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Gastric ulcer is a common gastrointestinal disorder worldwide. Although its pathogenesis is unclear, the overproduction of reactive oxygen species (ROS), which results in an oxidative imbalance, has been reported as a central driving mechanism. Within the scope of this investigation, we developed two different self-assembling redox nanoparticles (RNPs) with ROS-scavenging features for the oral treatment of gastric ulcers. One of them, referred to as RNPN, disintegrates in response to acidic pH, whereas the other, denoted as RNPO, remains intact regardless of pH variations. Both types of RNPs showed different free radical scavenging activities in vitro. Protonation of the amino linkages in the side chains of RNPN caused the micelle structure to collapse and the nitroxide radicals encapsulated in the core were exposed to the outside, resulting in a significant increase in antioxidant capacity as the pH decreases. In contrast, RNPO maintained its spherical structure and consistent antioxidant reactivity irrespective of pH changes. The in vivo gastric retention of orally administered RNPN was significantly improved compared to that of RNPO which might be explained by the increased exposure of cationic protonating segments in RNPN on the negatively charged gastric mucosal surface. Owing to its improved gastric retention and enhanced ROS scavenging capacity under acidic pH conditions, RNPN exhibited superior protective effects against oxidative stress induced by aspirin in a gastric ulcer mouse model compared to RNPO. In addition, neither RNPN nor RNPO resulted in severe lethal effects or significant changes in the morphology of zebrafish embryos, indicating their biosafety. Our results suggest that the oral administration of RNPs has a high therapeutic potential for gastric ulcer treatment. [Display omitted] • pH sensitive and pH non-sensitive redox nanoparticles (RNPN and RNPO, respectively) were developed and effectively scavenged various reactive oxygen species; • Orally admistered RNPN exhibited higher gastric accumulation and retention compared to RNPO; • Both RNPs, especially RNPN, showed a significantly protective effects in aspirin-induced gastric ulcer via oral administration; • Both RNPs exhibited extremely low toxicity in zebrafish embryos compared to control polymeric nanoparticles (without ROS scavenging moieties). [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are a rampant public health threat. Environmental contaminants, such as Cadmium (Cd), a toxic metal, are risk factors for cardiovascular diseases. Given that human exposure to Cd is increasing, there is a need for therapies to ameliorate Cd toxicity. Selenium (Se), an essential trace element, has been proposed to rescue the effects of Cd toxicity, with mixed effects. Se's narrow therapeutic window necessitates precise dosing to avoid toxicity. Here, we assessed the effects of various waterborne Cd and Se concentrations and sequences on cardiac function using zebrafish (Danio rerio). We showed that Cd induced pericardial edemas and modified heart rates in zebrafish larvae in a concentration-dependent manner. To identify the therapeutic range of Se for Cd-induced cardiotoxicity, zebrafish embryos were treated with 0, 10, 50, 100, 150, or 200 μg/L Se for 1–4 days prior to exposure to 2.5 and 5 μg/L Cd. We found that a 50 µg/L Se pre-treatment before 2.5 μg/L Cd, but not 5 μg/L Cd, reduced the prevalence of pericardial edemas and ameliorated Cd-induced bradycardia in zebrafish. Zebrafish exposed to 10 and 50 μg/L of Se for up to 4 days showed typical heart morphology, whereas other Se-exposed and control fish presented pericardial edemas. Longer Se pre-treatment durations led to fewer incidences of pericardial edemas. Overall, this study highlights the importance of optimizing Se concentrations and pre-treatment periods to harness its protective effects against Cd-induced cardiotoxicity. These findings provide insights into potential therapeutic strategies for reducing Cd-related cardiovascular damage in humans. [ABSTRACT FROM AUTHOR]

