Showing papers on "Toxicity published in 2019"

Reproducing human and cross-species drug toxicities using a Liver-Chip

Abstract: Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds. A multispecies Liver-Chip may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.

Toxic Effect of Acute Cadmium and Lead Exposure in Rat Blood, Liver, and Kidney.

Abstract: Background: Cadmium and lead are widespread and non-biodegradable pollutants of great concern to human health. In real life scenarios, we are exposed to mixtures of chemicals rather than single chemicals, and it is therefore of paramount importance to assess their toxicity. In this study, we investigated the toxicity of Cd and Pb alone and as a mixture in an animal model of acute exposure. Methods: Experimental groups received a single treatment of aqueous solution of Cd-chloride (15 and 30 mg/kg body weight (b.w.) and Pb-acetate (150 mg/kg b.w.), while the mixture group received 15 mg Cd/kg b.w. and 150 mg Pb/kg b.w. Toxic effects of individual metals and their mixture were investigated on hematological and biochemical parameters, and the redox status in the plasma, liver, and kidneys of treated Wistar rats. Results: Tissue-specific changes were recorded in various parameters of oxidative damage, while the accumulation of metals in tissues accompanied the disturbances of both hematological and biochemical parameters. It was observed that the level of toxic metals in tissues had a different distribution pattern after mixture and single exposure. Conclusions: Comprehensive observations suggest that exposure to Cd and Pb mixtures produces more pronounced effects compared to the response observed after exposure to single metal solutions. However, further research is needed to confirm toxicokinetic or toxicodynamic interactions between these two toxic metals in the organisms.

Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1-Based Immunotherapy.

Abstract: Purpose: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity. Experimental Design: The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids. Results: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51–0.84; P = 0.037] and 0.70 at EDT (95% CI, 0.55–0.85; P = 0.017) using ROC analysis. Conclusions: The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity. See related commentary by Johnson and Balko, p. 1452

Bioaccumulation of polystyrene nanoplastics and their effect on the toxicity of Au ions in zebrafish embryos.

Abstract: As nano- and micro-sized plastics accumulate in the environment and the food chain of animals, including humans, it is imperative to assess the effects of nanoplastics in living organisms in a systematic manner, especially because of their ability to adsorb potential toxicants such as pollutants, heavy metals, and organic macromolecules that coexist in the environment. Using the zebrafish embryo as an animal model, we investigated the bioaccumulation and in vivo toxicity of polystyrene (PS) nanoplastics individually or in combination with the Au ion. We showed that smaller PS nanoplastics readily penetrated the chorion and developing embryos and accumulated throughout the whole body, mostly in lipid-rich regions such as in yolk lipids. We also showed that PS nanoplastics induced only marginal effects on the survival, hatching rate, developmental abnormalities, and cell death of zebrafish embryos but that these effects were synergistically exacerbated by the Au ion in a dose- and size-dependent manner. Such exacerbation of toxicity was well correlated with the production of reactive oxygen species and the pro-inflammatory responses synergized by the presence of PS, supporting the combined toxicity of PS and Au ions. The synergistic effect of PS on toxicity appeared to relate to mitochondrial damage as determined by ultrastructural analysis. Taken together, the effects of PS nanoplastics were marginal but could be a trigger for exacerbating the toxicity induced by other toxicants such as metal ions.

Nanoplastics Decrease the Toxicity of a Complex PAH Mixture but Impair Mitochondrial Energy Production in Developing Zebrafish.

Abstract: Plastics are recognized as a worldwide threat to the environment, possibly affecting human health and wildlife. Small forms of plastics such as micro- and nanoplastics can interact with other organic contaminants, potentially acting as chemical carriers and modulating their toxicity. In this study, we investigated the toxicity of polystyrene nanoparticles (Nano-PS) and a real-world environmental PAH mixture (Elizabeth River Sediment Extract, ERSE, comprised of 36 detected PAHs) to zebrafish embryos and larvae. Embryos were exposed to Nano-PS (0.1–10 ppm) or ERSE (0.1–5% v/v, equivalent to ΣPAH 5.07–25.36 ppb) or coexposed to a combination of both. Larvae exposed to Nano-PS did not exhibit developmental defects, while larvae exposed to ERSE (2–5%) showed classic signs of PAH toxicity such as heart malformation and deformities in the jaw, fin, and tail. ERSE (5%) also impaired vascular development in the brain. When coexposed, Nano-PS decreased the developmental deformities and impaired vascular development...

