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Chemical Research in Toxicology

Lauren C Smith, Lucy Lin, Candy S Hwang, Bin Zhou, Diane M Kubitz, Huiying Wang, Kim D Janda
The leaves of the Mitragynine speciosia tree (also known as Kratom) have long been chewed, smoked, or brewed into a tea by people in Southeastern Asian countries, such as Malaysia and Thailand. Just this past year, the plant Kratom gained popularity in the United States as a "legal opioid" and scheduling it as a drug of abuse is currently pending. The primary alkaloid found in Kratom is a μ-opioid receptor agonist, mitragynine, whose structure contains a promising scaffold for immunopharmacological use...
November 16, 2018: Chemical Research in Toxicology
Xiaojing Yang, Weiwei Li, Hui Li, Xu Wang, Yan Chen, Xiucai Guo, Ying Peng, Jiang Zheng
Pyrrolizidine alkaloids (PAs) are known hepatotoxins. Children appear reportedly to be particularly susceptible to PA-induced hepatotoxicity. To facilitate the understanding of the mechanisms of the age-dependent difference in susceptibility to PA hepatotoxicity, a comparative study on hepatotoxicities of retrorsine (RTS), a representative PA, was performed in new weaned (age of 3~4 week) and adult mice (age of 8~12 week). Intraperitoneal administration of RTS at 50 mg/kg induced limited elevation of serum ALT and AST activities in adult mice, while the same dosage of RTS caused intensified increase of serum ALT and AST in new weaned mice...
November 14, 2018: Chemical Research in Toxicology
Samantha M Reilly, Reema Goel, Neil Trushin, Zachary T Bitzer, Ryan J Elias, Joshua Muscat, John P Richie
Previous literature has shown that adding charcoal to cigarette filters can have varying effects on the delivery of toxic carbonyls depending on filter design, amount of charcoal, and puffing profiles. However, these studies have relied on either comparisons between commercially available charcoal and non-charcoal filtered cigarettes or experimental modification of filters to insert a charcoal plug into existing cellulose acetate filters. Make-your-own (MYO) cigarettes can help obviate many of the potential pitfalls of previous studies; thus, we conducted studies using commercial charcoal cigarettes and MYO cigarettes to determine the effects of charcoal on carbonyl delivery...
November 14, 2018: Chemical Research in Toxicology
Lubin Xie, Xiaoheng Li, Jiaying Mo, Linchao Li, Xianwu Chen, Lanlan Chen, Leikai Ma, Yong Chen, Fei Ge, Junzhao Zhao, Ren-Shan Ge
Ziram is a dimethyldithiocarbamate fungicide, which may influence the male reproductive system as a potential endocrine disruptor. We interrogated the disruption of ziram on rat progenitor Leydig cell development. Prepubertal male Sprague-Dawley rats were orally treated with 0, 2, 4, or 8 mg/kg ziram for 2 weeks. We investigated the effects of ziram on serum testosterone levels, Leydig cell number, and Leydig and Sertoli cell gene and protein expression, SIRT1/PGC-1α levels and phosphorylation of AKT1, ERK1/2, and AMPK in vivo...
November 13, 2018: Chemical Research in Toxicology
Rami Bechara, Myriam Nabhan, Diane Antonios, Hayat Azouri, Marc Pallardy
Allergic contact dermatitis (ACD) is a major cause of occupational skin disease and nickel is among the most prevalent contact allergen. Dendritic cells (DCs) play an important role in ACD and in the type of the ensuing immune response through differential phenotypes and cytokines production. The interleukin (IL)-12 cytokine family is composed of heterodimeric cytokines sharing homology at the subunit, receptor, and signaling levels. We previously showed that nickel can upregulate the production of IL-12p40 and IL-23, both known to be pro-inflammatory...
November 13, 2018: Chemical Research in Toxicology
Jing Bai, Yingqian Zhang, Zhen Xi, Marc M Greenberg, Chuanzheng Zhou
8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is a common primary product of cellular oxidative DNA damage. 8-OxodGuo is more readily oxidized than 2'-deoxyguanosine (dG); a two-electron oxidation generates a highly reactive intermediate (OGox), which forms covalent adducts with nucleophiles, including OH-, free amines, and the side chains of amino acids such as lysine. We determined here that K3Fe(CN)6 oxidation of 8-oxodGuo in nucleosome core particles (NCPs) produces high yields, quantitative (i.e. 100%) in some cases, of DNA-protein cross-links (DPCs)...
