A PGC-1{alpha}-Mediated Transcriptional Network Maintains Mitochondrial Redox and Bioenergetic Homeostasis against Doxorubicin-Induced Toxicity in Human Cardiomyocytes: Implementation of TT21C
Chemical toxicity testing is fast moving in a direction that relies increasingly on cell-based in vitro assays anchored on toxicity pathways according to the toxicity testing in the 21st century vision. Identifying points of departure (POD) via these assays and revealing their mechanistic underpinnings via computational modeling of the relevant pathways are critical and challenging steps. Here we used doxorubicin (DOX) as a prototype chemical to study mitochondrial toxicity in human AC16 cells. Mitochondrial toxicity has been linked to cardiovascular risk of DOX, which has limited its clinical use as an antitumor drug. Our...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Yuan, H., Zhang, Q., Guo, J., Zhang, T., Zhao, J., Li, J., White, A., Carmichael, P. L., Westmoreland, C., Peng, S. Tags: Doxorubicin-Induced Cardiomyocyte Toxicty and Transcriptional Networks Source Type: research
A Systematic Strategy for Screening and Application of Specific Biomarkers in Hepatotoxicity Using Metabolomics Combined With ROC Curves and SVMs
Current studies that evaluate toxicity based on metabolomics have primarily focused on the screening of biomarkers while largely neglecting further verification and biomarker applications. For this reason, we used drug-induced hepatotoxicity as an example to establish a systematic strategy for screening specific biomarkers and applied these biomarkers to evaluate whether the drugs have potential hepatotoxicity toxicity. Carbon tetrachloride (5 ml/kg), acetaminophen (1500 mg/kg), and atorvastatin (5 mg/kg) are established as rat hepatotoxicity models. Fifteen common biomarkers were screened by multivariate statistical analy...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Li, Y., Wang, L., Ju, L., Deng, H., Zhang, Z., Hou, Z., Xie, J., Wang, Y., Zhang, Y. Tags: Metabolomic Biomarkers of Hepatotoxicity Source Type: research
Immunogenicity, Inflammation, and Lipid Accumulation in Cynomolgus Monkeys Infused with a Lipidated Tetranectin-ApoA-I Fusion Protein
In conclusion, multiple infusions of lipidated TN-ApoA-I resulted in high immunogenicity, lipid accumulation and were not well tolerated in nonhuman primates. (Source: Toxicological Sciences)
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Regenass-Lechner, F., Staack, R. F., Mary, J.-L., Richter, W. F., Winter, M., Jordan, G., Justies, N., Langenkamp, A., Garrido, R., Albassam, M., Singer, T., Atzpodien, E.-A. Tags: High Density Lipoprotein Mimetic and Multiorgan Inflammation Source Type: research
Increased R2* in the Caudate Nucleus of Asymptomatic Welders
This study examined differences in the apparent transverse relaxation rates [R2* (1/T2*), estimate of Fe accumulation] in the basal ganglia (caudate nucleus, putamen, and globus pallidus) between welders and controls, and the dose–response relationship between estimated Fe exposure and R2* values. Occupational questionnaires estimated recent and lifetime Fe exposure, and blood Fe levels and brain magnetic resonance imaging (MRI) were obtained. Complete exposure and MRI R2* and R1 (1/T1: measure to estimate Mn accumulation) data from 42 subjects with welding exposure and 29 controls were analyzed. Welders had signific...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Lee, E.-Y., Flynn, M. R., Du, G., Li, Y., Lewis, M. M., Herring, A. H., Van Buren, E., Van Buren, S., Kong, L., Fry, R. C., Snyder, A. M., Connor, J. R., Yang, Q. X., Mailman, R. B., Huang, X. Tags: MRI Analysis of Brains of Welders Source Type: research
Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure
This study was designed to distinguish Mn effect on the critical stage of adult neurogenesis, ie, proliferation, migration, survival and differentiation from the SVZ via the rostral migratory stream to the olfactory bulb (OB). Adult rats received a single ip-dose of BrdU at the end of 4-week Mn exposure to label proliferating cells. Immunostaining and cell-counting showed a 48% increase of BrdU(+) cells in Mn-exposed SVZ than in controls (P < .05). These BrdU(+) cells were identified as a mixed population of mainly GFAP(+) type-B neural stem cells, Nestin(+) type-C transit progenitor cells, DCX(+) migratory neuroblasts ...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Fu, S., Jiang, W., Gao, X., Zeng, A., Cholger, D., Cannon, J., Chen, J., Zheng, W. Tags: Altered Brain Neurogenesis and Manganese Exposure Source Type: research
Tungsten Promotes Sex-Specific Adipogenesis in the Bone by Altering Differentiation of Bone Marrow-Resident Mesenchymal Stromal Cells
Tungsten is a naturally occurring metal that increasingly is being incorporated into industrial goods and medical devices, and is recognized as an emerging contaminant. Tungsten preferentially and rapidly accumulates in murine bone in a concentration-dependent manner; however the effect of tungsten deposition on bone biology is unknown. Other metals alter bone homeostasis by targeting bone marrow-derived mesenchymal stromal cell (MSC) differentiation, thus, we investigated the effects of tungsten on MSCs in vitro and in vivo. In vitro, tungsten shifted the balance of MSC differentiation by enhancing rosiglitazone-induced a...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Bolt, A. M., Grant, M. P., Wu, T. H., Flores Molina, M., Plourde, D., Kelly, A. D. R., Negro Silva, L. F., Lemaire, M., Schlezinger, J. J., Mwale, F., Mann, K. K. Tags: Tungsten and Mesenchymal Stromal Cell Differentiation Source Type: research
High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells
Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2060 chemical samples on steroidogenesis via high-performance liquid chromatography followed by tandem mass spectrometry quantification of 10 steroid hormones, including progestagens, glucocorticoids, androgens, and estrogens. The study employed a 3 stage screening strategy. The first stage established the maximum tolerated concentration (MTC; ≥ 70% viability) per sa...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Karmaus, A. L., Toole, C. M., Filer, D. L., Lewis, K. C., Martin, M. T. Tags: Toxicant Screen for Altered Steroid Synthesis Source Type: research
Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats
Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent bilateral adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1 ppm), 4 h/day for 1 or 2 days and responses assessed immediately postexposure. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to SHAM. Corticosteron...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Miller, D. B., Snow, S. J., Schladweiler, M. C., Richards, J. E., Ghio, A. J., Ledbetter, A. D., Kodavanti, U. P. Tags: Adrenal Gland Function and Pulmonary Response to Ozone Source Type: research
Structure-Activity Relationships for DNA Damage by Alkenylbenzenes in Turkey Egg Fetal Liver
Certain alkenylbenzenes (AB), flavoring chemicals naturally occurring in spices and herbs, are established to be cytotoxic and hepatocarcinogenic in rodents. The purpose of the present study was to determine the DNA damaging potential of key representatives of this class using the Turkey Egg Genotoxicity Assay. Medium white turkey eggs with 22- to 24-day-old fetuses received three injections of nine AB with different carcinogenic potentials: safrole (1, 2 mg/egg), methyl eugenol (2, 4 mg/egg), estragole (20, 40 mg/egg), myristicin (25, 50 mg/egg), elemicin (20, 50 mg/egg), anethole (5, 10 mg/egg), methyl isoeugenol (40, 80...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Kobets, T., Duan, J.-D., Brunnemann, K. D., Etter, S., Smith, B., Williams, G. M. Tags: Alkenylbenzenes and DNA Damage Source Type: research
Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimers Disease and Nondemented Elderly Controls
An essential metal hypothesis for neurodegenerative disease suggests an alteration in metal homeostasis contributing to the onset and progression of disease. Similar associations have been proposed for nonessential metals. To examine the relationship between metal levels in brain tissue and ventricular fluid (VF), postmortem samples of frontal cortex (FC) and VF from Alzheimer’s disease (AD) cases and nondemented elderly subjects were analyzed for arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), tin (Sn), vanadium (V), and zinc (Zn) ...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Szabo, S. T., Harry, G. J., Hayden, K. M., Szabo, D. T., Birnbaum, L. Tags: Metal Analysis in Alzheimer ' s Disease Source Type: research
Beauvericin Inhibits Neuromuscular Transmission and Skeletal Muscle Contractility in Mouse Hemidiaphragm Preparation
The effects of Beauvericin (BEA) produced by the fungus Beauveria bassiana and Fusarium sp. on neuromuscular transmission and contractility were determined in an isolated neuromuscular mouse hemidiaphragm preparation. BEA (5 µM) significantly inhibits indirectly elicited twitch amplitude. At higher concentrations (7.5 and 10 µM), BEA produces a significant reduction of directly elicited, or complete block of indirectly evoked, muscle contraction. BEA also appears to be myotoxic, as indicated by a slowly developing muscle contracture. Development of neuromuscular blockade and contracture is concentration depende...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Zuzek, M. C., Grandic, M., Jakovac Strajn, B., Frangez, R. Tags: The Mycotoxin Beauvericin Alters Neurotransmission Source Type: research
PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water
The risk of human exposure to total chlorotriazines (TCT) in drinking water was evaluated using a physiologically based pharmacokinetic (PBPK) model. Daily TCT (atrazine, deethylatrazine, deisopropylatrazine, and diaminochlorotriazine) chemographs were constructed for 17 frequently monitored community water systems (CWSs) using linear interpolation and Krieg estimates between observed TCT values. Synthetic chemographs were created using a conservative bias factor of 3 to generate intervening peaks between measured values. Drinking water consumption records from 24-h diaries were used to calculate daily exposure. Plasma TCT...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Breckenridge, C. B., Campbell, J. L., Clewell, H. J., Andersen, M. E., Valdez-Flores, C., Sielken, R. L. Tags: Chlorotriazine Risk Assessment in Drinking Water Source Type: research
Tipping the Balance: Hepatotoxicity and the 4 Apical Key Events of Hepatic Steatosis
Hepatic steatosis is a condition were fat accumulates in the liver and it is associated with extra-hepatic diseases related to metabolic syndrome and systemic energy metabolism. If not reversed, steatosis can progress to steatohepatitis and irreversible stages of liver disease including fibrosis, cirrhosis, hepatocellular carcinoma, and death. From a public health standpoint, identifying chemical exposures that may be factors in steatosis etiology are important for preventing hepatotoxicity and liver disease progression. It is therefore important to identify the biological events that are key for steatosis pathology mediat...
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Angrish, M. M., Kaiser, J. P., McQueen, C. A., Chorley, B. N. Tags: Biological Network of Hepatic Steatosis Source Type: research
Society of Toxicology Board of Publications Best Paper Award for 2016
(Source: Toxicological Sciences)
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Authors: Miller, G. W. Tags: Editorial Source Type: research
From the Editors Desk, Editors Highlights
(Source: Toxicological Sciences)
Source: Toxicological Sciences - March 27, 2016 Category: Toxicology Tags: Look Inside Toxsci Source Type: research
