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    The potential of phenylbutyrate as adjuvant chemotherapy: an overview of cellular and molecular anticancer mechanisms.
    Chem Res Toxicol 2017 Sep 20. Epub 2017 Sep 20.
    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. Read More

    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 2017 Sep 19. Epub 2017 Sep 19.
    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. Read More

    Copper Inhibits the AlkB Family DNA Repair Enzymes under Wilson's Disease Condition.
    Chem Res Toxicol 2017 Sep 19. Epub 2017 Sep 19.
    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. Read More

    Dose-dependent response to 3-nitrobenzanthrone exposure in human urothelial cancer cells.
    Chem Res Toxicol 2017 Sep 18. Epub 2017 Sep 18.
    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. Read More

    Investigation of Dioscorea bulbifera rhizome-induced hepatotoxicity in rats by a multi-sample integrated metabolomics approach.
    Chem Res Toxicol 2017 Sep 13. Epub 2017 Sep 13.
    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. Read More

    Transcriptomic analysis of thalidomide challenged chick embryo suggests possible link between impaired vasculogenesis and defective organogenesis.
    Chem Res Toxicol 2017 Sep 11. Epub 2017 Sep 11.
    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. Read More

    Immunopurification of acetylcholinesterase from red blood cells for detection of nerve agent exposure.
    Chem Res Toxicol 2017 Sep 11. Epub 2017 Sep 11.
    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. Read More

    Multidrug resistance protein 4 (MRP4/ABCC4) protects cells from the toxic effects of halobenzoquinones.
    Chem Res Toxicol 2017 Sep 8. Epub 2017 Sep 8.
    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. Read More

    Multi-platform approach for the discovery of novel drug-induced kidney injury biomarkers.
    Chem Res Toxicol 2017 Sep 8. Epub 2017 Sep 8.
    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. Read More

    Coordination and Substitution of DNA Polymerases in Response to Genomic Obstacles.
    Chem Res Toxicol 2017 Sep 7. Epub 2017 Sep 7.
    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. Read More

    Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants.
    Chem Res Toxicol 2017 Sep 15. Epub 2017 Sep 15.
    Department of Chemistry, University of North Texas , 1155 Union Circle, Denton, Texas 76203, United States.
    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. Read More

    New Insights into DNA Polymerase Function Revealed by Phosphonoacetic Acid-Sensitive T4 DNA Polymerases.
    Chem Res Toxicol 2017 Sep 15. Epub 2017 Sep 15.
    Marine Science & Technology Institute Department of Environmental Science and Engineering, Yangzhou University , No. 196 Huayang West Road, Hanjiang, Yangzhou, Jiangsu 225127, China.
    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 nonherpes 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. Read More

    Structures of a DNA Polymerase Inserting Therapeutic Nucleotide Analogues.
    Chem Res Toxicol 2017 Sep 1. Epub 2017 Sep 1.
    Department of Biochemistry and Molecular Biology, University of Kansas Medical Center , Kansas City, Kansas 66160, United States.
    Members of the nucleoside analogue class of cancer therapeutics compete with canonical nucleotides to disrupt numerous cellular processes, including nucleotide homeostasis, DNA and RNA synthesis, and nucleotide metabolism. Nucleoside analogues are triphosphorylated and subsequently inserted into genomic DNA, contributing to the efficacy of therapeutic nucleosides in multiple ways. In some cases, the altered base acts as a mutagen, altering the DNA sequence to promote cellular death; in others, insertion of the altered nucleotide triggers DNA repair pathways, which produce lethal levels of cytotoxic intermediates such as single and double stranded DNA breaks. Read More

    Occupational Respiratory Exposure to Platinum Group Metals: A Review and Recommendations.
    Chem Res Toxicol 2017 Sep 15. Epub 2017 Sep 15.
    Occupational Hygiene and Health Research Initiative (OHHRI), North-West University , Potchefstroom 2520, South Africa.
    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. Read More

    Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes.
    Chem Res Toxicol 2017 Sep 13. Epub 2017 Sep 13.
    Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University , P.O. Box 616, Maastricht 6200 MD, The Netherlands.
    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 dysfunction. 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). Read More