November 9, 2018: Chemical Research in Toxicology
Yasuhiro Uno, Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki
Cytochromes P450 (P450s) and their genetic variants in humans are important drug-metabolizing enzymes partly accounted for inter-individual variations in drug metabolism and toxicity. However, these genetic variants in P450s have not been fully investigated in cynomolgus macaques, a non-human primate species widely used in toxicological studies. In this study, genetic variants found in cynomolgus CYP1A1, CYP2C9 (formerly CYP2C43), CYP2C19 (CYP2C75), and CYP3A4 (CYP3A8) were assessed on functional importance...
November 9, 2018: Chemical Research in Toxicology
Xiaomin Xia, Bin Lu, Wenjing Dong, Bingwei Yang, Yawen Wang, Qi Qin, Zixuan Liu, Erqun Song, Yang Song
Our previous study showed that tetrachlorobenzoquinone (TCBQ) mediated the activation of Nod-like receptor protein 3 (NLRP3) inflammasome, which involves K+ efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage. In addition, TCBQ down-regulates NLRP3 ubiquitination and promotes the activation of NLRP3 inflammasome. However, the induction of NLRP3 inflammasome by atypical pathways has not yet been characterized. Using human umbilical vein endothelial cells (HUVEC), we discovered that TCBQ activates caspase 1/4/5 and cleaves gasdermin D (GSDMD) into N-terminal and C-terminal cleavage products...
November 9, 2018: Chemical Research in Toxicology
Jessica R Murray, Clementina A Mesaros, Volker M Arlt, Albrecht Seidel, Ian A Blair, Trevor M Penning
3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen detected in diesel exhaust particulate and ambient air pollution. It requires metabolic activation via nitroreduction to promote DNA adduct formation and tumorigenesis. NAD(P)H:quinone oxidoreductase 1 (NQO1) has been previously implicated as the major nitroreductase responsible for 3-NBA activation, but it has recently been reported that human aldo-keto reductase 1C3 (AKR1C3) displays nitroreductase activity toward the chemotherapeutic agent PR-104A...
November 8, 2018: Chemical Research in Toxicology
Bei Gao, Liang Chi, Pengcheng Tu, Nan Gao, Kun Lu
The gut microbiome is highly involved in numerous aspects of host physiology, from energy harvest to stress response, and can confer many benefits to the host. The gut microbiome development could be affected by genetic and environmental factors, including the pesticides. The carbamate insecticide aldicarb has been extensively used in agriculture, which raises serious public health concern. However, the impact of aldicarb on the gut microbiome, host metabolome and lipidome has not been well studied yet. Herein, we use multi-omics approaches, including16S rRNA sequencing, shotgun metagenomics sequencing, metabolomics and lipidomics, to elucidate aldicarb-induced toxicity in the gut microbiome and the host metabolic homeostasis...
November 8, 2018: Chemical Research in Toxicology
Casey Krawic, Anatoly Zhitkovich
Epidemiological studies in chromate production have established hexavalent chromium as a potent lung carcinogen. Inhalation of chromium(VI) most often occurs in mixtures with other metals as among stainless steel welders, which is the largest occupational group with Cr(VI) exposure. Surprisingly, carcinogenicity of Cr(VI)-containing welding fumes is moderate and not consistently higher than that of Cr-free welding. Here, we investigated interactions between chromate and three other metal ions [Fe(III), Mn(II), Ni(II)] that are typically released from stainless steel welding particles...
November 6, 2018: Chemical Research in Toxicology
Hana Jansová, Jan Kubeš, Petra Reimerová, Petra Štěrbová-Kovaříková, Jaroslav Roh, Tomáš Šimůnek
Salicylaldehyde isonicotinoyl hydrazone (SIH) is a small molecule and lipophilic chelating agent that firmly binds ferric ions from the cellular labile iron pool and is able to protect various tissues against oxidative damage. Previously, SIH possessed the best ratio of cytoprotective efficiency to toxicity among various iron chelators, including the desferrioxamine, deferiprone, and deferasirox used in clinical practice. Here, we prepared a series of 2,6-dihydroxybenzaldehyde aroylhydrazones as SIH analogues with an additional hydroxyl group that can be involved in the chelation of metal ions...
November 5, 2018: Chemical Research in Toxicology
Jingshu Guo, Peter W Villalta, Christopher J Weight, Radha Bonala, Francis Johnson, Thomas A Rosenquist, Robert J Turesky
Epidemiological studies have linked aromatic amines (AAs) from tobacco smoke and some occupational exposures with bladder cancer risk. Several epidemiological studies have also reported a plausible role for structurally related heterocyclic aromatic amines present in tobacco smoke or formed in cooked meats with bladder cancer risk. DNA adduct formation is an initial biochemical event in bladder carcinogenesis. We examined paired fresh-frozen (FR) and formalin-fixed paraffin-embedded (FFPE) non-tumor bladder tissues from 41 bladder cancer patients for DNA adducts of 4-aminobiphenyl (4-ABP), a bladder carcinogen present in tobacco smoke, and 2-amino-9H-pyrido[2,3-b]indole, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, possible human carcinogens, which occur in tobacco smoke and cooked meats...