AAV cis-regulatory sequences are correlated with ocular toxicity

Abstract: Adeno-associated viral vectors (AAVs) have become popular for gene therapy, given their many advantages, including their reduced inflammatory profile compared with that of other viruses. However, even in areas of immune privilege such as the eye, AAV vectors are capable of eliciting host-cell responses. To investigate the effects of such responses on several ocular cell types, we tested multiple AAV genome structures and capsid types using subretinal injections in mice. Assays of morphology, inflammation, and physiology were performed. Pathological effects on photoreceptors and the retinal pigment epithelium (RPE) were observed. Muller glia and microglia were activated, and the proinflammatory cytokines TNF-α and IL-1β were up-regulated. There was a strong correlation between cis-regulatory sequences and toxicity. AAVs with any one of three broadly active promoters, or an RPE-specific promoter, were toxic, while AAVs with four different photoreceptor-specific promoters were not toxic at the highest doses tested. There was little correlation between toxicity and transgene, capsid type, preparation method, or cellular contaminants within a preparation. The toxic effect was dose-dependent, with the RPE being more sensitive than photoreceptors. Our results suggest that ocular AAV toxicity is associated with certain AAV cis-regulatory sequences and/or their activity and that retinal damage occurs due to responses by the RPE and/or microglia. By applying multiple, sensitive assays of toxicity, AAV vectors can be designed so that they can be used safely at high dose, potentially providing greater therapeutic efficacy.

The effects of hesperidin on sodium arsenite-induced different organ toxicity in rats on metabolic enzymes as antidiabetic and anticholinergics potentials: A biochemical approach.

Abstract: In our work, it was purposed to investigate the effects of sodium arsenite (SA) and hesperidin (HSP) administered to rats on some metabolic enzymes including carbonic anhydrase (CA), aldose reductase (AR), paraoxonase-1 (PON1), α-glycosidase (α-Gly), butyrylcholine esterase (BChE), acetylcholine esterase (AChE) enzymes activities in the brain, heart, liver, testis, and kidney tissues of rats. CA activities were significantly decreased in testis, liver, and heart tissues of rats given HSP, SA, SA+HSP-100, and SA+HSP-200 compared to control (p < 0.05). In liver tissue, AChE and BChE enzymes activities were significantly reduced given in all groups. In all tissues, α-Gly activity was reduced given in all groups. In the current study, aldose reductase enzyme activity was reduced significantly in testis, brain, and heart tissues of all groups compared to standard (p < 0.05). PON1 enzyme activity was increased significantly in kidney and liver tissues of rats HSP groups and decreased SA groups compared to control. PRACTICAL APPLICATIONS: α-Glycosidase is the key enzyme involved in the digestion of the carbohydrate. Another enzyme α-amylase hydrolyzes the α-linked polysaccharide derivatives into oligosaccharide molecules, and α-glycosidase enzymes, which are characterized in small intestine, catalyze the final stage in the digestive mechanism of carbohydrate molecule to release absorbable monosaccharides like glucose. Conforming to the cholinergic hypothesis, impairment of the cholinergic pathways plays a good role in the development of neurodegenerative diseases like depression, schizophrenia, Alzheimer's disease (AD) problems with the regulation of traumatic brain injury and sleep. The AD is the main reason for dementia disease, and mild to moderate cases are generally treated with AChE inhibitors. Human CA inhibitor compounds are clinically used for more than 70 years as antiglaucoma and diuretics drugs.

