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Chemical Research in Toxicology

Preetleen Kathuria, Purshotam Sharma, Richard A Manderville, Stacey D Wetmore
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 post-replication 2-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...
July 18, 2017: Chemical Research in Toxicology
Christopher O Miles
Microcystins are potent cyclic heptapeptide toxins found in some cyanobacteria, and usually contain an α,β-unsaturated carbonyl group that is readily conjugated to thiol-containing amino acids, peptides, and proteins in vivo and in vitro. Methods for deconjugating these types of adducts have recently been reported, but the reactions are slow or result in derivatized microcystins. Mercaptoethanol derivatives of a range of microcystins were therefore used as model compounds to develop deconjugation procedures in which the dialkyl sulfide linkage was oxidized to a sulfoxide or sulfone that, when treated with base, rapidly eliminated the adducted thiol as its sulfenate or sulfinate via β-elimination to afford free microcystins with the α,β-unsaturated carbonyl group intact...
July 17, 2017: Chemical Research in Toxicology
José Soares, Emanuele Alves, André Silva, Natália Figueiredo, João F Neves, Sara Cravo, Maria Rangel, Annibal Netto, Félix Carvalho, Ricardo Jorge Dinis-Oliveira, Carlos Afonso
"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 the opioid claimed to be the main component of krokodil and the main responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed by a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS)...
July 14, 2017: Chemical Research in Toxicology
Josh Eixenberger, Catherine Anders, Rebecca Hermann, Raquel Brown, K M Reddy, Alex Punnoose, Denise Wingett
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...
July 10, 2017: Chemical Research in Toxicology
Bahar Edrissi, Koli Taghizadeh, Benjamin C Moeller, Rui Yu, Dean Kracko, Melanie Doyle-Eisele, James A Swenberg, Peter C Dedon
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 (6h/day) and investigated adduct loss over a 7-day post-exposure period using liquid chromatography-coupled tandem mass spectrometry...
July 10, 2017: Chemical Research in Toxicology
D W Boukhvalov, T H Yoon
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)...
July 10, 2017: Chemical Research in Toxicology
Ahmad El Hellani, Rachel El-Hage, Rola Salman, Soha Talih, Alan Shihadeh, Najat Aoun Saliba
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 are normally associated with counter anions in tobacco products. The chemical and physical properties of counter anions may differently influence the nicotine form and emissions in ECIG aerosols. In this study, we examined how these anions influence nicotine emissions as well as their evaporation behavior and potential decomposition during ECIG operation...
July 7, 2017: Chemical Research in Toxicology
Joseph Tillotson, Christopher J Zerio, Bryan Harder, Andrew J Ambrose, Kevin S Jung, MinJin Kang, Donna D Zhang, Eli Chapman
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. In this article, a link between arsenic and protein quality control is reported. Biochemical and cellular data demonstrate a misregulation of the ATPase cycle of the ATPase associated with various cellular activities (AAA+) chaperone, p97...
July 7, 2017: Chemical Research in Toxicology
Samantha M Reilly, Reema Goel, Zachary Bitzer, Ryan J Elias, Jonathan Foulds, Joshua Muscat, John P Richie
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. Carbonyls including formaldehyde, acetaldehyde, crotonaldehyde, propionaldehyde, methyl ethyl ketone (MEK), acrolein, and acetone were determined in cigarette smoke by HPLC after derivatization with 2,4-dinitrophenylhydrazine (DNPH)...
July 5, 2017: Chemical Research in Toxicology
Patrick Tarnow, Steffi Bross, Lisa Wollenberg, Yoshihiro Nakajima, Yoshihiro Ohmiya, Tewes Tralau, Andreas Luch
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. Here, we report on the development of a new cellular dual-color reporter assay that allows for time-resolved and quantitative recording of estrogen receptor (ER) and aryl hydrocarbon receptor (AHR) activation in living cells...
July 3, 2017: Chemical Research in Toxicology
Min Yang, Maria Ospina, Chui Tse, Stephen Toth, Samuel P Caudill, Hubert Vesper
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. We developed a robust, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantifying FA-Hb adducts in red blood cells. The method measures the FA-VHLTPEEK peptide after trypic digestion. The peptide is a FA adduct at the N-terminus of the beta chain of human Hb...