Hypoglycin A (HGA) and methylenecyclopropylglycine (MCPrG) are protoxins produced by Sapindaceae plants, particularly Acer pseudoplatanus, and are responsible for causing atypical myopathy (AM) in equids. These protoxins metabolise into toxic compounds, such as methylenecyclopropylacetyl-CoA (MCPA-CoA), which alters energy metabolism and induces severe rhabdomyolysis. Currently, no specific treatment exists for this poisoning, in vitro models fail to reproduce HGA's toxic effects on equine primary myoblasts, and mammalian models are impractical for large-scale drug screening. This study aimed to develop a zebrafish embryo model for screening therapeutic compounds against AM. Zebrafish embryos were exposed to various concentrations of HGA, MCPrG, and methylenecyclopropylacetate (MCPA) for 72 h. MCPrG did not induce toxicity, while HGA and MCPA showed median lethal concentration (LC50) values of 1.7 µM and 1 µM after 72 h, respectively. The highest levels of the conjugated metabolite MCPA–carnitine were detected 24 h after HGA exposure, and the acylcarnitines profile was highly increased 48 h post-exposure. Isovaleryl-/2- methylbutyrylcarnitine levels notably rose after 24 h, suggesting potential exposition biomarkers. Glycine and carnitine effectively reduced mortality, whereas riboflavin showed no protective effect. These findings suggest that the zebrafish embryo represents a valuable model for identifying therapeutic compounds for Sapindaceae poisoning. [ABSTRACT FROM AUTHOR]

Habbe Sara is an herbal formulation used in the Unani system of medicine to treat convulsions in adults and children. It is believed to strengthen the brain and nervous system, reducing the frequency of fits. In this study, the effects of various concentrations of Habbe Sara ranging from 50 to 400 ppm on in zebrafish were examined. The study found that increasing concentrations of Habbe Sara resulted in higher mortality rates with an LC50 value of 251.18 ppm. In addition, its higher concentrations showed delayed growth, decreased in heartbeat rate, reduced hatchability, and various developmental defects in the treated embryos. Therefore, caution should be exercised when administering high doses of Habbe Sara to pregnant women. [ABSTRACT FROM AUTHOR]

The increasing use of UV filters, such as benzophenone-3 (BP-3) and titanium dioxide nanoparticles (TiO2 NPs), has raised concerns regarding their ecotoxicological effects on the aquatic environment. The aim of the present study was to examine the embryo-larval toxicity attributed to BP-3 or TiO2 NPs, either alone or in a mixture, utilizing zebrafish (Danio rerio) as a model after exposure to environmentally relevant concentrations of these compounds. Zebrafish embryos were exposed to BP-3 (10, 100, or 1000 ng/L) or TiO2 NPs (1000 ng/L) alone or in a mixture (BP-3 10, 100, or 1000 ng/L plus 1000 ng/L of TiO2 NPs) under static conditions for 144 hr. After exposure, BP-3 levels were determined by high-performance liquid chromatography (HPLC). BP-3 levels increased in the presence of TiO2 NPs, indicating that the BP-3 degradation decreased in the presence of the NPs. In addition, in the presence of zebrafish, BP-3 levels in water decreased, indicating that zebrafish embryos and larvae might absorb BP-3. Data demonstrated that, in general, environmentally relevant concentrations of BP-3 and TiO2 NPs, either alone or in a mixture, did not significantly induce changes in heart and spontaneous contractions frequencies, levels of reactive oxygen species (ROS), morphological and morphometric parameters as well as mortality rates during 144 hr exposure. However, the groups exposed to TiO2 NPs alone and in a mixture with BP-3 at 10 ng/L exhibited an earlier significant hatching rate than the controls. Altogether, the data indicates that a potential ecotoxicological impact on the aquatic environment exists. [ABSTRACT FROM AUTHOR]

