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PubMed Journal Database | Toxicological sciences : an official journal of the Society of Toxicology RSS

21:00 EDT 4th April 2020 | BioPortfolio

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Showing PubMed Articles 1–25 of 469 from Toxicological sciences : an official journal of the Society of Toxicology

Effects of Prenatal Exposure to a Mixture of Organophosphate Flame Retardants on Placental Gene Expression and Serotonergic Innervation in the Fetal Rat Brain.

There is a growing need to understand the potential neurotoxicity of organophosphate ester flame retardants (OPFRs) and plasticizers because use and, consequently, human exposure, is rapidly expanding. We have previously shown in rats that developmental exposure to the commercial FR mixture Firemaster® 550 (FM 550), which contains OPFRs, results in sex-specific behavioral effects, and identified the placenta as a potential target of toxicity. The placenta is a critical coordinator of fetal growth and neuro...

Per- and polyfluoroalkyl substances (PFAS) differentially inhibit placental trophoblast migration and invasion in vitro.

Per- and polyfluoroalkyl substances (PFAS)are used as industrial surfactants and chemical coatings for household goods such as Teflon. Despite regulatory efforts to phase out legacy PFAS, they remain detectable in drinking water throughout the United States. This is due to the stability of legacy PFAS and the continued use of replacement compounds. In humans, PFAS have been detected in placenta and cord blood and are associated with low birthweight and preeclampsia risk. Preeclampsia is a leading cause of m...

Late Protective Effect of Netrin-1 in the Murine Acetaminophen Hepatotoxicity Model.

Acetaminophen (APAP) overdose induced acute liver failure is an important clinical problem in the United States and the current antidote N-acetylcysteine, has a short early therapeutic window. Since most patients present late to the clinic, there is need for novel late acting therapeutic options. Though the neuronal guidance cue netrin-1, has been shown to promote hepatic repair and regeneration during liver ischemia/reperfusion injury, its effect in APAP - induced hepatotoxicity is unknown. In the quest fo...

In Utero and Lactational Exposure to Flame Retardants Disrupts Rat Ovarian Follicular Development and Advances Puberty.

Brominated flame retardants (BFRs), including polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD), leach out from consumer products into the environment. Exposure to BFRs has been associated with effects on endocrine homeostasis. To test the hypothesis that in utero and lactational exposure to BFRs may affect the reproductive system of female offspring, adult female Sprague-Dawley rats were fed diets formulated to deliver nominal doses (0, 0.06, 20, or 60 mg/kg/day) of a BFR dietary ...

Obesity as a Source of Endogenous Compounds Associated with Chronic Disease: A review.

In 2014, it was estimated that more than 1.9 billion adults were overweight with over 600 million classifiable as obese. Approximately two-thirds of US adults over 20 years of age are currently overweight with about 35% classified as obese, a figure thought likely to reach 42% by 2030 in those over 18 years of age. Adipose cells from stored body fat secrete estrogen and a very large number (> 500) of biologically active substances termed adipokines, in addition to inducing, by other cell-driven effects, pat...

Accounting for Multiple Comparisons in Statistical Analysis of the Extensive Bioassay Data on Glyphosate.

Glyphosate is a widely used herbicide worldwide. In 2015, the International Agency for Research on Cancer (IARC) reviewed glyphosate cancer bioassays and human studies and declared that the evidence for carcinogenicity of glyphosate is sufficient in experimental animals. We analyzed ten glyphosate rodent bioassays, including those in which IARC found evidence of carcinogenicity, using a multi-response permutation procedure that adjusts for the large number of tumors eligible for statistical testing and prov...

Combined maternal exposure to cypermethrin and stress affect embryonic brain and placental outcomes in mice.

Prenatal exposure to cypermethrin is a risk factor for adverse neurodevelopmental outcomes in children. In addition, maternal psychological stress during pregnancy has significant effects on fetal neurodevelopment and may influence end-stage toxicity to offspring by altering maternal xenobiotic metabolism. As such, this study examined effects of maternal exposure to alpha-cypermethrin and stress, alone and in combination, on offspring development; with a focus on fetal neurotoxicity. CD1 mouse dams were adm...

Targeted pathway-based in vivo testing using thyroperoxidase inhibition to evaluate plasma thyroxine as a surrogate metric of metamorphic success in model amphibian Xenopus laevis.

Chemical safety evaluation is in the midst of a transition from traditional whole-animal toxicity testing to molecular pathway-based in vitro assays and in silico modeling. However, to facilitate the shift in reliance on apical effects for risk assessment to predictive surrogate metrics having characterized linkages to chemical mechanisms of action, targeted in vivo testing is necessary to establish these predictive relationships. In this study, we demonstrate a means to predict thyroid-related metamorphic ...

Nitrosative stress and lipid homeostasis as a mechanism for zileuton hepatotoxicity and resistance in genetically sensitive mice.

Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zil...

Development and application of TK6-derived cells expressing human cytochrome P450s for genotoxicity testing.

Metabolism plays a key role in chemical genotoxicity; however, most mammalian cells used for in vitro genotoxicity testing lack effective metabolizing enzymes. We recently developed a battery of TK6-derived cell lines that individually overexpress one of eight cytochrome P450s (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, and 3A4) using a lentiviral expression system. The increased expression and metabolic function of each individual CYP in each established cell line were confirmed using real-time PCR, Western bl...

Arsenic Stimulates Myoblast Mitochondrial EGFR to Impair Myogenesis.

