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(Source: Toxicological Sciences)
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Tags: Cover Source Type: research
Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress
Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. We generated inducible cardiac-specific PDH E1α knockout (CreERT2-PDHflox/flox) mice that demonstrated a high mortality rate. It was hypothesized that PDH modulating cardiac glucose metabolism is crucial for heart functions under normal physiological and/or stress conditions. The myocardial infarction was conducted by a ligation of the left anterior descending coronary arteries. Cardiac PDH E1α deficiency caused large myocardial infarcts size and macrop...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Sun, W., Quan, N., Wang, L., Yang, H., Chu, D., Liu, Q., Zhao, X., Leng, J., Li, J. Tags: Pyruvate Dehydrogenase Deletion Enhances Effects of Heart Ischemia Source Type: research
3-MCPD 1-Palmitate Induced Tubular Cell Apoptosis In Vivo via JNK/p53 Pathways
This study investigated whether and how the JNK/p53 pathway may play a role in the nephrotoxic effect of 3-MCPD esters using 3-MCPD 1-palmitate (MPE) as a probe compound in Sprague Dawley rats. Microarray analysis of the kidney from the Sprague Dawley rats treated with MPE, using Gene Ontology categories and KEGG pathways, revealed that MPE altered mRNA expressions of the genes involved in the mitogen-activated protein kinase (JNK and ERK), p53, and apoptotic signal transduction pathways. The changes in the mRNA expressions were confirmed by qRT-PCR and Western blot analyses and were consistent with the induction of tubula...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Liu, M., Huang, G., Wang, T. T. Y., Sun, X., Yu, L. Tags: Fatty Acid Esters and Renal Tubule Apoptosis Source Type: research
Tiered High-Throughput Screening Approach to Identify Thyroperoxidase Inhibitors Within the ToxCast Phase I and II Chemical Libraries
High-throughput screening for potential thyroid-disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the U.S. Environmental Protection Agency ToxCast screening assay portfolio. To fill 1 critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast phase I and II chemical libraries, comprised of 1074 unique chemicals, we...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Paul Friedman, K., Watt, E. D., Hornung, M. W., Hedge, J. M., Judson, R. S., Crofton, K. M., Houck, K. A., Simmons, S. O. Tags: ToxCast Screening of Thyroperoxidase Inhibitors Source Type: research
Selective Targeting of Heme Protein in Cytochrome P450 and Nitric Oxide Synthase by Diphenyleneiodonium
Cytochrome P450 (CYP) enzymes mediate mixed-function oxidation reactions important in drug metabolism. The aromatic heterocyclic cation, diphenyleneiodonium (DPI), binds flavin in cytochrome P450 reductase and inhibits CYP-mediated activity. DPI also inhibits CYP by directly interacting with heme. Herein, we report that DPI effectively inhibits a number of CYP-related monooxygenase reactions including NADPH oxidase, a microsomal enzyme activity that generates hydrogen peroxide in the absence of metabolizing substrates. Inhibition of monooxygenase by DPI was time and concentration dependent with IC50's ranging from 0.06 to ...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Szilagyi, J. T., Mishin, V., Heck, D. E., Jan, Y.-H., Aleksunes, L. M., Richardson, J. R., Heindel, N. D., Laskin, D. L., Laskin, J. D. Tags: Diphenyleneiodonium Targets Heme Protein Source Type: research
NAD+ Supplementation Attenuates Methylmercury Dopaminergic and Mitochondrial Toxicity in Caenorhabditis Elegans
Methylmercury (MeHg) is a neurotoxic contaminant of our fish supply that has been linked to dopaminergic (DAergic) dysfunction that characterizes Parkinson’s disease. We have previously shown that MeHg causes both morphological and behavioral changes in the Caenorhabditis elegans DAergic neurons that are associated with oxidative stress. We were therefore interested in whether the redox sensitive cofactor nicotinamide adenine dinucleotide (NAD+) may be affected by MeHg and whether supplementation of NAD + may prevent MeHg-induced toxicities. Worms treated with MeHg showed depletion in cellular NAD + levels, which was...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Caito, S. W., Aschner, M. Tags: Methylmercury Toxicity in C. Elegans Source Type: research
