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Chemical Research in Toxicology

Bei Gao, Liang Chi, Ridwan Mahbub, Xiaoming Bian, Pengcheng Tu, Hongyu Ru, Kun Lu
Lead exposure remains as a global public health issue and recent Flint water crisis has again raised concern about lead toxicity in the public. The toxicity of lead has been well established in a variety of systems and organs. It has been increasingly appreciated that gut microbiome is highly involved in many critical physiological processes, such as food digestion, immune system development, and metabolic homeostasis, etc. However, despite the key role of gut microbiome in human health, the functional impact of lead exposure on gut microbiome has not been studied yet...
February 24, 2017: Chemical Research in Toxicology
Katarina Vazdar, Danijela Vojta, Davor Margetić, Mario Vazdar
4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) are biologically important reactive aldehydes formed during oxidative stress in phospholipid bilayers. They are highly reactive species due to presence of several reaction centers and can react with amino acids in peptides and proteins, as well as phosphoethanolamine (PE) lipids, thus modifying their biological activity. The aim of this work is to study in a molecular detail the reactivity of HNE and ONE towards PE lipids in a simplified system containing only lipids and reactive aldehydes in dichloromethane as an inert solvent...
February 21, 2017: Chemical Research in Toxicology
Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa Wakamatsu
The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-quinones...
February 20, 2017: Chemical Research in Toxicology
Alessia Stornetta, Peter W Villalta, Frederike Gossner, William R Wilson, Silvia Balbo, Shana J Sturla
PR104A is an experimental DNA-alkylating hypoxia-activated prodrug that can also be activated in an oxygen-independent manner by the two-electron aldo-keto reductase 1C3. Nitroreduction leads to the formation of cytotoxic hydroxylamine (PR104H) and amine (PR104M) metabolites, which induce DNA mono and cross-linked adducts in cells. PR104A-derived DNA adducts can be utilized as drug-specific biomarkers of efficacy and as a mechanistic tool to elucidate the cellular and molecular effects of PR104A. Toward this goal, a mass spectrometric bioanalysis approach based on a stable isotope-labeled adduct mixture (SILAM) and selected reaction monitoring (SRM) data acquisition for relative quantitation of PR104A-derived DNA adducts in cells was developed...
February 19, 2017: Chemical Research in Toxicology
Lina Gao, Esra Mutlu, Leonard B Collins, Nigel J Walker, Hadley J Hartwell, James R Olson, Wei Sun, Avram Gold, Louise M Ball, James A Swenberg
DNA oxidation damage has been regarded as one of the possible mechanisms for the hepatic carcinogenesis of dioxin-like compounds (DLCs). In this study, we evaluated the toxic equivalency factor (TEF) from the standpoint of induced DNA oxidation products and their relationship to toxicity and carcinogenicity. Nine DNA oxidation products were analyzed in the liver of female Sprague-Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alone or the tertiary mixture of TCDD, 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) by gavage for 14, 31, and 53 weeks (5 days/week) by LC-MS/MS: 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo); 1,N(6)-etheno-2'-deoxyadenosine (1,N(6)-εdAdo); N(2),3-ethenoguanine (N(2),3-εG); 7-(2-oxoethly)guanine (7-OEG); 1,N(2)-etheno-2'-deoxyguanosine (1,N(2)-εdGuo); malondialdehyde (M1dGuo); acrolein (AcrdGuo); crotonaldehyde (CrdGuo); and 4-hydroxynonenal (HNEdGuo) derived 2'-deoxyguanosine adducts...
February 16, 2017: Chemical Research in Toxicology
Swati S More, Jaime Nugent, Ashish P Vartak, Steffan M Nye, Robert Vince
Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios...
February 16, 2017: Chemical Research in Toxicology
Peter P Fu, Qingsu Xia, Xiaobo He, Shimon Barel, Nir Edery, Frederick A Beland, Jakob A Shimshoni
Pyrrolizidine alkaloids are among the most common poisonous plants affecting livestock, wildlife, and humans. Exposure of humans and livestock to toxic pyrrolizidine alkaloids through the intake of contaminated food and feed may result in poisoning, leading to devastating epidemics. During February 2014, 73 mixed breed female beef cows from the Galilee region of Israel were accidently fed pyrrolizidine alkaloid contaminated hay for 42 days, resulting in the sudden death of 24 cows over a period of 63 days. The remaining cows were slaughtered 2...
