Designing More Efficient Preclinical Experiments: A Simulation Study in Chemotherapy-Induced Myelosupression
A new more efficient preclinical study design (referred to as a compact design) is proposed that removes the need for satellite animals for the collection of toxicokinetic (TK) data by sampling from the main study animals, taking no more than one sample in 24 h to build up a full profile over the course of the study. The compact design’s performance was tested with a simulation study, using an example of chemotherapy-induced myelosupression in rats. Data sets were simulated from a model based on available data, following both the compact design and a traditional design using satellite animals, with 100 studies being ...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Martin, E. C., Aarons, L., Yates, J. W. T. Tags: Improving Toxicokinetic Assessment in Preclinical Studies Source Type: research
Acute Exposure to Di(2-Ethylhexyl) Phthalate in Adulthood Causes Adverse Reproductive Outcomes Later in Life and Accelerates Reproductive Aging in Female Mice
This study tested the hypothesis that acute DEHP exposure causes infertility, disrupts estrous cyclicity, alters hormone levels, and depletes follicle numbers by inducing atresia later in life, leading to accelerated reproductive aging. Adult CD-1 mice were orally dosed with vehicle or DEHP (20 μg/kg/day–500 mg/kg/day) daily for 10 days, and reproductive outcomes were assessed at 6 and 9 months postdosing. Acute DEHP exposure significantly altered estrous cyclicity compared to controls at 6 and 9 months postdosing by increasing the percentage of days the mice were in estrus and metestrus/diestrus, respectively. DE...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Hannon, P. R., Niermann, S., Flaws, J. A. Tags: Phthalate and Reproductive Effects in Female Mice Source Type: research
MiR-17 Downregulation by High Glucose Stabilizes Thioredoxin-Interacting Protein and Removes Thioredoxin Inhibition on ASK1 Leading to Apoptosis
In this study, we investigated the mechanism underlying high glucose-induced ASK1 activation. High glucose suppressed miR-17 expression, which led to an increase in its target gene Txnip (Thioredoxin-interacting protein). High glucose-increased Txnip enhanced its binding to the ASK1 inhibitor, thioredoxin (Trx), and thereby sequestered Trx from the Trx-ASK1 complex. High glucose-induced ASK1 activation and consequent apoptosis were abrogated by either the miR-17 mimic or Txnip siRNA knockdown. In contrast, the miR-17 inhibitor or Txnip ectopic overexpression mimicked the stimulative effect of high glucose on ASK1 and apopt...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Dong, D., Fu, N., Yang, P. Tags: Glucose, microRNA and Thioredoxin Signaling Source Type: research
Diphenylarsinic Acid Induced Activation of Cultured Rat Cerebellar Astrocytes: Phosphorylation of Mitogen-Activated Protein Kinases, Upregulation of Transcription Factors, and Release of Brain-Active Cytokines
Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenas...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Negishi, T., Matsumoto, M., Kojima, M., Asai, R., Kanehira, T., Sakaguchi, F., Takahata, K., Arakaki, R., Aoyama, Y., Yoshida, H., Yoshida, K., Yukawa, K., Tashiro, T., Hirano, S. Tags: Arsenic Effects on Cerebellar Astrocytes Source Type: research
Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model
In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their comb...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Lee, M., Huang, R., Tong, W. Tags: Identification of Transcriptional Targets Using Computational Approaches Source Type: research
Aflatoxin B1 Induced Compositional Changes in Gut Microbial Communities of Male F344 Rats
Aflatoxins are a group of potent foodborne toxicants naturally occurring in maize and groundnuts. Differential species-specific sensitivity to aflatoxins has been documented but cannot be fully explained by the differences in metabolism of these toxicants among animal species. Commensal microbial communities (microbiota) are critical to human and animal health, but few studies have assessed interactions between xenobiotic toxins and those microbiota, and its potential effects to humans and animals. Here, an exploratory dosing experiment was conducted to explore effects of Aflatoxin B1 (AFB1) on the gut microbiota in a comm...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Wang, J., Tang, L., Glenn, T. C., Wang, J.-S. Tags: Aflatoxin B1 and Gut Microbiome Disruption Source Type: research
