From the Editors Desk, Editors Highlights
(Source: Toxicological Sciences)
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Tags: Look Inside Toxsci Source Type: research
Botulinum and Tetanus Neurotoxin-Induced Blockade of Synaptic Transmission in Networked Cultures of Human and Rodent Neurons
Clinical manifestations of tetanus and botulism result from an intricate series of interactions between clostridial neurotoxins (CNTs) and nerve terminal proteins that ultimately cause proteolytic cleavage of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and functional blockade of neurotransmitter release. Although detection of cleaved SNARE proteins is routinely used as a molecular readout of CNT intoxication in cultured cells, impaired synaptic function is the pathophysiological basis of clinical disease. Work in our laboratory has suggested that the blockade of synaptic neurotran...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Beske, P. H., Bradford, A. B., Grynovicki, J. O., Glotfelty, E. J., Hoffman, K. M., Hubbard, K. S., Tuznik, K. M., McNutt, P. M. Tags: Networked Cultures to Study Neurotoxin Actions on Synaptic Transmission Source Type: research
MicroRNA Responses to the Genotoxic Carcinogens Aflatoxin B1 and Benzo[a]pyrene in Human HepaRG Cells
Recent advances in toxicogenomics present an opportunity to develop new in vitro testing methodologies to identify human carcinogens. We have investigated microRNA expression responses to the treatment of human liver HepaRG cells with the human genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), and the structurally similar compounds aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) that exhibit minimal carcinogenic potential. We demonstrate that treatment of HepaRG cells with AFB1 or B[a]P resulted in specific changes in the expression of miRNAs as compared with their non-carcinogenic analogues, partic...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Marrone, A. K., Tryndyak, V., Beland, F. A., Pogribny, I. P. Tags: MicroRNA Expression in Response to Genotoxic Carcinogens Source Type: research
Classical and Alternative Activation of Cyanobacterium Oscillatoria sp. Lipopolysaccharide-Treated Rat Microglia in vitro
The purpose of this investigation was to test the hypothesis that an in vitro exposure to cyanobacterium Oscillatoria sp. Lipopolysaccharide (LPS) might result in classical and alternative activation of rat neonatal microglia. Using Escherichia coli LPS-primed microglia as a positive control, this study revealed that treatment of rat microglia with Oscillatoria sp. LPS for 17 h in vitro resulted in both classical and alternative activation as well as concomitant pro-inflammatory and anti-inflammatory mediator release, in a concentration-dependent manner: (1) treatment with 0.1–10 000 ng/ml Oscillatoria sp. ...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Mayer, A. M. S., Murphy, J., MacAdam, D., Osterbauer, C., Baseer, I., Hall, M. L., Feher, D., Williams, P. Tags: Cyanobacterial Lipopolysaccharide and Microglial Function Source Type: research
Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function
Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238)....
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Wahlberg, K., Kippler, M., Alhamdow, A., Rahman, S. M., Smith, D. R., Vahter, M., Lucchini, R. G., Broberg, K. Tags: Transporter Polymorphisms and Manganism Source Type: research
Natriuretic Peptides as Cardiovascular Safety Biomarkers in Rats: Comparison With Blood Pressure, Heart Rate, and Heart Weight
Cardiovascular (CV) toxicity is an important cause of failure during drug development. Blood-based biomarkers can be used to detect CV toxicity during preclinical development and prioritize compounds at lower risk of causing such toxicities. Evidence of myocardial degeneration can be detected by measuring concentrations of biomarkers such as cardiac troponin I and creatine kinase in blood; however, detection of functional changes in the CV system, such as blood pressure, generally requires studies in animals with surgically implanted pressure transducers. This is a significant limitation because sustained changes in blood ...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Engle, S. K., Watson, D. E. Tags: Natriuretic Peptides as Biomarkers of Cardiovascular Function Source Type: research
Effects of Cigarette Smoke, Cessation, and Switching to Two Heat-Not-Burn Tobacco Products on Lung Lipid Metabolism in C57BL/6 and Apoe-/- Mice--An Integrative Systems Toxicology Analysis
The impact of cigarette smoke (CS), a major cause of lung diseases, on the composition and metabolism of lung lipids is incompletely understood. Here, we integrated quantitative lipidomics and proteomics to investigate exposure effects on lung lipid metabolism in a C57BL/6 and an Apolipoprotein E-deficient (Apoe–/–) mouse study. In these studies, mice were exposed to high concentrations of 3R4F reference CS, aerosol from potential modified risk tobacco products (MRTPs) or filtered air (Sham) for up to 8 months. The 2 assessed MRTPs, the prototypical MRTP for C57BL/6 mice and the Tobacco Heating System 2.2 for A...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Titz, B., Boue, S., Phillips, B., Talikka, M., Vihervaara, T., Schneider, T., Nury, C., Elamin, A., Guedj, E., Peck, M. J., Schlage, W. K., Cabanski, M., Leroy, P., Vuillaume, G., Martin, F., Ivanov, N. V., Veljkovic, E., Ekroos, K., Laaksonen, R., Vansch Tags: Evaluation of Lung Lipid Toxicity of Non-Burn Tobacco Products Source Type: research
In Vitro Developmental Neurotoxicity Following Chronic Exposure to 50 Hz Extremely Low-Frequency Electromagnetic Fields in Primary Rat Cortical Cultures
Exposure to 50–60 Hz extremely low-frequency electromagnetic fields (ELF-EMFs) has increased considerably over the last decades. Several epidemiological studies suggested that ELF-EMF exposure is associated with adverse health effects, including neurotoxicity. However, these studies are debated as results are often contradictory and the possible underlying mechanisms are unknown. Since the developing nervous system is particularly vulnerable to insults, we investigate effects of chronic, developmental ELF-EMF exposure in vitro. Primary rat cortical neurons received 7 days developmental exposure to 50 Hz block-pu...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: de Groot, M. W. G. D. M., van Kleef, R. G. D. M., de Groot, A., Westerink, R. H. S. Tags: Electromagnetic Fields and Cortical Neuron Toxicity Source Type: research
