of Ascorbate Cannot Prevent the Potentially Damaging Reactions of Protein Radicals in Humans
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-29
    Thomas Nauser, Janusz M. Gebicki
    更新日期:2017-08-29
  • Living on the edge: DNA polymerase lambda between genome stability and mutagenesis
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-25
    Barbara van Loon, Ulrich Hubscher, Giovanni Maga

    In human cells, only four DNA polymerases (pols) are necessary and sufficient for the duplication of the genetic information. However, more than a dozen DNA pols are required to maintain its integrity. Such a high degree of specialization, makes DNA repair pols able to cope with specific lesions or repair pathways. On the other hand, the same DNA pols can have partially overlapping roles, which could result in possible conflicts of functions, if the DNA pols are not properly regulated. DNA pol λ is a typical example of such an enzyme. It is a multifunctional enzyme, endowed with special structural and biochemical properties, which make it capable of participating in different DNA repair pathways, such as base excision repair, non-homologous end joining and translesion synthesis. However, when mutated or deregulated, DNA pol λ can also be a source of genetic instability. Its multiple roles in DNA damage tolerance and its ability in promoting tumor progression, make it also a possible target for novel anticancer approaches.

    更新日期:2017-08-26
  • Translesion DNA synthesis in cancer: molecular mechanisms and therapeutic opportunities
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-25
    Maroof K. Zafar, Robert L. Eoff

    The genomic landscape of cancer is one marred by instability, but the mechanisms that underlie these alterations are multi-faceted and remain a topic of intense research. Cellular responses to DNA damage and/or replication stress can affect genome stability in tumors and influence the response of patients to therapy. In addition to direct repair, DNA damage tolerance (DDT) is an element of genomic maintenance programs that contributes to the etiology of several types of cancer. DDT mechanisms primarily act to resolve replication stress, and this can influence the effectiveness of genotoxic drugs. Translesion DNA synthesis (TLS) is an important component of DDT that facilitates direct bypass of DNA adducts and other barriers to replication. The central role of TLS in the bypass of drug-induced DNA lesions, the promotion of tumor heterogeneity, and the involvement of these enzymes in the maintenance of the cancer stem cell (CSC) niche presents an opportunity to leverage inhibition of TLS as a way of improving existing therapies. In the review that follows, we summarize mechanisms of DDT, mis-regulation of TLS in cancer, and discuss the potential for targeting these pathways as means of improving cancer therapies.

    更新日期:2017-08-26
  • Exposure to Electrophiles Impairs Reactive Persulfide-dependent Redox Signaling in Neuronal Cells
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-24
    Hideshi Ihara, Shingo Kasamatsu, Atsushi Kitamura, Akira Nishimura, Hiroyasu Tsutsuki, Tomoaki Ida, Kento Ishizaki, Takashi Toyama, Eiko Yoshida, Hisyam Abdul Hamid, Minkyung Jung, Tetsuro Matsunaga, Shigemoto Fujii, Tomohiro Sawa, Motohiro Nishida, Yoshito Kumagai, Takaaki Akaike

    Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species, and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.

    更新日期:2017-08-25
  • Arsenite Binds to the Zinc Finger Motif of TIP60 Histone Acetyltransferase and Induces Its Degradation via the 26S Proteasome
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-24
    Lok Ming Tam, Ji Jiang, Pengcheng Wang, Lin Li, Weili Miao, Xuejiao Dong, Yinsheng Wang

    Arsenic is a ubiquitous environmental contaminant with widespread public health concern. Epidemiological studies have revealed that chronic human exposure to arsenic in drinking water is associated with the prevalence of skin, lung and bladder cancers. Aberrant histone modifications (e.g. methylation, acetylation and ubiquitination) were previously found to be accompanied with arsenic exposure; thus, perturbation of epigenetic pathways is thought to contribute to arsenic carcinogenesis. Arsenite is known to interact with zinc finger motifs of proteins, and zinc finger motif is present in, and indispensable for the enzymatic activities of crucial histone-modifying enzymes especially the MYST family of histone acetyltransferases (e.g. TIP60). Hence, we reasoned that trivalent arsenic may target the zinc finger motif of these enzymes, disturb their enzymatic activities, and alter histone acetylation. Herein, we found that As3+ could bind directly to the zinc-finger motif of TIP60 in vitro and in cells. In addition, exposure to As3+ could lead to a dose-dependent decrease in TIP60 protein level via the ubiquitin-proteasome pathway. Thus, the results from the present study revealed, for the first time, that arsenite may target cysteine residues in the zinc-finger motif of the TIP60 histone acetyltransferase, thereby altering the H4K16Ac histone epigenetic mark. Our results also shed some new light on the mechanisms underlying the arsenic-induced epigenotoxicity and carcinogenesis in humans.

