Disposition of the Emerging Brominated Flame Retardant, 2-Ethylhexyl 2,3,4,5-Tetrabromobenzoate, in Female SD Rats and Male B6C3F1 Mice: Effects of Dose, Route, and Repeated Administration
2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB; MW 549.92 g/mol; CAS 183658-27-7) is a brominated component of flame retardant mixtures used as substitutes for some PBDEs. EH-TBB is added to various consumer products, including polyurethane foams, and has been detected in humans. The present study characterized the fate of EH-TBB in rodents. [14C]-labeled EH-TBB was absorbed, metabolized, and eliminated via the urine and feces following single administrations of 0.1–100 µmol/kg (~0.05–55 mg/kg) or repeated administration (0.1 µmol/kg/day x 5–10 days) by gavage to female Hsd:Sprague DawleySD (...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Knudsen, G. A., Sanders, J. M., Birnbaum, L. S. Tags: Toxicokinetics of Emerging Brominated Flame Retardant Source Type: research
From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis
Emerging evidence supports a role for environmental chemical exposure in the pathology of non-alcoholic fatty liver disease (NAFLD), a disease process tightly linked to increased activity of the blood coagulation cascade. Exposure of C57BL/6 mice to the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) recapitulates features of the NAFLD spectrum, including steatosis, hepatic injury, inflammation, and fibrosis. We assessed coagulation cascade activation, and determined the role of the thrombin receptor protease activated receptor-1 (PAR-1) in experimental TCDD-elicited NAFLD. Chronic exposure ...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Nault, R., Fader, K. A., Kopec, A. K., Harkema, J. R., Zacharewski, T. R., Luyendyk, J. P. Tags: Role of PAR-1 and Fibrosis in Model of TCDD-Induced Steatohepatitis Source Type: research
Endoplasmic Reticulum Stress Induction and ERK1/2 Activation Contribute to Nefazodone-Induced Toxicity in Hepatic Cells
In this report, using biochemical and molecular analyses, we characterized the molecular mechanisms underlying the hepatotoxicity of nefazodone. We found that nefazodone induced endoplasmic reticulum (ER) stress in HepG2 cells, as the expression of typical ER stress markers, including CHOP, ATF-4, and p-eIF2α, was significantly increased, and splicing of XBP1 was observed. Nefazodone-suppressed protein secretion was evaluated using a Gaussia luciferase reporter assay that measures ER stress. The ER stress inhibitors (4-phenylbutyrate and salubrinal) and knockdown of ATF-4 gene attenuated nefazodone-induced ER stress ...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Ren, Z., Chen, S., Zhang, J., Doshi, U., Li, A. P., Guo, L. Tags: Nefazodone Causes Endoplasmic Reticulum Stress and Hepatic Cell Toxicity Source Type: research
Editors Highlight: Modeling Compound-Induced Fibrogenesis In Vitro Using Three-Dimensional Bioprinted Human Liver Tissues
Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate- and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to thes...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Norona, L. M., Nguyen, D. G., Gerber, D. A., Presnell, S. C., LeCluyse, E. L. Tags: In Vitro Fibrogenesis Using 3D Bioprinted Human Liver Tissues Source Type: research
From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity
Sulfur mustard (bis 2-chloroethyl ethyl sulfide, SM) is a powerful bi-functional vesicating chemical warfare agent. SM tissue injury is partially mediated by the overproduction of reactive oxygen species resulting in oxidative stress. We hypothesized that using a catalytic antioxidant (AEOL 10150) to alleviate oxidative stress and secondary inflammation following exposure to SM would attenuate the toxic effects of SM inhalation. Adult male rats were intubated and exposed to SM (1.4 mg/kg), a dose that produces an LD50 at approximately 24 h. Rats were randomized and treated via subcutaneous injection with either sterile PBS...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: McElroy, C. S., Min, E., Huang, J., Loader, J. E., Hendry-Hofer, T. B., Garlick, R. B., Rioux, J. S., Veress, L. A., Smith, R., Osborne, C., Anderson, D. R., Holmes, W. W., Paradiso, D. C., White, C. W., Day, B. J. Tags: Attenuation of Sulfur Mustard Lung Toxicity with Catalytic Antioxidants Source Type: research