Proinflammatory Effects of Pyrogenic and Precipitated Amorphous Silica Nanoparticles in Innate Immunity Cells
In conclusion, the results presented here demonstrate that, compared to precipitated, pyrogenic ASNP exhibit enhanced interaction with serum proteins and cell membrane, and cause a larger oxidative stress and stronger proinflammatory effects in macrophages. Therefore, these 2 nanomaterials should not be considered biologically equivalent. (Source: Toxicological Sciences)
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Di Cristo, L., Movia, D., Bianchi, M. G., Allegri, M., Mohamed, B. M., Bell, A. P., Moore, C., Pinelli, S., Rasmussen, K., Riego-Sintes, J., Prina-Mello, A., Bussolati, O., Bergamaschi, E. Tags: Silica Nanoparticles and Immune Function Source Type: research
Human Sulfotransferases Enhance the Cytotoxicity of Tolvaptan
Tolvaptan, a vasopressin receptor 2 antagonist used to treat hyponatremia, has recently been reported to be associated with liver injury. Sulfotransferases (SULTs) have been implicated as important detoxifying and/or activating enzymes for numerous xenobiotics, drugs, and endogenous compounds. To characterize better the role of SULTs in tolvaptan metabolism, HEK293 cells stably overexpressing 12 human SULTs were generated. Using these cell lines, the extent of tolvaptan sulfate formation was assessed by reversed-phase high-performance liquid chromatography through comparison to a synthetic standard. Of the 12 known human S...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Fang, J.-L., Wu, Y., Gamboa da Costa, G., Chen, S., Chitranshi, P., Beland, F. A. Tags: Sulfotransferases and Tolvaptan Toxicity Source Type: research
Dietary Manganese Modulates PCB126 Toxicity, Metal Status, and MnSOD in the Rat
PCB126 (3,3',4,4',5-pentachlorobiphenyl) is a potent aryl hydrocarbon receptor agonist and induces oxidative stress. Because liver manganese (Mn) levels decrease in response to PCB126, a Mn dietary study was designed to investigate the role of Mn in PCB126 toxicity. Male Sprague Dawley rats received diets containing 0, 10, or 150 ppm added Mn for 3 weeks, followed by a single ip injection of corn oil or PCB126 (5 µmol/kg body weight). After 2 weeks, Mn, Cu, Zn, and Fe levels in the heart, liver, and liver mitochondria, and Mn-containing superoxide dismutase (MnSOD) and metallothionein mRNA, MnSOD protein, and MnSOD a...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Wang, B., Klaren, W. D., Wels, B. R., Simmons, D. L., Olivier, A. K., Wang, K., Robertson, L. W., Ludewig, G. Tags: Polychlorinated Biphenyls and Manganese Toxicity Source Type: research
Table of Contents
(Source: Toxicological Sciences)
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Tags: Standing Material Source Type: research
Subscriptions
(Source: Toxicological Sciences)
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Tags: Standing Material Source Type: research
Beyond miR-122: Identification of MicroRNA Alterations in Blood During a Time Course of Hepatobiliary Injury and Biliary Hyperplasia in Rats
In this study, miRNA profiling was conducted over a time course of hepatobiliary injury and repair using alpha-naphthylisothiocyanate (ANIT) and a proprietary compound, FP004BA. ANIT administration (50 mg/kg) to rats caused significant biliary epithelial cell and hepatocellular necrosis between 24 and 72 h, followed by resolution and progression to biliary hyperplasia by 120 h which was associated with miRNA release into the blood. FP004BA (100 mg/kg) was used to confirm associations of miRNA along a time course with similar hepatic pathology to ANIT. Treatment with ANIT or FP004BA resulted in significant alterations of ov...
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Church, R. J., Otieno, M., McDuffie, J. E., Singh, B., Sonee, M., Hall, L., Watkins, P. B., Ellinger-Ziegelbauer, H., Harrill, A. H. Tags: Profiling of microRNA after Liver Injury Source Type: research
Editorial Board
(Source: Toxicological Sciences)
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Tags: Standing Material Source Type: research
Toxicology: Cajun Style
(Source: Toxicological Sciences)
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Authors: Miller, G. W. Tags: Editorial Source Type: research
Cover
(Source: Toxicological Sciences)
Source: Toxicological Sciences - February 25, 2016 Category: Toxicology Tags: Cover Source Type: research
