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Toxicological Sciences: An Official Journal of the Society of Toxicology

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https://www.readbyqxmd.com/read/28453788/usage-of-dexamethasone-increases-the-risk-of-cranial-neural-crest-dysplasia-in-the-chick-embryo
#1
Xin Cheng, He Li, Yu Yan, Guang Wang, Zachary Berman, Manli Chuai, Xuesong Yang
Dexamethasone (Dex) is commonly used in the treatment of a variety of benign and malignant conditions. Unfortunately, although it has a variety of teratogenic effects, it remains used in clinical practice for pregnant women mainly due to limited alternatives. However, there is limited knowledge of the mechanisms that lead to the observed teratogenic effects. In this study, the effects of Dex during embryogenesis on neural crest development were evaluated in the early chick embryos. First, we demonstrated that 100µL 10-6 M Dex treatment leads to craniofacial developmental defects, and also retards embryo growth and plausibly can cause embryo demise...
April 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28453772/hepatic-hazard-assessment-of-silver-nanoparticle-exposure-in-healthy-and-chronically-alcohol-fed-mice
#2
Ali Kermanizadeh, Nicklas R Jacobsen, Martin Roursgaard, Steffen Loft, Peter Møller
Silver (Ag) nanoparticles (NPs) are currently among one of the most widely used nanomaterials. This in turn, implies an increased risk of human and environmental exposure. Alcohol abuse is a global issue with millions of people in the general population affected by the associated adverse effects. The excessive consumption of alcohol is a prominent cause of chronic liver disease which manifest in multiple disorders. In this study the adverse health effects of Ag NP exposure were investigated in models of alcoholic hepatic disease in vitro and in vivo...
April 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28453742/blinded-contractility-analysis-in-hipsc-cardiomyocytes-in-engineered-heart-tissue-format-comparison-with-human-atrial-trabeculae
#3
Ingra Mannhardt, Alexandra Eder, Berengere Dumotier, Maksymilian Prondzynski, Elisabeth Krämer, Martin Traebert, Klaus-Dieter Söhren, Frederik Flenner, Konstantina Stathopoulou, Marc D Lemoine, Lucie Carrier, Torsten Christ, Thomas Eschenhagen, Arne Hansen
Objective: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) may serve as a new assay for drug testing in a human context, but their validity particularly for the evaluation of inotropic drug effects remains unclear. In this blinded analysis, we compared the effects of 10 indicator compounds with known inotropic effects in electrically stimulated (1.5 Hz) hiPSC-CM-derived 3 dimensional engineered heart tissue (EHT) and human atrial trabeculae (hAT). Methods and results: Human EHTs were prepared from iCell® hiPSC-CM, hAT obtained at routine heart surgery...
April 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28453659/udp-glucuronosyltransferase-ugt-2b-subfamily-interspecies-differences-in-carnivores
#4
Takamitsu Kondo, Yoshinori Ikenaka, Shouta M M Nakayama, Yusuke K Kawai, Hazuki Mizukawa, Yoko Mitani, Kei Nomyama, Shinsuke Tanabe, Mayumi Ishizuka
UDP-glucuronosyltransferases (UGTs) are among the most important xenobiotic metabolizing enzymes that conjugate a wide range of chemicals. Previous studies showed that Felidae and Pinnipedia species have very low UGT activities toward some phenolic compounds because of the UGT1A6 pseudogene and small numbers of UGT1A isozymes. In addition to the UGT1As, UGT2Bs isozymes also conjugate various endogenous (e.g., estrogens, androgens, and bile acids) and exogenous compounds (opioids, NSAIDs, and environmental pollutants)...
April 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28453831/sortilin-1-loss-of-function-protects-against-cholestatic-liver-injury-by-attenuating-hepatic-bile-acid-accumulation-in-bile-duct-ligated-mice
#5
Jibiao Li, Benjamin L Woolbright, Wen Zhao, Yifeng Wang, David Matye, Bruno Hagenbuch, Hartmut Jaeschke, Tiangang Li
Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid metabolism. This study further investigated the role of Sort1 in modulating bile acid detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 KO mice had attenuated liver injury 24 h after BDL, which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger bile acid pool size than sham-operated WT mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic bile acid accumulation and smaller bile acid pool size...