E-Cigarette Aerosol Exposure Induces Reactive Oxygen Species, DNA Damage, and Cell Death in Vascular Endothelial Cells
This study evaluates the effects of e-cigarette aerosol extract (EAE) and conventional cigarette smoke extract (CSE) on human umbilical vein endothelial cells (HUVECs). A laboratory apparatus was designed to produce extracts from e-cigarettes and conventional cigarettes according to established protocols for cigarette smoking. EAE or conventional CSE was applied to human vascular endothelial cells for 4–72 h, dependent on the assay. Treated cells were assayed for reactive oxygen species, DNA damage, cell viability, and markers of programmed cell death pathways. Additionally, the anti-oxidants α-tocopherol and n...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Anderson, C., Majeste, A., Hanus, J., Wang, S. Tags: E-Cigarette Aerosol Induces Reactive Oxygen Species and Cell Damage Source Type: research
The Use of Ratiometric Fluorescence Measurements of the Voltage Sensitive Dye Di-4-ANEPPS to Examine Action Potential Characteristics and Drug Effects on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
This study evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in card...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Hortigon-Vinagre, M. P., Zamora, V., Burton, F. L., Green, J., Gintant, G. A., Smith, G. L. Tags: Voltage-Sensitive Dyes in Human iPSC-Derived Cardiomyocytes Source Type: research
From the Cover: Volatile Anesthetics Transiently Disrupt Neuronal Development in Neonatal Rats
Volatile anesthetics can cause neuronal and glial toxicity in the developing mammalian brain, as well as long-term defects in learning and memory. The goals of this study were to compare anesthetics using a clinically relevant exposure paradigm, and to assess the anesthetic effects on hippocampal development and behavior. Our hypothesis was that volatile anesthetics disrupt hippocampal development, causing neurobehavioral defects later in life. Bromodeoxyuridine (BrdU) was administered to rats on postnatal day (P)1, and the rats were exposed to volatile anesthetics (isoflurane, sevoflurane, or desflurane) for 2 h on P2. On...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Drobish, J. K., Gan, Z. S., Cornfeld, A. D., Eckenhoff, M. F. Tags: Anesthetic Actions on Neonatal Neuronal Development Source Type: research
Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies
Fluensulfone is a nematicide for agricultural use. Chronic dietary exposure led to bronchiolo-alveolar hyperplasia and bronchiolo-alveolar adenomas in CD-1 mice but not in rats. Genotoxicity could be excluded as a mode of action (MOA). An earlier publication (Strupp, C., Banas, D. A., Cohen, S. M., Gordon, E. B., Jaeger, M., and Weber, K. (2012). Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework. Toxicol. Sci. 128, 284–294.) reported MOA studies identifying the following key events: increased me...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Strupp, C., Bomann, W., Cohen, S. M., Weber, K. Tags: Metabolism and Cell Proliferation in Fluensulfone-Induced Lung Tumors Source Type: research
Interplay Between Membrane Lipid Peroxidation and Photoproduct Formation in the Ultraviolet A-Induced Phototoxicity of Vemurafenib in Skin Keratinocytes
According to some authors, the phototoxic response to ultraviolet A (UVA) of patients treated with vemurafenib (VB) may involve VB metabolites. However, the production of singlet oxygen and free radicals and photoproduct formation upon UVA light absorption by the lipophilic VB have been demonstrated. This work is aimed at determining the contribution of reactive oxygen species (ROS), lipid photoperoxidation, and VB photochemistry in the UVA-induced photocytotoxicity in NCTC 2544 keratinocytes. The potent membrane lipid peroxidation effectiveness of VB-photosensitization has been proved by the observation of an effective ph...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Teixeira, A., Morliere, P., Ferreira, J., Conte, M.-A., Galmiche, A., Maziere, J.-C., Santus, R., Filipe, P. Tags: Mechanisms of Vemurafenib-Mediated UVA Phototoxicity Source Type: research
Compensatory Renal Hypertrophy and the Uptake of Cysteine S-Conjugates of Hg2+ in Isolated S2 Proximal Tubular Segments