    更新日期:2017-08-25
  • Strong Inhibitory Effect of Heme on hIAPP Fibrillation
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-23
    Jinming Wu, Jie Zhao, Zhen Yang, Hailing Li, Zhonghong Gao
    更新日期:2017-08-23
  • Variation in Extracellular Detoxification Is a Link to Different Carcinogenicity among Chromates in Rodent and Human Lungs
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-20
    Casey Krawic, Michal W. Luczak, Anatoly Zhitkovich
    更新日期:2017-08-20
  • Effect of Subcellular Translocation of Protein Disulfide Isomerase on Tetrachlorobenzoquinone-induced Signaling Shift from Endoplasmic Reticulum Stress to Apoptosis
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-20
    Zixuan Liu, Yawen Wang, Yuxin Wang, Wenjing Dong, Xiaomin Xia, Erqun Song, Yang Song

    Our previous studies illustrated tetrachlorobenzoquinone (TCBQ)-caused toxicities in neuron-like cells which implies its association with neurodegenerative disorders. Although it is known that TCBQ induces oxidative damage, in turn results in endoplasmic reticulum (ER) stress and apoptosis, however, it is unclear how the signaling switch from pro-survival (to restore cellular homeostasis) to pro-death (trigger apoptosis). Protein disulfide isomerase family proteins (PDIs) regulate the progress of various neurodegenerative disorders, including Parkinson’s disease and Alzheimer’s disease. We tested the hypothesis that PDIs subcellular translocation implicates survival/death signaling switch by inducing mitochondrial outer membrane permeabilization (MOMP). PC12 cells were exposed to TCBQ and the concentration-dependent ER stress was observed upon TCBQ treatment, as indicated by increase in IRE1α phosphorylation, CHOP expression, XBP1 splicing and caspase 12 activation. Interestingly, pharmaceutical (or siRNA) abrogation of PDIA1/PDIA3 aggravated cell viability loss induced by relative low concentration (10 μM) of TCBQ. However, PDIA1/PDIA3 inhibition rescued high concentration (20 μM) of TCBQ-caused cell death. Further mechanistic study illustrated that PDIs initially acted to restore cellular homeostasis to pro-survival, but constant ER stress promoted signaling switch to pro-apoptotic by the release of PDIA1/PDIA3 from ER lumen to induce Bak-dependent MOMP. Our findings suggested that PDIs subcellular translocation contributed to the “live or death” fate of PC12 cells to TCBQ-induced oxidative insult.

    更新日期:2017-08-20
  • Human Y-family DNA polymerase kappa is more tolerant to changes in its active site loop than its ortholog E. coli DinB
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-19
    Nicole M. Antczak, Morgan R. Packer, Xueguang Lu, Ke Zhang, Penny J. Beuning

    DNA damage is a constant threat and can be bypassed in a process called translesion synthesis, which is typically carried out by Y-family DNA polymerases. Y-family DNA polymerases are conserved in all domains of life and tend to have specificity for certain types of DNA damage. Escherichia coli DinB and its human ortholog pol κ can bypass specific minor groove deoxyguanine adducts efficiently and are inhibited by major groove adducts, as Y-family DNA polymerases make contacts with the minor groove side of the DNA substrate and lack contacts with the major groove at the nascent base pair. DinB is inhibited by major groove adducts more than pol κ, and they each have active site loops of different lengths, with four additional amino acids in the DinB loop. We previously showed that the R35A active site loop mutation in DinB allows for bypass of the major groove adduct N6-furfuryl-dA. These observations led us to investigate the different active site loops by creating loop swap chimeras of DinB with a pol κ loop and vice versa by changing the loop residues in a step-wise fashion. We then determined their activity with undamaged DNA or DNA containing N2-furfuryl-dG or N6-furfuryl-dA. The DinB proteins with the pol kappa loop have low activity on all templates but have decreased misincorporation compared to either wild-type protein. The kappa proteins with the DinB loop retain activity on all templates and have decreased misincorporation compared to either wild-type protein. We assessed the thermal stability of the proteins and observed an increase in stability in the presence of all DNA templates and additional increases generally only in the presence of the undamaged and N2-furfuryl-dG adduct and dCTP, which correlates with activity. Overall we find that pol κ is more tolerant to changes in the active site loop than DinB.