The Salacia reticulata, a medicinal woody climbing shrub, was utilized for our study, the green synthesis of CuO nanoparticles, which were analyzed through SEM, EDX, FTIR, XRD, and UV‒Vis spectroscopy. This study assessed the toxicity to zebrafish embryos and explored the antibacterial, cytotoxic, antidiabetic, and anti-inflammatory properties of the synthesized nanoparticles. In results, the UV absorption of the CuO NPs showed that the intensity of nanoparticle green colloidal suspension changed from blue to green, which also confirmed that the spectrum of the green CuO NPs changed from colorless to black. in FT-IR and XRD spectral analysis to identify functional groups and determine the particle size of CuO NPs prepared by green and chemical methods. Its showed that CuO NPs (green) had a size of approximately 42.2 nm, while CuO NPs (chemical) had a size of approximately 84 nm. The morphology of these NPs was analyzed using SEM–EDX. Compared with their chemically prepared counterparts, the green-synthesized CuO nanoparticles demonstrated superior dispersion. Additionally, both green and chemical CuO nanoparticles at a concentration of 200 µL/mL caused developmental anomalies and increased mortality in zebrafish embryos and larvae. The green and chemical CuO NPs inhibited α-glucosidase enzyme activity at concentrations between 10 and 50 µL/mL, with IC50 values of 22 µL/mL and 26 µL/mL, respectively. The extract exhibited anti-inflammatory activity, with IC50 values of 274 and 109 µL/mL. The authors concluded that this green nanoparticle method has potential as a more eco-friendly and cost-effective alternative to traditional synthetic methods. NPs are widely used in human contact fields (medicine and agriculture), hence synthesis methods that do not involve toxic substances are becoming increasingly important. [ABSTRACT FROM AUTHOR]

Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer's disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein–huprine hybrid lead by hydroxy group removal—ring contraction—ring opening—ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC50 >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification. [ABSTRACT FROM AUTHOR]

In order to clarify the combined acute toxic effects of the fungicide fenbuconazole and copper to zebrafish, the acute toxicity of fenbuconazole and copper alone, as well as their combination at equaltoxicity ratio or at different mass concentration ratios to zebrafish during different life stages were determined. The combined acute toxic effects were evaluated using the additional index (AI) method and co-toxicity coefficient (CTC) method. The results showed that the 96 h-LC50 values of fenbuconazole for adults, embryos, and larvae of zebrafish were 2.615, 4.121 and 4.140 mg/L, respectively, while that of copper were 0.235, 0.353, and 0.429 mg/L, respectively. The order of the acute toxicity was adult > embryo > larvae. The toxic effects of the mixtures on both zebrafish larvae and embryos showed an enhancement tendency. At equitoxicity ratio, the 96 h-LC50 of the mixed fenbuconazole and copper for larvae and embryos was 2.051 and 2.207 mg/L, respectively, and the evaluation results with AI and CTC methods were both additive; while the 96 h-LC50 of the mixture for adults was 1.755 mg/L, and the evaluation results of the two methods were different, which were antagonistic and additive effects, respectively. At different mass concentration ratios, the 96 h-LC50 values of fenbuconazole and copper mixed at 2 : 8, 5 : 5, and 8 : 2 were 0.272, 0.378 and 0.785 mg/L for embryos, respectively, which showed synergistic effects; the 96 h-LC50 values were 0.532, 0.621 and 0.934 mg/L for larvae, respectively, which showed either synergistic or additive effects. The results of the two methods were consistent for the embryos and larvae. As for the adults zebrafish, the 96 h-LC50 values were 0.434、0.653 and 1.053 mg/L, respectively, and the mixtures showed antagonistic effects except that it showed antagonistic and additive effects at 8:2 ratio with the two different methods. The results suggested that the acute toxicity of the mixture of fenbuconazole and copper was stronger to zebrafish at early life stages. This finding will help us to better evaluate the impact of contamination of fenbuconazole and copper on aquatic organisms. [ABSTRACT FROM AUTHOR]

Developmental toxicity studies help to understand the impact of a pollutant on this crucial phase of the living organisms which can affect their population dynamics. Zebrafish has become an ideal model for studying environmental and embryo toxicity. The present study was carried out using zebrafish embryos for assessing the environmental toxicity of Di(2-ethylhexyl) phthalate (DEHP) which is universally considered to be an omnipresent environmental contaminant as it is the most widely used plasticizer. The embryos were exposed to DEHP for a range of five concentrations of 0.2, 20, 80, 140 and 200 μg/L for the duration of 96 hours. The treatment resulted in increased mortality and decreased hatch rate, hatchability and heartrate. It also induced teratogenic endpoints like yolk sac edema, pericardial edema and spinal deformity in the embryos which increased in dose and time dependent manner. [ABSTRACT FROM AUTHOR]