    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 2017 Sep 8;30(9):1655-1660. Epub 2017 Sep 8.
    Ecole Nationale Supérieure des Mines de Saint-Etienne, CIS-EMSE, SAINBIOSE, F-42023 Saint Etienne, France.
    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. Read More

    Translesion DNA synthesis in cancer: molecular mechanisms and therapeutic opportunities.
    Chem Res Toxicol 2017 Aug 25. Epub 2017 Aug 25.
    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. Read More

    Living on the Edge: DNA Polymerase Lambda between Genome Stability and Mutagenesis.
    Chem Res Toxicol 2017 Sep 8. Epub 2017 Sep 8.
    DNA Enzymology & Molecular Virology and Cell Nucleus & DNA replication Units, Institute of Molecular Genetics IGM-CNR , via Abbiategrasso 207, I-27100 Pavia, Italy.
    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. Read More

    Arsenite Binds to the Zinc Finger Motif of TIP60 Histone Acetyltransferase and Induces Its Degradation via the 26S Proteasome.
    Chem Res Toxicol 2017 Sep 7;30(9):1685-1693. Epub 2017 Sep 7.
    Environmental Toxicology Graduate Program, ‡Cell, Molecular, and Developmental Biology Graduate Program, and §Department of Chemistry, University of California at Riverside , Mail Drop 027, Riverside, California 92521-0403, United States.
    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. Read More

    Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells.
    Chem Res Toxicol 2017 Sep 7;30(9):1673-1684. Epub 2017 Sep 7.
    Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine , Sendai 980-8575, Japan.
    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. Read More

    Effect of Subcellular Translocation of Protein Disulfide Isomerase on Tetrachlorobenzoquinone-Induced Signaling Shift from Endoplasmic Reticulum Stress to Apoptosis.
    Chem Res Toxicol 2017 Sep 11. Epub 2017 Sep 11.
    Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University , Chongqing, People's Republic of China 400715.
    Our previous studies illustrated tetrachlorobenzoquinone (TCBQ)-caused toxicities in neuron-like cells which imply its association with neurodegenerative disorders. Although it is known that TCBQ induces oxidative damage that in turn results in endoplasmic reticulum (ER) stress and apoptosis, it is unclear how TCBQ triggers 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. Read More

    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 2017 Sep 6. Epub 2017 Sep 6.
    Department of Chemistry & Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.
    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. Read More

    Conformational Flexibility of the Benzyl-Guanine Adduct in a Bypass Polymerase Active Site Permits Replication: Insights from Molecular Dynamics Simulations.
    Chem Res Toxicol 2017 Aug 31. Epub 2017 Aug 31.
    Department of Chemistry and Biochemistry, University of Lethbridge , 4401 University Drive West, Lethbridge, Alberta, Canada T1K 3M4.
    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. Read More

    Reaction of Dimethyl Trisulfide with Hemoglobin.
    Chem Res Toxicol 2017 Sep 18;30(9):1661-1663. Epub 2017 Aug 18.
    Department of Chemistry, Sam Houston State University , Huntsville, Texas 77341, United States.
    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. Read More

    Strong Inhibitory Effect of Heme on hIAPP Fibrillation.
    Chem Res Toxicol 2017 Sep 23;30(9):1711-1719. Epub 2017 Aug 23.
    School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology , Wuhan 430074, People's Republic of China.
    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. We speculate that binding may affect the aggregation of hIAPP. Read More

    Development of High Capacity Enterosorbents for Aflatoxin B1 and Other Hazardous Chemicals.
    Chem Res Toxicol 2017 Sep 5;30(9):1694-1701. Epub 2017 Sep 5.
    Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University , College Station, Texas 77845, United States.
    Previously, a calcium montmorillonite clay (NovaSil) included in the 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. Read More

    Predicting organ toxicity using in vitro bioactivity data and chemical structure.
    Chem Res Toxicol 2017 Aug 2. Epub 2017 Aug 2.
    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. Read More

    Thiol-Dependent Reduction of the Triester and Triamide Derivatives of Finland Trityl Radical Triggers O2-Dependent Superoxide Production.
    Chem Res Toxicol 2017 Sep 14;30(9):1664-1672. Epub 2017 Aug 14.
    Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, P. R. China.
    Tetrathiatriaylmethyl (trityl) radicals have found wide biomedical applications as magnetic resonance probes. Trityl radicals and their derivatives are generally stable toward biological reducing agents such as glutathione (GSH) and ascorbate. We demonstrate that the triester (ET-03) and triamide (AT-03) derivatives of the 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. Read More