February 10, 2017: Chemical Research in Toxicology
George J Brewer
Alzheimer's disease, the most common cause of dementia, is at epidemic proportions (15 to 44% depending on age, of those age 65 to 84) in the U.S. and other developed countries, but remains relatively rare in undeveloped countries. Surprisingly, solid historical data reveals the epidemic is a creature of the last century. That is the disease was also rare in developed countries, until the 20th century. It is disappointing that these historical and demographic facts have been ignored by the Alzheimer's disease scientific community...
February 6, 2017: Chemical Research in Toxicology
Peter James O'Brien, Anna Edvardsson
A multiparametric, live-cell, high-content-screening (HCS) cytotoxicity assay was first demonstrated in 2006 (Arch Toxicol 80, 580-604) to be highly concordant with human hepatotoxicity, including idiosyncratic hepatotoxicities, and other target organ toxicities, in contrast to historical assays. The success of the assay was attributed to its simultaneous measurement of multiple, appropriate "cytobiomarkers; use of human cells with xenometabolic competence for toxicities mediated by metabolites, 72-hour exposure to enable expression of slower-acting toxicants, exposure to a wide-range of concentrations, up to 30- to 100-fold the efficacious concentration, and normalising the in vitro cytotoxic concentration to an estimate of the in vivo concentration of exposure...
February 2, 2017: Chemical Research in Toxicology
Fan Zhang, Yongsheng Xiao, Yinsheng Wang
Humans are exposed to arsenic species through inhalation, ingestion and dermal contact, which may lead to skin, liver, and bladder cancers as well as cardiovascular and neurological diseases. The mechanisms underlying the cytotoxic and carcinogenic effects of arsenic species, however, remain incompletely understood. To exploit the mechanisms of toxicity of As(III), we employed stable isotope labeling by amino acids in cell culture (SILAC) together with LC-MS/MS analysis to assess quantitatively the As(III)-induced perturbation of the entire proteome of cultured human skin fibroblast cells...
January 31, 2017: Chemical Research in Toxicology
Ryan S Wible, Thomas R Sutter
The unique biophysical and electronic properties of cysteine make this molecule one of the most biologically critical amino acids in the proteome. The defining sulfur atom in cysteine is much larger than the oxygen and nitrogen atoms more commonly found in the other amino acids. As a result of its size, the valence electrons of sulfur are highly polarizable. Unique protein microenvironments favor the polarization of sulfur thus increasing the overt reactivity of cysteine. Here we provide a brief overview of the endogenous generation of reactive oxygen and electrophilic species and specific examples of enzymes and transcription factors in which the oxidation or covalent modification of cysteine in those proteins modulates their function...
January 25, 2017: Chemical Research in Toxicology
Carine Poussin, Vincenzo Belcastro, Florian Martin, Stéphanie Boué, Manuel C Peitsch, Julia Hoeng
Systems toxicology intends to quantify the effect of toxic molecules in biological systems and unravel their mechanisms of toxicity. The development of advanced computational methods is required for analyzing and integrating high throughput data generated for this purpose as well as for extrapolating predictive toxicological outcomes and risk estimates. To ensure performance and reliability of the methods and verify conclusions from systems toxicology data analysis, it is important to conduct unbiased evaluations by independent third parties...
January 13, 2017: Chemical Research in Toxicology
Claudia Otto, Graciela Spivak, Claudia Marie Nathalie Aloisi, Mirco Menigatti, Hanspeter Nägeli, Philip C Hanawalt, Marina Tanasova, Shana J Sturla
Bioactivation as well as DNA repair affect the susceptibility of cancer cells to the action of DNA-alkylating chemotherapeutic drugs. However, information is limited with regard to the relative contributions of these processes to the biological outcome of metabolically activated DNA alkylating agents. We evaluated the influence of cellular bioactivation capacity and DNA repair on cytotoxicity of the DNA alkylating agent, acylfulvene (AF). We compared cytotoxicity and RNA synthesis inhibition by AF and its synthetic activated analog iso-M0 in a panel of fibroblast cell lines with deficiencies in transcription-coupled (TC-NER) or global genome nucleotide excision repair (GG-NER)...
January 11, 2017: Chemical Research in Toxicology
M Shane Hutson, Maxwell C K Leung, Nancy Baker, Richard M Spencer, Thomas B Knudsen
Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from chemical-induced cellular alterations, we built a multi-cellular agent-based model in CompuCell3D that recapitulates the cellular networks and collective cell behavior underlying growth and fusion of the mammalian secondary palate. The model incorporated multiple signaling pathways (TGFβ, BMP, FGF, EGF, SHH) in a biological framework to recapitulate morphogenetic events from palatal outgrowth through midline fusion...