April 26, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28453775/deconvoluting-kinase-inhibitor-induced-cardiotoxicity
#6
Sarah D Lamore, Ernst Ahlberg, Scott Boyer, Michelle L Lamb, Maria P Hortigon-Vinagre, Victor Rodriguez, Godfrey L Smith, Johanna Sagemark, Lars Carlsson, Stephanie M Bates, Allison L Choy, Jonna Stålring, Clay W Scott, Matthew F Peters
Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte beating...
April 26, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28453771/interplay-between-ifn-%C3%AE-and-il-6-impacts-the-inflammatory-response-and-expression-of-interferon-regulated-genes-in-environmental-induced-autoimmunity
#7
David M Cauvi, Gabrielle Cauvi, Christopher B Toomey, Eric Jacquinet, K Michael Pollard
IFN-γ has been found to be robustly important to disease pathogenesis in both idiopathic and induced models of murine lupus. In transgenic mice, over production of IFN-γ in the skin results in an inflammatory response and autoimmunity. This suggests that localized exposure to environmental factors that induce autoimmunity may be associated with expression of an IFN-γ dependent inflammatory response. Using murine mercury-induced autoimmunity (mHgIA), the severity of inflammation and proinflammatory cytokine expression, including the cellular source of IFN-γ, were assessed at the site of subcutaneous exposure and in secondary lymphoid organs...
April 26, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28444390/characterisation-of-drug-specific-signalling-between-primary-human-hepatocytes-and-immune-cells
#8
Monday O Ogese, Lee Faulkner, Roz E Jenkins, Neil S French, Ian M Copple, Daniel J Antoine, Mohamed Elmasry, Hasan Malik, Christopher E Goldring, B Kevin Park, Catherine Betts, Dean J Naisbitt
It is now apparent that antigen-specific T-cells are activated in certain patients with drug-induced liver injury (DILI). Since cross-talk between hepatocytes and immune cells is likely to be critical in determining the outcome of drug exposure, the aim of this study was to profile the signals released by drug-treated hepatocytes and to characterise the impact of these molecules on dendritic cells. Human hepatocytes were exposed to three drugs (flucloxacillin, amoxicillin and isoniazid) associated with DILI potentially mediated by the adaptive immune system as drug-specific T-cells have been isolated from DILI patients, and the metabolite nitroso-sulfamethoxazole (SMX-NO)...
April 21, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28431163/an-evaluation-of-the-human-relevance-of-the-lung-tumors-observed-in-female-mice-treated-with-permethrin-based-on-mode-of-action
#9
Tomoya Yamada, Miwa Kondo, Kaori Miyata, Keiko Ogata, Masahiko Kushida, Kayo Sumida, Satoshi Kawamura, Thomas G Osimitz, Brian G Lake, Samuel M Cohen
Permethrin increased the incidence of bronchiolo-alveolar adenomas in female mice but not male mice or female or male rats. Studies were conducted to determine whether permethrin has mitogenic activity in Club cells in mouse lung as the basis for the mode of action (MOA) for the lung adenoma induction. Several short term experiments focusing on time-course, dose-response, reversibility, sex difference, strain difference, and species difference were evaluated for Club cell proliferation and morphology. The findings demonstrated that permethrin slightly and continuously enhanced Club cell proliferation at tumor-associated dose levels in female mice, but did not increase proliferation in male mice or in female rats...
April 18, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28431184/congener-specific-disposition-of-chiral-polychlorinated-biphenyls-in-lactating-mice-and-their-offspring-implications-for-pcb-developmental-neurotoxicity
#10
Izabela Kania-Korwel, Tracy Lukasiewicz, Christopher D Barnhart, Marianna Stamou, Haeun Chung, Kevin M Kelly, Stelvio Bandiera, Pamela J Lein, Hans-Joachim Lehmler
Chiral polychlorinated biphenyl (PCB) congeners have been implicated by laboratory and epidemiological studies in PCB developmental neurotoxicity. These congeners are metabolized by cytochrome P450 (P450) enzymes to potentially neurotoxic hydroxylated metabolites (OH-PCBs). The present study explores the enantioselective disposition and toxicity of two environmentally relevant, neurotoxic PCB congeners and their OH-PCB metabolites in lactating mice and their offspring following dietary exposure of the dam. Female C57BL/6N mice (8 weeks old) were fed daily, beginning two weeks prior to conception and continuing throughout gestation and lactation, with 3...