Trodusquemine enhances Aβ 42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

Abstract: Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ42) are key pathogenic agents in Alzheimer’s disease (AD). To investigate the relationship between Aβ42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ42-induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.

Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics

Abstract: A pumpless, reconfigurable, multi-organ-on-a-chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological microelectromechanical systems. In the first configuration of the system, primary human hepatocytes were cultured with two cancer-derived human bone marrow cell lines for antileukemia drug analysis in which diclofenac and imatinib demonstrated a cytostatic effect on bone marrow cancer proliferation. Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%. The second configuration housed a multidrug-resistant vulva cancer line, a non-multidrug-resistant breast cancer line, primary hepatocytes, and induced pluripotent stem cell-derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. Both tamoxifen alone and coadministration with verapamil produced off-target cardiac effects as indicated by a reduction of contractile force, beat frequency, and conduction velocity but did not affect viability. These systems demonstrate the utility of a human cell-based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites; these systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies.

The antidiabetic and anticholinergic effects of chrysin on cyclophosphamide-induced multiple organ toxicity in rats: Pharmacological evaluation of some metabolic enzyme activities.

Abstract: Chrysin (CH) or 5,7-dihydroxyflavone is a flavonoid present in various plants, bee propolis, and honey. Cyclophosphamide (CYP) is a chemotherapeutic drug, which is extensively used in the treatment of multiple human malignancies. In our study, we aimed to investigate the effects of CYP and CH on some metabolic enzymes including carbonic anhydrase, aldose reductase, paraoxonase-1, α-glycosidase, acetylcholinesterase, and butyrylcholinesterase enzyme activities in the brain, heart, testis, liver, and kidney tissues of rats. Thirty-five adult male Wistar rats were used. The animals were pretreated with CH (25 and 50 mg/kg b.w.) for seven days before administering a single dose of CYP (200 mg/kg b.w.) on the seventh day. In all the tissues, the treatment of CH significantly regulated these enzyme activities in CYP-induced rats. These results showed that CH exhibited an ameliorative effect against CYP-induced brain, heart, liver, testis, and kidney toxicity.

Humic acid alleviates the toxicity of polystyrene nanoplastic particles to Daphnia magna

Abstract: With worldwide environmental accumulation of plastics and their recognized degradation into smaller particles, attention to their impacts on ecological systems and humans has been increasing recently. However, environmental factors and their impacts are seldom considered during their eco-toxicity evaluation. In this study, D. magna neonates were used to assess and compare the acute toxicities of polystyrene microplastic particles (MPPs) and nanoplastic particles (NPPs) in the absence and presence of humic acids (HAs), an important environmental factor in aquatic systems. Four stress response and detoxification genes (CAT, GST, HSP70, and P-GP) were used to characterize the toxic response of the neonates to the exposure. Our results showed that NPPs were much more toxic than MPPs in that 10 mg L−1 NPPs induced over 70% of death in 96 h but MPPs (as high as 400 mg L−1) caused no mortality under all tested conditions. More importantly, we revealed a potent protective role of HA against NPP toxicity at environmentally relevant concentrations. The effect was concentration dependent, as 50 mg L−1 HA subdued the NPP (400 mg L−1) toxicity effect completely. NPPs elicited the up-regulation of all examined genes while HA diminished the change appreciably, further confirming its detoxifying role against NPP toxicity. Through fluorescence and dynamic light scattering measurements, we found that HA was adsorbed on NPPs and formed a corona, without causing agglomeration or precipitation, but changed NPP distribution in the D. magna neonates in a way similar to that of MPPs, leading to alleviated toxicity. Our results suggest that it is essential to consider environmental factors in evaluating and monitoring NPP toxicity as this presents a more relevant exposure state.

Exposure to PbSe Nanoparticles and Male Reproductive Damage in a Rat Model.