    更新日期:2017-08-19
  • Reaction of Dimethyl Trisulfide with Hemoglobin
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-18
    Xinmei Dong, Lóránd Kiss, Ilona Petrikovics, David E. Thompson
    更新日期:2017-08-19
  • Conformational Flexibility of the Benzyl-guanine Adduct in a Bypass Polymerase Active Site Permits Replication: Insights from Molecular Dynamics Simulations
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-15
    Katie A Wilson, Stacey D Wetmore

    Although translesion synthesis (TLS) polymerases play key roles in replicating DNA that contains nucleobase addition products (adducts), there are many unknowns about their function. The present work gains indispensable structural insights from molecular dynamics simulations on the replication of O6-benzyl-guanine (Bz-dG) prior to bond formation during dCTP insertion opposite the adduct by Dpo4. When combined with previous X-ray crystal structures of the Bz-dG extension complex, molecular details are now available for each stage during a single TLS replication cycle for this carcinogenic lesion. Our calculations illustrate that Bz-dG preferentially adopts an intercalated bulky moiety orientation in the Dpo4 pre-insertion complex, which stabilizes the complex through Bz-dG interactions with the previously replicated 3-base pair and positions the carcinogenic group in the dNTP binding position. Nevertheless, the maintained inherent flexibility of Bz-dG due to a stark lack of interactions with the polymerase or template DNA allows the bulky moiety to adopt a major groove position opposite an incoming dCTP in an orientation that is conducive for the experimentally-observed nonmutagenic bypass. Comparison of Bz-dG and canonical dG replication clarifies that the experimentally observed decrease in dCTP binding affinity and replication efficiency upon adduct formation is likely caused by a combination of factors, including the required template nucleotide conformational change and destabilized template–dCTP hydrogen bonding. Although additional aspects of the replication process, such as the impact of the adduct on the nucleotidyl-transfer reaction, may also be important for fully rationalizing experimental replication data and must be considered in future work, the present contribution emphasizes the importance of considering the effect of DNA damage on the early stages of the TLS process.

    更新日期:2017-08-15
  • Reaction of Dimethyl Trisulfide with Hemoglobin
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-15
    Xinmei Dong, Lorand Kiss, Ilona Petrikovics, David E Thompson

    Dimethyl trisulfide (DMTS) is a promising antidotal candidate for cyanide intoxication. DMTS acts as a sulfur donor in the conversion of cyanide to the less-toxic thiocyanate. The alternate reaction pathways of DMTS in the blood are not well understood. We report changes in the hemoglobin absorption spectrum upon reaction with DMTS. These changes closely match those induced by the known methemoglobin former, sodium nitrite. The kinetics of methemoglobin formation with DMTS are slower than with sodium nitrite. These results support the hypothesis that a potentially significant side-reaction of the therapeutically administered DMTS is the oxidization of hemoglobin to methemoglobin.

    更新日期:2017-08-15
  • Thiol-Dependent Reduction of the Triester and Triamide Derivatives of Finland Trityl Radical Triggers O2-Dependent Superoxide Production
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-14
    Xiaoli Tan, Li Chen, Yuguang Song, Antal Rockenbauer, Frederick A. Villamena, Jay L. Zweier, Yangping Liu
    更新日期:2017-08-15
  • Rapid Dissolution of ZnO Nanoparticles Induced by Biological Buffers Significantly Impacts Cytotoxicity
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-11
    Josh E. Eixenberger, Catherine B. Anders, Rebecca J. Hermann, Raquel J. Brown, Kongara M. Reddy, Alex Punnoose, Denise G. Wingett
    更新日期:2017-08-11
  • Repair-Resistant DNA Lesions
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-10
    Nicholas E. Geacintov, Suse Broyde
    更新日期:2017-08-10
  • A strong inhibitory effect of heme on hIAPP fibrillation
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-08
    Jinming Wu, Jie Zhao, Zhen Yang, Hailing Li, Zhonghong Gao