Arsenic exposure impairs muscle metabolism, maintenance, progenitor cell differentiation, and regeneration following acute injury. Low to moderate arsenic exposures target muscle fiber and progenitor cell mitochondria to epigenetically decrease muscle quality and regeneration. However, the mechanisms for how low levels of arsenic signal for prolonged mitochondrial dysfunction are not known. In this study, arsenic attenuated murine C2C12 myoblasts differentiation and resulted in abnormal undifferentiated myo...

Potent inhibitors of organic anion transporter 1 and 3 from natural compounds and their protective effect on aristolochic acid nephropathy.

Organic anion transporter 1 and 3 (OAT1 and OAT3) play a critical role in renal drug-drug interactions and are involved in the nephrotoxicity of many anionic xenobiotics. To date, relatively little is known about the interaction of natural compounds with OAT1 and OAT3. Of the 270 natural compounds screened in the present study, 21 compounds inhibited OAT1 and 45 compounds inhibited OAT3. Further concentration-dependent studies identified 7 OAT1 inhibitors and 10 OAT3 inhibitors with IC50 values of 

Development of an improved T cell assay to assess the intrinsic immunogenicity of haptenic compounds.

The prediction of drug hypersensitivity is difficult due to the lack of appropriate models and known risk factors. In vitro naïve T cell priming assays that assess immunogenicity have been developed. However, their application is limited due requirements for two batches of autologous dendritic cells (DC) and inconsistent results; a consequence of single well readouts when exploring reactions where compound-specific T-cell frequency is undefined. Hence, we aimed to develop an improved, but simplified assay,...

Impaired tubular reabsorption is the main mechanism explaining increases in urinary NGAL excretion following acute kidney injury in rats.

Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted low-molecular weight iron-siderophore binding protein. NGAL overexpression in injured tubular epithelia partly explain its utility as a sensitive and early urinary biomarker of acute kidney injury (AKI). Herein, we extend mechanistic insights into the source and kinetics of urinary NGAL excretion in experimental AKI. Three models of experimental AKI were undertaken in adult male Wistar rats; renal ischemia-reperfusion injury (IRI) and gentamici...

ToxPoint: Dissecting Functional RNA Modifications in Responses to Environmental Exposure-Mechanistic Toxicology Research Enters a New Era.

Expression of Concern: "The Dual Roles of c-Jun NH2-Terminal Kinase Signaling in Cr(VI)-Induced Apoptosis in JB6 Cells".

Expression of Concern: "Cadmium Induces Intracellular Ca2+- and H2O2-Dependent Apoptosis through JNK- and p53-Mediated Pathways in Skin Epidermal Cell line".

Metabolism and Effects on Endogenous Metabolism of Paracetamol (Acetaminophen) in a Porcine Model of Liver Failure.

The metabolic fate, toxicity and effects on endogenous metabolism of paracetamol (acetaminophen, APAP) in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF). Anaesthetized pigs were initially dosed at 250 mg/kg via an oroduodenal tube with APAP serum concentrations maintained above 300 mg/L using maintenance doses of 0.5-4g/h until ALF. Studies were undertaken to determine both the metabolic fate of APAP and its effects on the endogenous metabolic phenotype ...

Bioelution, Bioavailability, and Toxicity of Cobalt Compounds Correlate.

Based on the wide use of cobalt substances in a range of important technologies, it has become important to predict the toxicological properties of new or lesser-studied substances as accurately as possible. We studied a group of six cobalt substances with inorganic ligands, which were tested for their bioaccessibility (surrogate measure of bioavailability) through in vitro bioelution in simulated gastric and intestinal fluids. Representatives of the group also underwent in vivo blood kinetics and mass bala...

Reducing the Toxicity of Radiotherapy for Pancreatic Cancer with Magnetic Resonance Guided Radiotherapy.

Pancreatic cancer is a highly fatal malignancy for which surgery is currently considered to be the only curative treatment. However, less than a quarter of patients have disease amenable to definitive surgical resection. Local treatment with radiation therapy is a promising alternative to surgery for those patients with unresectable disease. However, conventional radiation techniques with computed tomography (CT) - guided therapy have yielded disappointing results due to the inability to deliver ablative do...

Consideration of styrene transcriptomic data informs mouse lung Cyp2F2-mediated AOP.

Assessing Effects of BHV-0223 40 mg Zydis® Sublingual Formulation and Riluzole 50 mg Oral Tablet on Liver Function Test Parameters Utilizing DILIsym®.

For patients with Amyotrophic Lateral Sclerosis (ALS) who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3x ULN, and 2% above 5x ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis®) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of live...

A Targeted Metabolomics-Based Assay Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Identifies Structural and Functional Cardiotoxicity Potential.

Implementing screening assays that identify functional and structural cardiotoxicity earlier in the drug development pipeline has the potential to improve safety and the cost and time required to bring new drugs to market. In this study, a metabolic biomarker-based assay was developed that predicts the cardiotoxicity potential of a drug based on changes in the metabolism and viability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Assay development and testing was conducted in two...

An evaluation of the human relevance of the liver tumors observed in female mice treated with permethrin based on mode of action.

In 2 year studies, the nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, we demonstrated that the mode of action (MOA) for mouse liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), resulting in a mitogenic effect. In the present study the effects of permethrin and two major permethrin metabolites, namely 3-phenoxybenzoic acid and trans-dichlorochrysanthemic acid, o...

Potential of ToxCast data in the safety assessment of food chemicals.

Tox21 and ToxCast are high-throughput in vitro screening (HTS) programmes coordinated by the U.S. National Toxicology Program and the U.S. Environmental Protection Agency, respectively, with the goal of forecasting biological effects in vivo based on bioactivity profiling. The present study investigated whether mechanistic insights in the biological targets of food-relevant chemicals can be obtained from ToxCast results, when the chemicals are grouped according to structural similarity. Starting from the 55...


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