November 2, 2018: Chemical Research in Toxicology
Hauh-Jyun Candy Chen, Sun Wai Ip
Methylation of biomolecules is involved in many important biological processes. The contributing methylating agents arise from endogenous and exogenous sources (such as cigarette smoking). Human hemoglobin is easily accessible from blood and has been used as a molecular dosimeter for monitoring chemical exposure. We recently developed a method for characterization and quantification of the extents of methylation and ethylation in hemoglobin by nanoflow liquid chromatography tandem mass spectrometry under the selected reaction monitoring mode...
November 2, 2018: Chemical Research in Toxicology
Zixuan Liu, Wenjing Dong, Bingwei Yang, Lu Peng, Xiaomin Xia, Lanxiang Pu, Na Zhang, Erqun Song, Yang Song
Our previous studies demonstrated that tetrachlorobenzoquinone (TCBQ) is toxic to neuron-like cells, which is related to endoplasmic reticulum (ER) stress-induced apoptosis. However, it remains unclear whether TCBQ causes the opening of cellular defense responses. Here we found that activation of nuclear factor erythroid-derived 2-like 2 (Nrf2) triggered an adaptive response against the neurotoxicity induced by TCBQ through the upregulation of intracellular glutathione (GSH) levels in rat pheochromocytoma PC12 cells...
November 2, 2018: Chemical Research in Toxicology
Luca Dellafiora, Gianni Galaverna, Chiara Dall'Asta
Fumonisins are mycotoxins produced by Fusarium fujikuroi species complex that may contaminate food and feed threatening human and animal health. Among the fumonisins group, fumonisin B1 is the most widespread and best characterized in terms of toxicity, while additional toxicological data on its congeners, such as N-acylated and hydrolyzed forms, need to be collected to support the group-based risk assessment. The inhibition of ceramide synthase has been identified as the key molecular mechanism of fumonisins toxicity resulting in modifications of sphingolipids rheostat...
November 2, 2018: Chemical Research in Toxicology
Sisi Wang, Tiffany M Scharadin, Maike Zimmermann, Michael A Malfatti, Kenneth W Turteltaub, Ralph de Vere White, Chong-Xian Pan, Paul T Henderson
Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision-making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue, and may be used to predict patient will response...
November 1, 2018: Chemical Research in Toxicology
Amanda Degner, Henrik Carlsson, Isabella Karlsson, Johan Eriksson, Suresh S Pujari, Natalia Y Tretyakova, Margareta Åsa Törnqvist
Humans are exposed to a wide range of electrophilic compounds present in our diet, environment, or formed endogenously as part of normal physiological processes. These electrophiles can modify nucleophilic sites of proteins and DNA to form covalent adducts. Recently, powerful untargeted adductomic approaches have been developed for systematic screening of these adducts in human blood. Our earlier untargeted adductomics study detected 19 unknown adducts to N-terminal valine in hemoglobin (Hb) in human blood...
October 30, 2018: Chemical Research in Toxicology
Peter Dornbos, Melanie Warren, Robert B Crawford, Norbert E Kaminski, David W Threadgill, John J LaPres
2,3,7,8-Tetrachlordibenzo- p-dioxin (TCDD) is an environmental pollutant that can cause various toxic effects, including chloracne, metabolic syndrome, and immune suppression. Most of the toxicity associated with TCDD is mediated through activation of the aryl hydrocarbon receptor (AHR). Recent research has suggested the presence of a wide-range of interindividual variability in TCDD-mediated suppression of the Immunoglobulin-M (IgM) response across the human population. In an attempt to identify putative modifiers of AHR-mediated immunosuppression beyond the AHR, B cells were isolated from a panel of genetically diverse mouse strain to scan for modulators that drive interstrain differences in TCDD-mediated suppression of the IgM response...
October 30, 2018: Chemical Research in Toxicology
Yue Chen, Hongbin Yang, Zengrui Wu, Guixia Liu, Yun Tang, Weihua Li
The farnesoid X receptor (FXR) emerges as a promising drug target involved in regulating various metabolic pathways, yet some xenobiotic compounds binding to FXR would be an important determinant to induce the receptor dysfunctions that lead to undesirable side effects. Thus, it is critical to identify potential xenobiotics that disrupt normal FXR functions. In this work, five machine learning methods coupled with eight molecular fingerprints and twenty molecular descriptors were used to develop classification models for prediction of FXR binders...
October 29, 2018: Chemical Research in Toxicology
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