    The deposition of human islet amyloid polypeptide (hIAPP) within β-cells is implicated in the etiology of type 2 diabetes mellitus (T2Dm). It was reported that heme could bind to hIAPP and we speculate that the binding may also correlate to the aggregation of hIAPP. In this study, UV-Vis spectroscopy was used to detect interaction pattern between heme and hIAPP. ThT and Bis-ANS fluorescence assay, circular dichroism spectroscopy, gel electrophoresis assay and transmission electron microscopy were employed to study the effect of heme on the aggregation of hIAPP. We found that heme dramatically inhibited hIAPP aggregation and fibril formation, even partially dismantled hIAPP aggregates by preventing its conformational changes. Moreover, similar inhibitory effect was also observed on mutant hIAPP. In the compare group, the inhibitory effect of protoporphyrin on hIAPP and its mutants aggregation was weaker. Similarly, its effect on the dismantlement of the aggregates was also weaker. On the basis of these results, we revealed heme iron center was not required for the inhibitory effect on hIAPP but affected the binding affinity of heme to hIAPP. Besides Arg11 and His18, other hydrophobic residues in hIAPP may also play an important role in the heme binding. Our results may help to develop a deep understanding of the interactions between heme and hIAPP that would be helpful in designing new therapeutic strategies against the T2Dm.

    更新日期:2017-08-09
  • 更新日期:2017-08-08
  • Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-04
    José Xavier Soares, Emanuele Amorim Alves, André M. N. Silva, Natália Guimarães de Figueiredo, João F. Neves, Sara Manuela Cravo, Maria Rangel, Annibal Duarte Pereira Netto, Félix Carvalho, Ricardo Jorge Dinis-Oliveira, Carlos Manuel Afonso
    更新日期:2017-08-04
  • Predicting organ toxicity using in vitro bioactivity data and chemical structure
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-02
    Jie Liu, Grace Patlewicz, Antony Williams, Russell S. Thomas, Imran Shah

    Animal testing alone cannot practically evaluate the health hazard posed by tens of thousands of environmental chemicals. Computational approaches making use of high-throughput experimental data may provide more efficient means to predict chemical toxicity. Here, we use a supervised machine learning strategy to systematically investigate the relative importance of study type, machine learning algorithm, and type of descriptor on predicting in vivo repeat-dose toxicity at the organ-level. A total of 985 compounds were represented using chemical structural descriptors, ToxPrint chemotype descriptors, and bioactivity descriptors from ToxCast in vitro high-throughput screening assays. Using ToxRefDB, a total of 35 target organ outcomes were identified that contained at least 100 chemicals (50 positive and 50 negative). Supervised machine learning was performed using Naïve Bayes, k-nearest neighbor, random forest, classification and regression trees, and support vector classification approaches. Model performance was assessed based on F1 scores using five-fold cross-validation with balanced bootstrap replicates. Fixed effects modeling showed the variance in F1 scores was explained mostly by target organ outcome, followed by descriptor type, machine learning algorithm, and interactions between these three factors. A combination of bioactivity and chemical structure or chemotype descriptors were the most predictive. Model performance improved with more chemicals (up to a maximum of 24%) and these gains were correlated (ρ= 0.92) with the number of chemicals. Overall, the results demonstrate that a combination of bioactivity and chemical descriptors can accurately predict a range of target organ toxicity outcomes in repeat-dose studies, but specific experimental and methodologic improvements may increase predictivity.

    更新日期:2017-08-03
  • Development of High Capacity Enterosorbents for Aflatoxin B1 and Other Hazardous Chemicals
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-02
    Meichen Wang, Cody R Maki, Youjun Deng, Yanan Tian, Timothy D. Phillips