April 14, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28402575/impaired-proliferation-and-differentiation-of-the-conducting-airway-epithelium-associated-with-bronchiolitis-obliterans-after-sulfur-mustard-inhalation-injury-in-rats
#11
Matthew D McGraw, Jaqueline S Rioux, Rhonda B Garlick, Raymond C Rancourt, Carl W White, Livia A Veress
RationaleSulfur mustard (SM) is a chemical warfare agent that causes chronic airway remodeling. The current study's objective was to assess for changes to the bronchiolar epithelium after SM exposure to explain its contribution to chronic airway remodeling.Materials and MethodsAdult male rats were exposed to a sub-lethal dose of SM inhalation (1.0 - 1.2 mg/kg) for 50 minutes. Histological sections of the bronchiolar epithelium were analyzed for changes using H&E, trichrome, and immunofluorescent staining for acetylated tubulin (AT) and club cell secretory protein (CCSP)...
April 11, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28402547/perfluorododecanoic-acid-induces-cognitive-deficit-in-adult-rats
#12
Kohei Kawabata, Hirokazu Matsuzaki, Sahoko Nukui, Mari Okazaki, Ayako Sakai, Yoichi Kawashima, Naomi Kudo
The brain level of perfluorododecanoic acid (PFDoA) was compared with those of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in rats 9 days after a single oral dose (50 mg/kg). The PFDoA level in the brain was 44.0 ± 2.0 [mu]g/g, which was higher than that in the serum (24.4 ± 1.0 [mu]g/ml). By contrast, the concentrations of PFOA and PFDA in the brain were low (<0.8 and 4.7 ± 0.4 [mu]g/g, respectively), and less than one-tenth of those in the serum. Next, to investigate the effects on brain function, the cognitive function alterations of PFOA, PFDA, and PFDoA were estimated by the novel object recognition test 5-6 days after dosing...
April 11, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28402492/predicting-transport-of-3-5-6-trichloro-2-pyridinol-tcpy-into-saliva-using-a-combination-experimental-and-computational-approach
#13
Jordan Ned Smith, Zana A Carver, Thomas J Weber, Charles Timchalk
A combination experimental and computational approach was developed to predict chemical transport into saliva. A serous-acinar chemical transport assay was established to measure chemical transport with non-physiological (standard cell culture medium) and physiological (using surrogate plasma and saliva medium) conditions using 3,5,6-trichloro-2-pyridinol (TCPy) a metabolite of the pesticide chlorpyrifos. High levels of TCPy protein binding were observed in cell culture medium and rat plasma resulting in different TCPy transport behaviors in the two experimental conditions...
April 11, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28402537/performance-assessment-and-translation-of-physiologically-based-pharmacokinetic-models-from-acslx%C3%A2-to-berkeley-madonna%C3%A2-matlab%C3%A2-and-r-language-oxytetracycline-and-gold-nanoparticles-as-case-examples
#14
Zhoumeng Lin, Majid Jaberi-Douraki, Chunla He, Shiqiang Jin, Raymond S H Yang, Jeffrey W Fisher, Jim E Riviere
Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslXTM. However, acslXTM has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications. This forum article aimed to: (1) demonstrate the performance of four PBPK modeling software packages (acslXTM, Berkeley MadonnaTM, MATLAB®, and R language) tested using two existing models (oxytetracycline and gold nanoparticles); (2) provide a tutorial of PBPK model code conversion from acslXTM to Berkeley MadonnaTM, MATLAB®, and R language; (3) discuss the advantages and disadvantages of each software package in the implementation of PBPK models in toxicology, and (4) share our perspective about future direction in this field...
April 8, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28398592/tributyltin-alters-the-bone-marrow-microenvironment-and-suppresses-b-cell-development
#15
Amelia H Baker, Ting Hua Wu, Alicia M Bolt, Louis C Gerstenfeld, Koren K Mann, Jennifer J Schlezinger
Organotins are industrial chemicals and agricultural pesticides, and they contaminate both outdoor and indoor environments. Organotins are detectable in human sera at biologically active concentrations and are immuno-and neuro-toxicants. Triphenyltin, tributyltin (TBT) and dibutyltin activate peroxisome proliferator-activated receptor γ (PPARγ) in bone marrow multipotent mesenchymal stromal cells (BM-MSC) and promote adipogenesis. TBT also has been shown to suppress osteogenesis; osteoblasts not only support bone homeostasis but also support B lymphopoiesis...