MCPIP1 Regulates Alveolar Macrophage Apoptosis and Pulmonary Fibroblast Activation After in vitro Exposure to Silica
Conclusion: Our data suggest a vital role for MCPIP1 in AMO apoptosis and PFB activation/migration induced by SiO2. (Source: Toxicological Sciences)
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Wang, X., Zhang, Y., Zhang, W., Liu, H., Zhou, Z., Dai, X., Cheng, Y., Fang, S., Zhang, Y., Yao, H., Chao, J. Tags: A Role for Monocyte Chemotactic Protein-Induced Protein 1 in Alveolar Macrophagae Response to Silica Source Type: research
Colorimetric Evaluation of the Viability of the Microalga Dunaliella Salina as a Test Tool for Nanomaterial Toxicity
A diagnostic test system was developed to determine the toxicity of nanomaterials to the saltwater microalga Dunaliella salina through evaluation of cell death and changes in the culture growth rate at various toxicant concentrations, providing LC50 and other toxicological metrics. The viability of cells was shown to decrease with decreasing chlorophyll absorption of red light by damaged cells. This correlation was confirmed by independent fluorescence microscopic measurements of live and dead cells in the population. Two standard colorless pollutants, hydrogen peroxide and formaldehyde, were used to validate the colorimet...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Golubev, A. A., Prilepskii, A. Y., Dykman, L. A., Khlebtsov, N. G., Bogatyrev, V. A. Tags: Microalgal Tool for Assessing Nanomaterial Toxicity Source Type: research
Subacute Cardiovascular Toxicity of the Marine Phycotoxin Azaspiracid-1 in Rats
Azaspiracids (AZAs) are marine toxins produced by Azadinium spinosum that get accumulated in filter feeding shellfish through the food-web. The first intoxication was described in The Netherlands in 1990, and since then several episodes have been reported worldwide. Azaspiracid-1, AZA-2, and AZA-3 presence in shellfish is regulated by food safety authorities of several countries to protect human health. Azaspiracids have been related to widespread organ damage, tumorogenic properties and acute heart rhythm alterations in vivo but the mechanism of action remains unknown. Azaspiracid toxicity kinetics in vivo and in vitro su...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Ferreiro, S. F., Vilarino, N., Carrera, C., Louzao, M. C., Cantalapiedra, A. G., Santamarina, G., Cifuentes, J. M., Vieira, A. C., Botana, L. M. Tags: Marine Toxin Azaspiracid-1 and Cardiovascular Toxicity Source Type: research
Moving Toward Integrating Gene Expression Profiling Into High-Throughput Testing: A Gene Expression Biomarker Accurately Predicts Estrogen Receptor {alpha} Modulation in a Microarray Compendium
Microarray profiling of chemical-induced effects is being increasingly used in medium- and high-throughput formats. Computational methods are described here to identify molecular targets from whole-genome microarray data using as an example the estrogen receptor α (ERα), often modulated by potential endocrine disrupting chemicals. ERα biomarker genes were identified by their consistent expression after exposure to 7 structurally diverse ERα agonists and 3 ERα antagonists in ERα-positive MCF-7 cells. Most of the biomarker genes were shown to be directly regulated by ERα as determine...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Ryan, N., Chorley, B., Tice, R. R., Judson, R., Corton, J. C. Tags: Integration of Microarray and High Throughput Toxicity Testing for Estrogen Receptor Function Source Type: research
Dose- and Time-Dependent Transcriptional Response of Ishikawa Cells Exposed to Genistein