June 29, 2017: Chemical Research in Toxicology
Gary M Williams, Tetyana Kobets, Jian-Dong Duan, Michael J Iatropoulos
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. Two other groups were administered either acrylonitrile in drinking water at 100 ppm or drinking water alone for 27 days, followed by a single oral gavage dose of 11 mg/kg bw (14)C-acrylonitrile on day 28...
June 29, 2017: Chemical Research in Toxicology
Razan Charif, Christine Granotier-Beckers, Hélène Charlotte Bertrand, Joel Poupon, Evelyne Segal-Bendirdjian, Marie-Paule Teulade-Fichou, François D Boussin, Sophie Bombard
Telomeres protect the end 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. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ)...
June 28, 2017: Chemical Research in Toxicology
Manuel Antonio Ruiz-Rodríguez, Angelo Vedani, Ana Lidia Flores-Mireles, Manuel Humberto Chairez-Ramirez, Jose Alberto Gallegos-Infante, Ruben F Gonzalez-Laredo
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. To identify further potential applications of lupeol and its analogues, it is necessary to investigate their mechanisms of action, particularly, their interaction with off-target proteins that may trigger adverse effects or toxicity...
June 27, 2017: Chemical Research in Toxicology
Peter J Lipowicz, Jeffrey Ira Seeman
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...
June 27, 2017: Chemical Research in Toxicology
Shaojun Yang, Yi-Hua Jan, Vladimir Mishin, Diane E Heck, Debra L Laskin, Jeffrey D Laskin
Reactive carbonyls such as diacetyl (2,3-butanedione) and 2,3-pentanedione in tobacco and many food and consumer products are known to cause severe respiratory diseases. Many of these chemicals are detoxified by carbonyl reductases in the lung, in particular, dicarbonyl/l-xylulose reductase (DCXR), a multifunctional enzyme important in glucose metabolism. DCXR is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Using recombinant human enzyme, we discovered that DCXR mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals...
June 26, 2017: Chemical Research in Toxicology
Elana R Elkin, Marie S O'Neill
For decades, many studies have linked maternal smoking to an increased risk of preterm birth. As a result, the scientific community has long hypothesized that exposure to environmental tobacco smoke (ETS), commonly referred to as second-hand smoke, is also associated with an increased risk of preterm birth. Multiple studies have examined this proposed association through different strategies and approaches. Recently, a small number of epidemiology studies have examined preterm birth trends before and after the implementation of antismoking legislation in various jurisdictions...
June 20, 2017: Chemical Research in Toxicology
Peng Wang, Maria Voronkova, Sudjit Luanpitpong, Xiaoqing He, Heimo Riedel, Cerasela Z Dinu, Liying Wang, Yon Rojanasakul
Carbon nanotubes (CNTs) represent a major class of engineered nanomaterials that are being used in diverse fields. However, their use has increasingly become a concern because of their carcinogenic potential. Accumulating evidence has demonstrated that certain types of CNTs are carcinogenic or tumor-promoting in animal models. However, the underlying molecular and cellular mechanisms are unclear. Here, we report that chronic exposure to single-walled (SW) CNTs results in the induction of Slug, a key transcription factor that induces an epithelial-mesenchymal transition (EMT), in human lung epithelial cells...
June 20, 2017: Chemical Research in Toxicology
Pan Wang, Laura H Mills, Ji-Hoon Song, Jina Yu, Bao-Ting Zhu
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. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E2 in several organs...
June 15, 2017: Chemical Research in Toxicology
Da Yang, Min Zhang, Barry Gold
Wnt signaling is compromised early in the development of human colorectal cancer (CRC) due to truncating nonsense mutations in adenomatous polyposis coli (APC). CRC induced by chemical carcinogens, such as heterocyclic aromatic amines and azoxymethane, in mice also involves dysregulation of Wnt signaling but via activating missense mutations in the β-catenin oncogene despite the fact that genetically modified mice harboring an inactive APC allele efficiently develop CRC. In contrast, activating mutations in β-catenin are rarely observed in human CRC...
June 15, 2017: Chemical Research in Toxicology
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