    Variation in Extracellular Detoxification Is a Link to Different Carcinogenicity among Chromates in Rodent and Human Lungs.
    Chem Res Toxicol 2017 Sep 20;30(9):1720-1729. Epub 2017 Aug 20.
    Department of Pathology and Laboratory Medicine, Brown University , 70 Ship Street, Providence, Rhode Island 02912, United States.
    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. Read More

    Repair-Resistant DNA Lesions.
    Chem Res Toxicol 2017 Aug 10;30(8):1517-1548. Epub 2017 Aug 10.
    Chemistry and Biology Departments, New York University , New York, New York 10003-5180, United States.
    The eukaryotic global genomic nucleotide excision repair (GG-NER) pathway is the major mechanism that removes most bulky and some nonbulky 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. Read More

    Physiological Concentrations of Ascorbate Cannot Prevent the Potentially Damaging Reactions of Protein Radicals in Humans.
    Chem Res Toxicol 2017 Sep 29;30(9):1702-1710. Epub 2017 Aug 29.
    Department of Biological Sciences, Macquarie University , Sydney, New South Wales 2109, Australia.
    The principal initial biological targets of free radicals formed under conditions of oxidative stress are the proteins. The most common products 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. Read More

    The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.
    Chem Res Toxicol 2017 Aug 2;30(8):1622-1628. Epub 2017 Aug 2.
    Departments of Chemistry and Life Sciences, SONS, Shiv Nadar University , Greater Noida, Uttar Pradesh 201314, India.
    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. Read More

    Molecular Modeling of the Major DNA Adduct Formed from Food Mutagen Ochratoxin A in NarI Two-Base Deletion Duplexes: Impact of Sequence Context and Adduct Ionization on Conformational Preference and Mutagenicity.
    Chem Res Toxicol 2017 Aug 8;30(8):1582-1591. Epub 2017 Aug 8.
    Department of Chemistry and Biochemistry, University of Lethbridge , Lethbridge, Alberta T1K 3M4, Canada.
    Exposure to ochratoxin A (OTA), a possible human carcinogen, leads to many different DNA mutations. As a first step toward understanding the structural basis of OTA-induced mutagenicity, the present work uses a robust computational approach and a slipped mutagenic intermediate model previously studied for C(8)-dG aromatic amine adducts to analyze the conformational features of postreplication two-base deletion DNA duplexes containing OT-dG, the major OTA lesion at the C(8) position of guanine. Specifically, a total of 960 ns of molecular dynamics simulations (excluding trial simulations) were carried out on four OT-dG ionization states in three sequence contexts within oligomers containing the NarI recognition sequence, a known hotspot for deletion mutations induced by related adducts formed from known carcinogens. Read More

    Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans.
    Chem Res Toxicol 2017 Aug 4;30(8):1609-1621. Epub 2017 Aug 4.
    Department of Chemical Sciences, Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto , José Viterbo Ferreira Stree No. 228, 4050-313 Porto, Portugal.
    "Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. Read More

    Rapid Dissolution of ZnO Nanoparticles Induced by Biological Buffers Significantly Impacts Cytotoxicity.
    Chem Res Toxicol 2017 Aug 11;30(8):1641-1651. Epub 2017 Aug 11.
    Biomolecular Sciences Graduate Program, ‡Department of Physics, §Biomolecular Research Center, and ⊥Department of Biological Sciences, Boise State University , Boise, Idaho 83725, United States.
    Zinc oxide nanoparticles (nZnO) are one of the most highly produced nanomaterials and are used in numerous applications including cosmetics and sunscreens despite reports demonstrating their cytotoxicity. Dissolution is viewed as one of the main sources of nanoparticle (NP) toxicity; however, dissolution studies can be time-intensive to perform and complicated by issues such as particle separation from solution. Our work attempts to overcome some of these challenges by utilizing new methods using UV/vis and fluorescence spectroscopy to quantitatively assess nZnO dissolution in various biologically relevant solutions. Read More