To further define the utility of the Ishikawa cells as a reliable in vitro model to determine the potential estrogenic activity of chemicals of interest, transcriptional changes induced by genistein (GES) in Ishikawa cells at various doses (10 pM, 1 nM, 100 nM, and 10 μM) and time points (8, 24, and 48 h) were identified using a comprehensive microarray approach. Trend analysis indicated that the expression of 5342 unique genes was modified by GES in a dose- and time-dependent manner (P ≤ 0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest dose of GES evalu...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Naciff, J. M., Khambatta, Z. S., Carr, G. J., Tiesman, J. P., Singleton, D. W., Khan, S. A., Daston, G. P. Tags: Use of Endometrial Cell-Derived Ishikawa Cells to Test Estrogenic Actions Source Type: research
Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling
In this study, a physiologically based pharmacokinetic (PBPK) model was integrated with a pharmacodynamic (PD) model to establish internal doses capable of inhibiting TPO in relation to external exposure levels predicted through exposure modeling. The PBPK/PD model was evaluated using published serum or thyroid gland chemical concentrations or circulating thyroxine (T4) and triiodothyronine (T3) hormone levels measured in rats and humans. After evaluation, the model was used to estimate human equivalent intake doses resulting in reduction of T4 and T3 levels by 10% (ED10) for 6 chemicals of varying TPO-inhibiting potencies...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Leonard, J. A., Tan, Y.-M., Gilbert, M., Isaacs, K., El-Masri, H. Tags: Estimation of Margin of Exposure for Thyroid Peroxidase Inhibitors Source Type: research
Loss of Mrp1 Potentiates Doxorubicin-Induced Cytotoxicity in Neonatal Mouse Cardiomyocytes and Cardiac Fibroblasts
Doxorubicin (DOX) induces dose-dependent cardiotoxicity in part due to its ability to induce oxidative stress. We showed that loss of multidrug resistance-associated protein 1 (Abcc1/Mrp1) potentiates DOX-induced cardiac dysfunction in mice in vivo. Here, we characterized DOX toxicity in cultured cardiomyocytes (CM) and cardiac fibroblasts (CF) derived from C57BL wild type (WT) and Mrp1 null (Mrp1–/–) neonatal mice. CM accumulated more intracellular DOX relative to CF but this accumulation did not differ between genotypes. Following DOX (0.3–4 μM), Mrp1–/– CM, and CF, especially CM, showed ...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Zhang, W., St Clair, D., Butterfield, A., Vore, M. Tags: Effects of MRP1 on Doxorubicin Toxicity in Cardiomyocytes Source Type: research
Immunomodulation By Subchronic Low Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Experimental Autoimmune Encephalomyelitis in the Absence of Pertussis Toxin
Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder, characterized by demyelination of neurons in the central nervous system. To investigate the pathogenicity of various T cell types in MS, especially IFN-- or IL-17-producing CD4+ cells (TH1 or TH17 cells, respectively), the mouse model, experimental autoimmune encephalomyelitis (EAE), is commonly used. One method by which EAE is induced is immunization with myelin oligodendrocyte glycoprotein (MOG) peptide (MOG35-55) followed by subsequent injections of pertussis toxin (PTX) as an adjuvant. We have an interest in the mechanisms by which EAE occurs in the a...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Yang, E.-J., Stokes, J. V., Kummari, E., Eells, J., Kaplan, B. L. F. Tags: TCDD and Experimental Autoimmune Encephalomyelitis Source Type: research
Nicotine Directly Induces Endoplasmic Reticulum Stress Response in Rat Placental Trophoblast Giant Cells
Nicotine exposure during pregnancy leads to placental insufficiency impairing both fetal and neonatal development. Previous studies from our laboratory have demonstrated that in rats, nicotine augmented endoplasmic reticulum (ER) stress in association with placental insufficiency; however, the underlying mechanisms remain elusive. Therefore, we sought to investigate the possible direct effect of nicotine on ER stress in Rcho-1 rat placental trophoblast giant (TG) cells during differentiation. Protein and/or mRNA expression of markers involved in ER stress (eg, phosphorylated PERK, eIF2α, CHOP, and BiP/GRP78) and TG c...
Source: Toxicological Sciences - April 29, 2016 Category: Toxicology Authors: Wong, M. K., Holloway, A. C., Hardy, D. B. Tags: Nicotine and ER Stress in Placental Cells Source Type: research