    Previously, a calcium montmorillonite clay (NovaSil) included in diet of animals has been shown to bind aflatoxin B1 (AfB1) and reduce the symptoms of aflatoxicosis. To investigate and improve the capacity and efficacy of clay-based materials as aflatoxin sorbents, we developed and tested calcium and sodium montmorillonite clays amended with nutrients including L-carnitine and choline. Also we determined the sorption of AfB1 by isothermal analysis and tested the ability of these amended sorbents to protect adult hydra from AfB1 toxicity. The results showed that exchanging montmorillonite clays with L-carnitine and choline inhibited swelling of the clays and increased the sorption capacity and efficacy of clay surfaces for AfB1. Results from dehydroxylated and heat-collapsed clays suggested that AfB1 was primarily adsorbed in the clay interlayer, as predicted from thermodynamic calculations and computational modeling. The hydra bioassay further indicated that the modified clays can significantly protect adult hydra from the AfB1 with as low as 0.005% clay inclusion. This enterosorbent therapy may also be applied to screen hazardous chemicals such as pesticides and PAHs based on similar sorption mechanisms. Taken together, enterosorbent therapy could be delivered in nutritional supplements, foods that are vulnerable to aflatoxin contamination, flavored liquids and animal feeds during emergencies and outbreaks of acute aflatoxicosis, and as a screening model for hazardous environmental chemicals.

    更新日期:2017-08-03
  • The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-08-02
    Tasaduq H. Wani, Anindita Chakrabarty, Norio Shibata, Hiroshi Yamazaki, F. Peter Guengerich, Goutam Chowdhury
    更新日期:2017-08-03
  • Thiol-dependent reduction of the triester and triamide derivatives of Finland trityl radical triggers O2-dependent superoxide production
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-07-31
    Xiaoli Tan, Li Chen, Yuguang Song, Antal Rockenbauer, Frederick A. Villamena, Jay L. Zweier, Yangping Liu

    Tetrathiatriaylmethyl (trityl) radicals have found wide biomedical applications as magnetic resonance probes. Trityl radicals and their derivatives are generally stable towards biological reducing agents such as glutathione (GSH) and ascorbate. We demonstrate that the triester (ET-03) and triamide (AT-03) derivatives of Finland trityl radical exhibit unique reduction by thiols such as GSH and cysteine (Cys) to generate the corresponding trityl carbanions as evidenced by the loss of EPR signal and appearance of characteristic UV-Vis absorbance at 644 nm under anaerobic conditions. The trityl carbanions can be quickly converted back to the original trityl radicals by oxygen (O2) in air, thus rendering the reaction between the trityl derivative and biothiol undetectable under aerobic conditions. The reduction product of O2 by the trityl carbanions was shown to be superoxide radical (O2•-) by EPR spin-trapping. Kinetic studies showed that the reaction rate constants (k) depend on types of both trityl radicals and thiols with the order of kET-03/Cys (0.336 M-1 s-1) > kET-03/GSH (0.070 M-1 s-1) > kAT-03/Cys (0.032 M-1 s-1) > kAT-03/GSH (0.027 M-1 s-1). The reactivity of trityl radicals with thiols is closely related to the para-substituents of trityl radicals as well as the pKa of the thiols and is further reflected by the rate of O2•- production and consumptions of O2 and thiols. This novel reaction represents a new metabolic process of trityl derivatives and should be considered in design and application of new trityl radical probes.

    更新日期:2017-08-02
  • Variation in extracellular detoxification is a link to different carcinogenicity among chromates in rodent and human lungs
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-07-31
    Casey Krawic, Michal Luczak, Anatoly Zhitkovich

    Inhalation of soluble chromium(VI) is firmly linked with higher risks of lung cancer in humans. However, comparative studies in rats have found a high lung tumorigenicity for moderately soluble chromates but no tumors for highly soluble chromates. These major species differences remain unexplained. We investigated the impact of extracellular reducers on responses of human and rat lung epithelial cells to different Cr(VI) forms. Extracellular reduction of Cr(VI) is a detoxification process and rat and human lung lining fluids contain different concentrations of ascorbate and glutathione. We found that reduction of chromate anions in simulated lung fluids was principally driven by ascorbate with only minimal contribution from glutathione. The addition of 500 M ascorbate (~rat lung fluid concentration) to culture media strongly inhibited cellular uptake of chromate anions and completely prevented their cytotoxicity even at otherwise lethal doses. While proportionally less effective, 50 M extracellular ascorbate (~human lung fluid concentration) also decreased uptake of chromate anions and their cytotoxicity. In comparison to chromate anions, uptake and cytotoxicity of respirable particles of moderately soluble CaCrO4 and SrCrO4 were much less sensitive to suppression by extracellular ascorbate, especially during early exposure times and in primary bronchial cells. In the absence of extracellular ascorbate, chromate anions and CaCrO4/SrCrO4 particles produced overall similar levels of DNA double-stranded breaks, with less soluble particles exhibiting a slower rate of breakage. Our results indicate that a gradual extracellular dissolution and a rapid internalization of calcium chromate and strontium chromate particles makes them resistant to detoxification outside the cells, which is extremely effective for chromate anions in the rat lung fluid. The detoxification potential of the human lung fluid is significant but much lower and insufficient to provide a threshold-type dose dependence for soluble chromates.