April 7, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28369659/organophosphate-diazinon-altered-quorum-sensing-cell-motility-stress-response-and-carbohydrate-metabolism-of-gut-microbiome
#16
Bei Gao, Xiaoming Bian, Liang Chi, Pengcheng Tu, Hongyu Ru, Kun Lu
The gut microbiome plays a key role in energy production, immune system development, and host resistance against invading pathogens, etc. Disruption of gut bacterial homeostasis is associated with a number of human diseases. Several environmental chemicals have been reported to induce alterations of the gut microbiome. Diazinon, one of important organophosphate insecticides, has been widely used in agriculture. Diazinon and its metabolites are readily detected in different environmental settings and human urine...
March 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28369613/collaborative-cross-mouse-population-enables-refinements-to-characterization-of-the-variability-in-toxicokinetics-of-trichloroethylene-and-provides-genetic-evidence-for-the-role-of-ppar-pathway-in-its-oxidative-metabolism
#17
Abhishek Venkatratnam, Shinji Furuya, Oksana Kosyk, Avram Gold, Wanda Bodnar, Kranti Konganti, David W Threadgill, Kevin M Gillespie, David L Aylor, Fred A Wright, Weihsueh A Chiu, Ivan Rusyn
Background: Trichloroethylene (TCE) is a known carcinogen in humans and rodents. Previous studies of inter-strain variability in TCE metabolism were conducted in multi-strain panels of classical inbred mice with limited genetic diversity to identify gene-environment interactions associated with chemical exposure. Objectives: To evaluate inter-strain variability in TCE metabolism and identify genetic determinants that are associated with TCE metabolism and effects using Collaborative Cross (CC), a large panel of genetically diverse strains of mice...
March 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28369609/4-bromodiphenyl-ether-bde-3-induces-germ-cell-apoptosis-by-induction-of-ros-and-dna-damage-in-caenorhabditis-elegans
#18
Xinyue You, Jing Xi, Yiyi Cao, Jinfu Zhang, Yang Luan
Polybrominated diphenyl ethers (PBDEs) may affect male reproductive function; however, the underlying mechanism is still uncertain. By using Caenorhabditis elegans (C. elegans), a commonly used model to study basic biological processes in apoptosis, we investigated the toxic effects of 4-bromodiphenyl ether (BDE-3), the most fundamental mono-BDE generated from degradation of PBDEs in the environment. We found that BDE-3 treated worms exhibited decreased life spans, impaired fecundity and delayed egg laying...
March 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28369588/in-vitro-drug-induced-liver-injury-prediction-criteria-optimization-of-efflux-transporter-ic50-and-physicochemical-properties
#19
Robert W Yucha, Kan He, Qin Shi, Lining Cai, Yukie Nakashita, Cindy Q Xia, Mingxiang Liao
Drug-induced liver injury (DILI) is a severe drug adverse response, which cannot always be reliably predicted in preclinical or clinical studies. Lack of observation of DILI during preclinical and clinical drug development has led to DILI being a leading cause of drug withdrawal from the market. As DILI is potentially fatal, pharmaceutical companies have been developing in vitro tools to screen for potential liver injury. Screens for physicochemical properties, mitochondrial function, and transport protein inhibition have all been employed to varying degrees of success...
March 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28369651/placental-disposition-and-effects-of-crizotinib-an-ex-vivo-study-in-the-isolated-dual-side-perfused-human-cotyledon
#20
Gaby A M Eliesen, Petra van den Broek, Jeroen J van den Heuvel, Albert Bilos, Jeanne Pertijs, Joris van Drongelen, Frans G M Russel, R Greupink
Background: Tyrosine kinase inhibitors (TKIs) play an important role in cancer pharmacotherapy, yet there is limited data on their use during pregnancy. We studied placental disposition and placental toxicity of crizotinib, a TKI used to treat non-small cell lung cancer. Material and methods: Term placentas were perfused for three hours with crizotinib (1µM) using the ex vivo dual-side cotyledon perfusion technique. Interference of TKIs with trophoblast viability was studied using BeWo cells...
March 24, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
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