January 3, 2017: Chemical Research in Toxicology
Alessia Stornetta, Maike Zimmermann, George D Cimino, Paul T Henderson, Shana J Sturla
Biomarker-driven drug selection plays a central role in cancer drug discovery and development, and in diagnostic strategies to improve the use of traditional chemotherapeutic drugs. DNA-modifying anticancer drugs are still used as first line medication, but drawbacks such as resistance and side effects remain an issue. Monitoring the formation and level of DNA modifications induced by anticancer drugs is a potential strategy for stratifying patients and predicting drug efficacy. In this perspective, preclinical and clinical data concerning the relationship between drug-induced DNA adducts and biological response for platinum drugs and combination therapies, nitrogen mustards and half-mustards, hypoxia-activated drugs, reductase-activated drugs, and minor groove binding agents are presented and discussed...
January 3, 2017: Chemical Research in Toxicology
Tanja Waldmann, Marianna Grinberg, André König, Eugen Rempel, Stefan Schildknecht, Margit Henry, Anna-Katharina Holzer, Nadine Dreser, Vaibhav Shinde, Agapios Sachinidis, Jörg Rahnenführer, Jan G Hengstler, Marcel Leist
Analysis of transcriptome changes has become an established method to characterize the reaction of cells to toxicants. Such experiments are mostly performed at compound concentrations close to the cytotoxicity threshold. At present, little information is available on concentration-dependent features of transcriptome changes, in particular, at the transition from noncytotoxic concentrations to conditions that are associated with cell death. Thus, it is unclear in how far cell death confounds the results of transcriptome studies...
December 21, 2016: Chemical Research in Toxicology
Cristina Pavan, Bice Fubini
The variability of quartz hazard stands as one of the most puzzling issues in particle toxicology, notwithstanding the fact that silicosis, the most ancient occupational disease, was the very topic from which the study of the toxicity of particulates developed. Over the years, other adverse effects of silica particles (i.e., lung cancer and autoimmune diseases) were detected and described. However, a few gaps are still present in the physicochemical determinants and cellular pathways involved in the mechanisms of silica pathogenicity...
December 19, 2016: Chemical Research in Toxicology
Steven Hiemstra, Marije Niemeijer, Esmee Koedoot, Steven Wink, Janna E Klip, Matthijs Vlasveld, Elisabeth de Zeeuw, Bram van Os, Andrew White, Bob van de Water
A quantitative dynamics pathway map of the Nrf2-mediated oxidative stress response and p53-related DNA damage response pathways as well as the cross-talk between these pathways has not systematically been defined. To allow the dynamic single cell evaluation of these pathways, we have used BAC-GFP recombineering to tag for each pathway's three key components: for the oxidative stress response, Keap1-GFP, Nrf2-GFP, and Srxn1-GFP; for the DNA damage response, 53bp1-GFP, p53-GFP, and p21-GFP. The dynamic activation of these individual components was assessed using quantitative high throughput confocal microscopy after treatment with a broad concentration range of diethyl maleate (DEM; to induce oxidative stress) and etoposide (to induce DNA damage)...
December 16, 2016: Chemical Research in Toxicology
Yoshito Kumagai, Yumi Abiko
Included among the many environmental electrophiles are aromatic hydrocarbon quinones formed during combustion of gasoline, crotonaldehyde in tobacco smoke, methylmercury accumulated in fish, cadmium contaminated in rice, and acrylamide in baked foods. These electrophiles can modify nucleophilic functions such as cysteine residues in proteins forming adducts and in the process activate cellular redox signal transduction pathways such as kinases and transcription factors. However, higher concentrations of electrophiles disrupt such signaling by nonselective covalent modification of cellular proteins...
December 16, 2016: Chemical Research in Toxicology
Suresh S Pujari, Natalia Tretyakova
DNA nucleobases are the prime targets for chemical modifications by endogenous and exogenous electrophiles. Alkylation of the N7 position of guanine and adenine in DNA triggers base-catalyzed imidazole ring opening and the formation of N(5)-substituted formamidopyrimidine (N(5)-R-FAPy) lesions. Me-FAPy-dG adducts induced by exposure to methylating agents and AFB-FAPy-dG lesions formed by aflatoxin B1 have been shown to persist in cells and to contribute to toxicity and mutagenicity. In contrast, the biological outcomes of other N(5)-substituted FAPy lesions have not been fully elucidated...
December 13, 2016: Chemical Research in Toxicology
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