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Etazene induces developmental toxicity in vivo Danio rerio and in silico studies of new synthetic opioid derivative.

ABSTRACT: Synthetic opioids are gaining more and more popularity among recreational users as well as regular abusers. One of such novel psychoactive substance, is etazene, which is the most popular opioid drug in the darknet market nowadays. Due to limited information available concerning its activity, we aimed to characterize its developmental toxicity, including cardiotoxicity with the use of in vivo Danio rerio and in silico tools. Moreover, we aimed, for the first time, to characterize the metabolite of etazene, which could become a potential marker of its use for future forensic analysis. The results of our study proved severe dose-dependent developmental toxicity of etazene (applied concentrations 10-300 µM), including an increase in mortality, developmental malformations, and serious cardiotoxic effects, as compared with well-known and used opioid-morphine (applied concentrations 1-50 mM). In silico findings indicate the high toxic potential of etazene which may lead to drug-drug interactions and accumulation of substances. Furthermore, phase I metabolite of etazene resulting from N-dealkylation reaction was identified, and therefore it should be considered as a target for toxicological screening. Nonetheless, the exact mechanism of observed effects in response to etazene should be further examined.

SUBMITTER: Kurach L

PROVIDER: S-EPMC8688443 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Etazene induces developmental toxicity in vivo Danio rerio and in silico studies of new synthetic opioid derivative.

Kurach Łukasz Ł Chłopaś-Konowałek Agnieszka A Budzyńska Barbara B Zawadzki Marcin M Szpot Paweł P Boguszewska-Czubara Anna A

Scientific reports 20211220 1

Synthetic opioids are gaining more and more popularity among recreational users as well as regular abusers. One of such novel psychoactive substance, is etazene, which is the most popular opioid drug in the darknet market nowadays. Due to limited information available concerning its activity, we aimed to characterize its developmental toxicity, including cardiotoxicity with the use of in vivo Danio rerio and in silico tools. Moreover, we aimed, for the first time, to characterize the metabolite ...[more]

PMID: 34931035

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Project description:Populations of plants and animals, including humans, living in close proximity to abandoned uranium mine sites are vulnerable to uranium exposure through drainage into nearby waterways, soil accumulation, and blowing dust from surface soils. Little is known about how the environmental impact of uranium exposure alters the health of human populations in proximity to mine sites, so we used developmental zebrafish (Danio rerio) to investigate uranium toxicity. Fish are a sensitive target for modeling uranium toxicity, and previous studies report altered reproductive capacity, enhanced DNA damage, and gene expression changes in fish exposed to uranium. In our study, dechorionated zebrafish embryos were exposed to a concentration range of uranyl acetate (UA) from 0 to 3000 μg/L for body burden measurements and developmental toxicity assessments. Uranium was taken up in a concentration-dependent manner by 48 and 120 h post fertilization (hpf)-zebrafish without evidence of bioaccumulation. Exposure to UA was not associated with teratogenic outcomes or 24 hpf behavioral effects, but larvae at 120 hpf exhibited a significant hypoactive photomotor response associated with exposure to 3 μg/L UA which suggested potential neurotoxicity. To our knowledge, this is the first time that uranium has been associated with behavioral effects in an aquatic organism. These results were compared to potential metal co-contaminants using the same exposure paradigm. Similar to uranium exposure, lead, cadmium, and iron significantly altered neurobehavioral outcomes in 120-hpf zebrafish without inducing significant teratogenicity. Our study informs concerns about the potential impacts of developmental exposure to uranium on childhood neurobehavioral outcomes. This work also sets the stage for future, environmentally relevant metal mixture studies. Summary Uranium exposure to developing zebrafish causes hypoactive larval swimming behavior similar to the effect of other commonly occurring metals in uranium mine sites. This is the first time that uranium exposure has been associated with altered neurobehavioral effects in any aquatic organism.

Project description:BackgroundDrinking water contamination related to the use of aqueous film-forming foam (AFFF) has been documented at hundreds of military bases, airports, and firefighter training facilities. AFFF has historically contained high levels of long-chain per- and polyfluoroalkyl substances (PFAS), which pose serious health concerns. However, the composition and toxicity of legacy AFFF mixtures are unknown, presenting great uncertainties in risk assessment and affected communities.ObjectivesThis study aimed to determine the fluorinated and nonfluorinated chemical composition of a legacy AFFF sample and its toxicity in zebrafish embryos.MethodsA sample of legacy AFFF (3% application formulation, manufactured before 2001) was provided by the Massachusetts Department of Environmental Protection. High resolution mass spectrometry (HRMS) was used to identify PFAS and nonfluorinated compounds, and a commercial laboratory measured 24 PFAS by a modified U.S. EPA Method 537.1. AFFF toxicity was assessed in zebrafish embryos in comparison with four major constituents: perfluorooctanesulfonic acid (PFOS); perfluorohexanesulfonic acid (PFHxS); sodium dodecyl sulfate (SDS); and sodium tetradecyl sulfate (TDS). End points included LC50 values, and sublethal effects on growth, yolk utilization, and pancreas and liver development.ResultsWe identified more than 100 PFAS. Of the PFAS detected, PFOS was measured at the highest concentration (9,410mg/L) followed by PFHxS (1,500mg/L). Fourteen nonfluorinated compounds were identified with dodecyl sulfate and tetradecyl sulfate the most abundant at 547.8 and 496.4mg/L, respectively. An LC50 of 7.41×10-4% AFFF was calculated, representing a dilution of the 3% formulation. TDS was the most toxic of the constituents tested but could not predict the AFFF phenotype in larval zebrafish. PFOS exposure recapitulated the reduction in length but could not predict effects on development of the liver, which was the tissue most sensitive to AFFF.DiscussionTo our knowledge, this research is the first characterization of the chemical composition and toxicity of legacy AFFF, which has important implications for regulatory toxicology. https://doi.org/10.1289/EHP6470.

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Etazene induces developmental toxicity in vivo Danio rerio and in silico studies of new synthetic opioid derivative.

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Etazene induces developmental toxicity in vivo Danio rerio and in silico studies of new synthetic opioid derivative.

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