    N(6)-Formyllysine as a Biomarker of Formaldehyde Exposure: Formation and Loss of N(6)-Formyllysine in Nasal Epithelium in Long-Term, Low-Dose Inhalation Studies in Rats.
    Chem Res Toxicol 2017 Aug 27;30(8):1572-1576. Epub 2017 Jul 27.
    Department of Environmental Sciences and Engineering, University of North Carolina , Chapel Hill, North Carolina 27514, United States.
    Exposure to both endogenous and exogenous formaldehyde has been established to be carcinogenic, likely by virtue of forming nucleic acid and proteins adducts such as N(6)-formyllysine. To better assess N(6)-formyllysine as a biomarker of formaldehyde exposure, we studied accumulation of N(6)-formyllysine adducts in tissues of rats exposed by inhalation to 2 ppm [(13)C(2)H2]-formaldehyde for 7, 14, 21, and 28 days (6 h/day) and investigated adduct loss over a 7-day postexposure period using liquid chromatography-coupled tandem mass spectrometry. Our results showed formation of exogenous adducts in nasal epithelium and to some extent in trachea but not in distant tissues of lung, bone marrow, or white blood cells, with a 2-fold increase over endogenous N(6)-formyllysine over a 3-week exposure period. Read More

    Carboxylate Counteranions in Electronic Cigarette Liquids: Influence on Nicotine Emissions.
    Chem Res Toxicol 2017 Aug 18;30(8):1577-1581. Epub 2017 Jul 18.
    Chemistry Department, Faculty of Arts and Sciences, American University of Beirut , Beirut 1107 2020, Lebanon.
    The wide pH range reported for electronic cigarette (ECIG) liquids indicates that nicotine may be present in one or more chemical forms. The nicotine form affects the bioavailability and delivery of nicotine from inhaled products. Protonated nicotine is normally associated with counteranions in tobacco products. Read More

    Ultraperformance Liquid Chromatography Tandem Mass Spectrometry Method To Determine Formaldehyde Hemoglobin Adducts in Humans as Biomarker for Formaldehyde Exposure.
    Chem Res Toxicol 2017 Aug 17;30(8):1592-1598. Epub 2017 Jul 17.
    Division of Laboratory Sciences, Centers for Disease Control and Prevention , Atlanta, Georgia 30341, United States.
    Formaldehyde (FA) is an environmental chemical classified as a human carcinogen. It is highly reactive and can bind covalently with hemoglobin (Hb) to produce Hb adducts. Measurement of these Hb adducts provides valuable information about exposure to this chemical. Read More

    Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption.
    Chem Res Toxicol 2017 Aug 18;30(8):1629-1640. Epub 2017 Jul 18.
    Université Paris Descartes, INSERM UMR-S-1007, 45 rue des Saints-Pères, 75006 Paris, France.
    Telomeres protect the ends of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. Read More

    In Silico Prediction of the Toxic Potential of Lupeol.
    Chem Res Toxicol 2017 Aug 13;30(8):1562-1571. Epub 2017 Jul 13.
    Department of Chemical and Biochemical Engineering, Tecnológico Nacional de México-Instituto Tecnológico de Durango , Boulevard Felipe Pescador 1830 Ote., 34080 Durango, México.
    Lupeol is a natural triterpenoid found in many plant species such as mango. This compound is the principal active component of many traditional herbal medicines. In the past decade, a considerable number of publications dealt with lupeol and its analogues due to the interest in their pharmacological activities against cancer, inflammation, arthritis, diabetes, and heart disease. Read More

    A Model To Estimate the Sources of Tobacco-Specific Nitrosamines in Cigarette Smoke.
    Chem Res Toxicol 2017 Aug 17;30(8):1556-1561. Epub 2017 Jul 17.
    SaddlePoint Frontiers , 12001 Bollingbrook Place, Richmond, Virginia 23236, United States.
    Tobacco-specific nitrosamines (TSNAs) are one of the most extensively and continually studied classes of compounds found in tobacco and cigarette smoke.1-5 The TSNAs N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) have been characterized by the US Food and Drug Administration (FDA) as harmful and potentially harmful constituents in tobacco products,6 and cigarette manufacturers report their levels in cigarette tobacco filler and cigarette smoke to the FDA. NNN and NNK are classified by IARC as carcinogenic to humans. Read More