Abstract: PbSe nanoparticles (PbSe-NPs) attract ever-growing interest owing to their great promise in various fields. However, potential toxic effects of PbSe-NPs on male reproductive systems have not been reported. This study aimed to determine whether early-life exposure to PbSe-NPs could affect male reproductive systems and other related health effects in rats. The male rats were intraperitoneally injected with 10 mg/kg/week PbSe-NPs for 60 days followed by a series of reproductive-related analyses. We found that the nanoparticles could accumulate in testes in a size-dependent manner. Furthermore, accumulation of PbSe-NPs resulted in oxidative stress and disorder of normal serum sex hormones. Endoplasmic reticulum and mitochondria-mediated cell apoptosis were triggered via oxidative stress, as shown by upregulation of cytoplasmic Cyt-c, Bax, cleaved Caspase-3, GRP78, and Caspase-12. Notably, PbSe-NP administration led to reduction in the quantity and quality of sperm, which caused a great fertility decrease. In contrast, released Pb2+ from PbSe-NPs did not result in any testis toxicity and fertility declines. These results demonstrate that PbSe-NPs could cause severe reproductive toxicity in a size-dependent manner and these toxic effects should be responsible for PbSe-NPs themselves rather than released Pb2+. The application of PbSe-NPs might be a double-edged sword, and corresponding measures should be taken before use.

Review of Biguanide (Metformin) Toxicity.

Abstract: In the 1920s, guanidine, the active component of Galega officinalis, was shown to lower glucose levels and used to synthesize several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal upset, vitamin B12 deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP) turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of H+ from ATP hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin, alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.

Biodistribution and targeting properties of iron oxide nanoparticles for treatments of cancer and iron anemia disease

Abstract: IONP (iron oxide nanoparticles) commercialized for treatments of iron anemia or cancer diseases can be administered at doses exceeding 1 g per patient, indicating their bio-compatibility wh...

Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent.

Abstract: ObjectivesThis preclinical study was devised to investigate potential cellular toxicity in human neurons induced by gadolinium-based contrast agents (GBCAs) used for contrast-enhanced magnetic resonance imaging (MRI). Neurons modeling a subset of those in the basal ganglia were tested, because the b

Characterizing Crude Oil Toxicity to Early-Life Stage Fish Based On a Complex Mixture: Are We Making Unsupported Assumptions?

Abstract: Numerous studies of the water-soluble fraction (WSF) from crude oil have concluded that polycyclic aromatic hydrocarbons (PAHs) are the primary causative agents for early life stage (ELS) fish toxicity. Noteworthy is the lack of studies demonstrating that the sum of PAHs are capable of causing toxic effects in ELS fish at the low levels claimed (0.1-5 μg/L) without being part of a complex crude oil mixture. Crude oil and the WSF are composed of thousands of other compounds that co-occur and likely contribute to crude oil toxicity. Based on the available data, it appears that the syndrome of effects (lower heart rate, edemas, and morphological abnormalities) for ELS fish exposed to the aqueous fraction of a crude oil mixture is commonly observed in studies exposing fish embryos to high concentrations of a variety of compounds and may be a nonspecific response. We conclude that the available data support the hypothesis that this syndrome of effects is likely the result of baseline toxicity (not receptor based) due to membrane disruption and resulting alteration in ion (e.g., calcium and potassium) homeostasis. We acknowledge the possibility of some compounds in the WSF capable of causing a specific receptor based toxicity response to ELS fish; however, such compounds have not been identified nor their receptor characterized. Concluding that PAHs are the main toxic compounds for crude oil exposure is misleading and does not result in guideline values that can be useful for environmental protection. Water quality guidelines for any single chemical or suite of chemicals must be based on a complete understanding of exposure concentrations, mechanism of action, potency, and resulting response. This review focuses on the toxic effects reported for fish embryos and the purported toxic concentrations observed in the aqueous phase of an oil/water mixture, the known levels of toxicity for individual PAHs, a toxic unit approach for characterizing mixtures, and the potential molecular initiating event for ELS toxicity in fish. This review also has implications for a large number of studies exposing ELS fish to a variety of compounds at high concentrations that result in a common baseline toxic response.