    更新日期:2017-07-31
  • Repair-Resistant DNA Lesions
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-07-27
    Nicholas E. Geacintov, Suse Broyde

    The eukaryotic global genomic nucleotide excision repair (GG-NER) pathway is the major mechanism that removes most bulky and some non-bulky lesions from cellular DNA. There is growing evidence that certain DNA lesions are repaired slowly, or are entirely resistant to repair in cells, tissues, and in cell extract model assay systems. It is well established that the eukaryotic DNA lesion-sensing proteins do not detect the damaged nucleotide, but recognize the distortions/destabilizations in the native DNA structure caused by the damaged nucleotides. In this article, the nature of the structural features of certain bulky DNA lesions that render them resistant to NER, or cause them to be repaired slowly, are compared to those that are good-to-excellent NER substrates. Understanding the structural features that distinguish NER-resistant DNA lesions from good NER substrates may be useful for interpreting the biological significance of biomarkers of exposure of human populations to genotoxic environmental chemicals. NER-resistant lesions can survive to replication and cause mutations that can initiate cancer and other diseases. Furthermore, NER diminishes the efficacy of certain chemotherapeutic drugs, and the design of more potent pharmaceuticals that resist repair can be advanced through a better understanding of the structural properties of DNA lesions that engender repair-resistance.

    更新日期:2017-07-28
  • The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-07-26
    Tasaduq Hussain Wani, Anindita Chakrabarty, Norio Shibata, Hiroshi Yamazaki, F. Peter Guengerich, Goutam Chowdhury

    Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10,000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS, inhibition of angiogenesis and inhibition of cereblon. All the theories have their merits and limitation. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low dose requirement reported by a number of groups. Recently we have provided convincing structural evidence in support of the presences of arene oxide and the quinone reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, di-hydroxythalidomide is responsible for generating ROS and DNA damage. We show using cell lines the formation of comet (DNA damage) and ROS. Using DNA cleavage assays we also show that catalase, radical scavengers and desferal is capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA damaging property but the metabolism, low concentration and species specificity requirements of thalidomide.

    更新日期:2017-07-28
  • Physiological concentrations of ascorbate cannot prevent the potentially damaging reactions of protein radicals in humans
    Chem. Res. Toxicol. (IF 3.278) Pub Date : 2017-07-26
    Thomas Nauser, Janusz Gebicki

    The principal initial biological targets of free radicals formed under condition of oxidative stress are the proteins. The most common product of the interaction are carbon-centered alkyl radicals which react rapidly with oxygen to form peroxyl radicals and hydroperoxides. All these species are reactive, capable of propagating the free radical damage to enzymes, nucleic acids, lipids and endogenous antioxidants, leading finally to the pathologies associated with oxidative stress. The best chance of preventing this chain of damage is in early repair of the protein radicals by antioxidants. Estimate of the effectiveness of the physiologically significant antioxidants requires knowledge of the antioxidant tissue concentrations and rate constants of their reaction with protein radicals. Previous studies by pulse radiolysis have shown that only ascorbate can repair the Trp and Tyr protein radicals before they form peroxyl radicals under physiological concentrations of oxygen. We have now extended this work to other protein C-centered radicals generated by hydroxyl radicals, because these and many other free radicals formed under oxidative stress can produce secondary radicals on virtually any amino acid residue. Pulse radiolysis identified two classes of rate constants for reactions of protein radicals with ascorbate, a faster one in the range (9-60)  107 M-1s-1 and a slow one with range of (0.5-2)  107 M-1 s-1. These results show that ascorbate can prevent further reactions of protein radicals only in the few human tissues where its concentrations exceeds about 2.5 mM.

    更新日期:2017-07-28
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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