    Development of Theoretical Descriptors for Cytotoxicity Evaluation of Metallic Nanoparticles.
    Chem Res Toxicol 2017 Aug 10;30(8):1549-1555. Epub 2017 Jul 10.
    Department of Chemistry, Hanyang University , 17 Haengdang-dong, Seongdong-gu, Seoul 04763, Korea.
    Motivated by the recent development of quantitative structure-activity relationship (QSAR) methods in the area of nanotoxicology, we proposed an approach to develop additional descriptors based on results of first-principles calculations. For the evaluation of the biochemical activity of metallic nanoparticles, we consider two processes: ion extraction from the surface of a specimen to aqueous media and water dissociation on the surface. We performed calculations for a set of metals (Al, Fe, Cu, Ag, Au, and Pt). Read More

    Effects of Topography-Related Puff Parameters on Carbonyl Delivery in Mainstream Cigarette Smoke.
    Chem Res Toxicol 2017 Jul 5;30(7):1463-1469. Epub 2017 Jul 5.
    Department of Public Health Sciences, Pennsylvania State University Tobacco Center of Regulatory Science (TCORS), Pennsylvania State University College of Medicine , Hershey, Pennsylvania 17033, United States.
    Smoking topography parameters differ substantially between individual smokers and may lead to significant variation in tobacco smoke exposure and risk for tobacco-caused diseases. However, to date, little is known regarding the impact of individual puff parameters on the delivery of many harmful smoke constituents including carbonyls. To examine this, we determined the effect of altering individual puff parameters on mainstream smoke carbonyl levels in machine-smoked reference cigarettes. Read More

    Arsenic Compromises Both p97 and Proteasome Functions.
    Chem Res Toxicol 2017 Jul 7;30(7):1508-1514. Epub 2017 Jul 7.
    Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , 1703 East Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
    Exposure to arsenic is a worldwide problem that affects more than 200 million people. The underlying mechanisms of arsenic toxicity have been difficult to ascertain due to arsenic's pleotropic effects. A number of recent investigations have shown that arsenic can compromise protein quality control through the ubiquitin proteasome system (UPS) or the endoplasmic reticulum associated protein degradation (ERAD) pathway. Read More

    Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase.
    Chem Res Toxicol 2017 Jul 15;30(7):1448-1462. Epub 2017 Jun 15.
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City, Kansas 66160, United States.
    In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E2), an endogenous metabolite of 17β-estradiol (E2), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E2 does not induce pituitary tumors in ACI female rats, whereas E2 produces 100% pituitary tumor incidence. Read More

    A Novel Dual-Color Luciferase Reporter Assay for Simultaneous Detection of Estrogen and Aryl Hydrocarbon Receptor Activation.
    Chem Res Toxicol 2017 Jul 3;30(7):1436-1447. Epub 2017 Jul 3.
    German Federal Institute for Risk Assessment , Department of Chemical and Product Safety, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
    Consumers are exposed to a plethora of anthropogenic and natural substances that can act as agonists or antagonists for various transcription factors. Depending on the exposure and potency, such interactions can potentially lead to adverse health effects, particularly for substances with multiple molecular targets. The early detection of such interactions is thus of high toxicological interest. Read More

    Assessment of DNA Binding and Oxidative DNA Damage by Acrylonitrile in Two Rat Target Tissues of Carcinogenicity: Implications for the Mechanism of Action.
    Chem Res Toxicol 2017 Jul 29;30(7):1470-1480. Epub 2017 Jun 29.
    Chemical Safety Program, Department of Pathology, New York Medical College , Valhalla, New York 10595, United States.
    Exposure to acrylonitrile induces formation of tumors at multiple sites in rats, with females being more sensitive. The present study assessed possible mechanisms of acrylonitrile tumorigenicity, covalent DNA binding, DNA breakage, and oxidative DNA damage, in two target tissues, the brain and Zymbal's glands, of sensitive female Fischer (F344) and Sprague-Dawley (SD) rats. One group received acrylonitrile in drinking water at 100 ppm for 28 days. Read More

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