Chronic kidney disease is characterized by a progressive and permanent loss of functioning nephrons. In order to compensate for this loss, the remaining functional nephrons undergo significant structural and functional changes. We hypothesize that luminal uptake of inorganic mercury (Hg2+), as a conjugate of cysteine (Cys; Cys-S-Hg-S-Cys), is enhanced in S2 segments of proximal tubules from the remnant kidney of uninephrectomized (NPX) rabbits. To test this hypothesis, we measured uptake and accumulation of Cys-S-Hg-S-Cys in isolated perfused S2 segments of proximal tubules from normal (control) and NPX rabbits. The remnan...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Bridges, C. C., Barfuss, D. W., Joshee, L., Zalups, R. K. Tags: Cysteine Conjugates of Mercury in S2 Proximal Tubular Segments Source Type: research
From the Cover: Cadmium Exposure Differentially Alters Odorant-Driven Behaviors and Expression of Olfactory Receptors in Juvenile Coho Salmon (Oncorhynchus kisutch)
Salmon exposed to waterborne metals can experience olfactory impairment leading to disrupted chemosensation. In the current study, we investigated the effects of cadmium (Cd) on salmon olfactory function by modeling an exposure scenario where juvenile salmon transiently migrate through a polluted waterway. Coho were exposed to environmentally relevant concentrations of waterborne Cd (2 and 30 µg/L) for 48 h and (0.3 and 2 μg/L) for 16 days, followed by a 16-day depuration associated with outmigration. Cadmium exposures inhibited behavioral responses towards L-cysteine and conspecific odorants, with effects persist...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Williams, C. R., MacDonald, J. W., Bammler, T. K., Paulsen, M. H., Simpson, C. D., Gallagher, E. P. Tags: Cadmium Exposure and Olfactory Function in Coho Salmon Source Type: research
Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis
We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 µg/kg treatment groups ...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Nault, R., Fader, K. A., Ammendolia, D. A., Dornbos, P., Potter, D., Sharratt, B., Kumagai, K., Harkema, J. R., Lunt, S. Y., Matthews, J., Zacharewski, T. Tags: Metabolic Reprogramming in TCDD Hepatic Fibrosis Source Type: research
Editors Highlight: Comparative Toxicity of Organophosphate Flame Retardants and Polybrominated Diphenyl Ethers to Caenorhabditis elegans
With the phasing-out of the polybrominated diphenyl ether (PBDE) flame retardants due to concerns regarding their potential developmental toxicity, the use of replacement compounds such as organophosphate flame retardants (OPFRs) has increased. Limited toxicity data are currently available to estimate the potential adverse health effects of the OPFRs. The toxicological effects of 4 brominated flame retardants, including 3 PBDEs and 3,3',5,5'-tetrabromobisphenol A, were compared with 6 aromatic OPFRs and 2 aliphatic OPFRs. The effects of these chemicals were determined using 3 biological endpoints in the nematode Caenorhabd...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Behl, M., Rice, J. R., Smith, M. V., Co, C. A., Bridge, M. F., Hsieh, J.-H., Freedman, J. H., Boyd, W. A. Tags: Flame Retardant Toxicity in C. elegans Source Type: research
MC1568 Inhibits Thimerosal-Induced Apoptotic Cell Death by Preventing HDAC4 Up-Regulation in Neuronal Cells and in Rat Prefrontal Cortex
Ethylmercury thiosalicylate (thimerosal) is an organic mercury-based compound commonly used as an antimicrobial preservative that has been found to be neurotoxic. In contrast, histone deacetylases (HDACs) inhibition has been found to be neuroprotective against several environmental contaminants, such as polychlorinated biphenyls, di-2-ethylhexyl phthalate, and methylmercury. The aim of this study was to investigate the effect of HDAC inhibition on thimerosal-induced neurotoxicity in neuroblastoma cells and cortical neurons. Interestingly, we found that thimerosal, at 0.5 μM in SH-SY5Y cells and at 1 μM in neurons, ca...
Source: Toxicological Sciences - December 4, 2016 Category: Toxicology Authors: Guida, N., Laudati, G., Mascolo, L., Cuomo, O., Anzilotti, S., Sirabella, R., Santopaolo, M., Galgani, M., Montuori, P., Di Renzo, G., Canzoniero, L. M. T., Formisano, L. Tags: The HDAC Inhibitor MC1568 Prevents Thimerosal Toxicity in Neuronal Cells Source Type: research