An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes
In conclusion, in this mouse model cessation or switching to THS2.2 retarded the progression of CS-induced atherosclerotic and emphysematous changes, while THS2.2 aerosol alone had minimal adverse effects. (Source: Toxicological Sciences)
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Phillips, B., Veljkovic, E., Boue, S., Schlage, W. K., Vuillaume, G., Martin, F., Titz, B., Leroy, P., Buettner, A., Elamin, A., Oviedo, A., Cabanski, M., De Leon, H., Guedj, E., Schneider, T., Talikka, M., Ivanov, N. V., Vanscheeuwijck, P., Peitsch, M. C Tags: Evaluation of Cardiovascular and Respiratory Toxicity of Non-Burn Tobacco Source Type: research
Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis
This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr–/– and Car–/– mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr–/– mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by ...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Wahlang, B., Prough, R. A., Falkner, K. C., Hardesty, J. E., Song, M., Clair, H. B., Clark, B. J., States, J. C., Arteel, G. E., Cave, M. C. Tags: Polychlorinated Biphenyls, PXR, CAR, and NASH Source Type: research
Methods for Individualized Determination of Methylmercury Elimination Rate and De-Methylation Status in Humans Following Fish Consumption
We describe here improved methods to obtain a MeHg elimination rate via longitudinal Hg analysis in hair using laser ablation-inductively coupled plasma-mass spectrometry. We measured MeHg elimination rates in eight individuals following the consumption of 3 fish meals in two 75-day trials separated by a 4-month washout period. In addition, since MeHg biotransformation to inorganic Hg (I-Hg) is associated with Hg excretion, we speciated Hg in feces samples to estimate individual MeHg de-methylation status. We observed a wide range of MeHg elimination rates between individuals and within individuals over time (kel = 0.0163&...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Rand, M. D., Vorojeikina, D., van Wijngaarden, E., Jackson, B. P., Scrimale, T., Zareba, G., Love, T. M., Myers, G. J., Watson, G. E. Tags: Assessment of Mercury Disposition after Human Fish Consumption Source Type: research
Calcium Contributes to the Cytotoxic Interaction Between Diclofenac and Cytokines
Diclofenac (DCLF) is a widely used non-steroidal anti-inflammatory drug that is associated with idiosyncratic, drug-induced liver injury (IDILI) in humans. The mechanisms of DCLF-induced liver injury are unknown; however, patients with certain inflammatory diseases have an increased risk of developing IDILI, which raises the possibility that immune mediators play a role in the pathogenesis. DCLF synergizes with the cytokines tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) to cause hepatocellular apoptosis in vitro by a mechanism that involves activation of the endoplasmic reticulum (ER) stress response pa...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Maiuri, A. R., Breier, A. B., Turkus, J. D., Ganey, P. E., Roth, R. A. Tags: Calcium and Cytokines Influence Nsaid-Induced Liver Injury Source Type: research
Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits dose-dependent hepatotoxicity that includes fat accumulation, inflammation, and fibrosis that may progress to hepatocellular carcinoma. To further investigate these effects, RNA-Seq data were integrated with computationally identified putative dioxin response elements, and complementary targeted metabolomic and aryl hydrocarbon receptor (AhR) ChIP-Seq data from female C57BL/6 mice gavaged with TCDD every 4 days for 28 days. Data integration using CytoKEGG with manual curation identified dose-dependent alterations in central carbon and amino ac...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Nault, R., Fader, K. A., Kirby, M. P., Ahmed, S., Matthews, J., Jones, A. D., Lunt, S. Y., Zacharewski, T. R. Tags: TCDD Causes Metabolic Reprogramming in Liver Source Type: research
Ah Receptor Activation by Dioxin Disrupts Activin, BMP, and WNT Signals During the Early Differentiation of Mouse Embryonic Stem Cells and Inhibits Cardiomyocyte Functions
The AHR is a ligand-activated transcription factor that mediates gene-environment interactions. Genome-wide expression profiling during differentiation of mouse ES cells into cardiomyocytes showed that AHR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin; Dioxin (TCDD), its prototypical ligand, disrupted the expression of multiple homeobox transcription factors and inhibited cardiomyocyte contractility. Here we treated ES cells with TCDD at daily differentiation intervals to investigate whether TCDD-induced loss of contractility had a developmental window of sensitivity. Surprisingly, contractility was an AHR-dependent TC...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Wang, Q., Kurita, H., Carreira, V., Ko, C.-I., Fan, Y., Zhang, X., Biesiada, J., Medvedovic, M., Puga, A. Tags: TCDD Disrupts Stem Cell and Cardiomyocyte Function Source Type: research
Developmental PCB Exposure Increases Audiogenic Seizures and Decreases Glutamic Acid Decarboxylase in the Inferior Colliculus
This study assessed susceptibility to AGS in young adult rats following developmental PCB exposure alone (without loud noise exposure) and investigated whether there was a decrease in GABA inhibitory neurotransmission in the inferior colliculus (IC) that could potentially explain this effect. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of an environmentally relevant PCB mixture from 28 days prior to breeding until the pups were weaned at postnatal day 21. One male-female pair from each litter was retained for the AGS study whilst another was retained for Western blot analysis of glutamic acid decarboxyla...
Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Bandara, S. B., Eubig, P. A., Sadowski, R. N., Schantz, S. L. Tags: Mechanisms of PCB-Mediated Seizure Activity Source Type: research