Isobavachalcone (IBC) is a flavonoid component of the traditional Chinese medicine Psoraleae Fructus, with a range of pharmacological properties. However, IBC causes some hepatotoxicity, and the mechanism of toxicity is unclear. The purpose of this paper was to investigate the possible mechanism of toxicity of IBC on HepG2 cells and zebrafish embryos. The results showed that exposure to IBC increased zebrafish embryo mortality and decreased hatchability. Meanwhile, IBC induced liver injury and increased expression of ALT and AST activity. Further studies showed that IBC caused the increase of ROS and MDA the decrease of CAT, GSH, and GSH‐Px; the increase of Fe2+ content; and the changes of ferroptosis related genes (acsl4, gpx4, and xct) and iron storage related genes (tf, fth, and fpn) in zebrafish embryos. Through in vitro verification, it was found that IBC also caused oxidative stress and increased Fe2+ content in HepG2 cells. IBC caused depolarization of mitochondrial membrane potential (MMP) and reduction of mitochondrial ATP, as well as altered expression of ACSl4, SLC7A11, GPX4, and FTH1 proteins. Treatment of HepG2 cells with ferrostatin‐1 could reverse the effect of IBC. Targeting the System Xc−‐GSH‐GPX4 pathway of ferroptosis and preventing oxidative stress damage might offer a theoretical foundation for practical therapy and prevention of IBC‐induced hepatotoxicity. Isobavachalcone (IBC) is a flavonoid component in the traditional Chinese medicine Psoraleae Fructus, which is widely used. However, IBC has toxicity and requires further in‐depth research. This study found that IBC was hepatotoxic to zebrafish embryos and HepG2 cells, while causing an imbalance in antioxidant capacity, an increase in Fe2+ content, and ferroptosis through the System Xc−‐ GSH‐GPX4 pathway. This provides a theoretical basis for the application and detoxification of IBC. [ABSTRACT FROM AUTHOR]

The morphological transformation of the pectoral/shoulder girdle is fundamental to the water-to-land transition in vertebrate evolution. Although previous studies have resolved the embryonic origins of tetrapod shoulder girdles, those of fish pectoral girdles remain uncharacterized, creating a gap in the understanding of girdle transformation mechanisms from fish to tetrapods. Here, we identify the embryonic origins of the zebrafish pectoral girdle, including the cleithrum as an ancestral girdle element lost in extant tetrapods. Our combinatorial approach of photoconversion and genetic lineage tracing demonstrates that cleithrum development combines four adjoining embryonic populations. A comparison of these pectoral girdle progenitors with extinct and extant vertebrates highlights that cleithrum loss, indispensable for neck evolution, is associated with the disappearance of its unique developmental environment at the head/trunk interface. Overall, our study establishes an embryological framework for pectoral/shoulder girdle formation and provides evolutionary trajectories from their origin in water to diversification on land. The embryonic origins of the pectoral girdle in fish remain unexplored. Here they show that the zebrafish pectoral girdle develops as an amalgam of four distinct cell populations. [ABSTRACT FROM AUTHOR]

Cyprodinil, a globally utilized broad-spectrum pyrimidine amine fungicide, has been observed to elicit cardiac abnormality. Resveratrol (RSV), a naturally occurring polyphenolic compound, showcases remarkable defensive properties in nurturing cardiac development. To investigate whether RSV could protect against cyprodinil-induced cardiac defects, we exposed zebrafish embryos to cyprodinil (500 μg/L) in the presence or absence of RSV (1 μM). Our results showed that RSV significantly mitigated the decrease of survival rate and embryo movement and the hatching delay induced by cyprodinil. In addition, RSV also improved cyprodinil-induced zebrafish cardiac developmental toxicity, including pericardial edema and cardiac function impairment. In mechanism, RSV attenuated the cyprodinil-induced changes in mRNA expression involved in cardiac development, such as myh6, myl7, tbx5, and gata4, and calcium ion channels, such as ncx1h, slc8a4a, and atp2a2b. We further showed that RSV might inhibit the activity of aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil. In summary, our findings establish that the protective effects of RSV against the cardiac developmental toxicity are induced by cyprodinil due to its remarkable ability to inhibit AhR activity. Our findings not only shed light on a new avenue for regulating and ensuring the safe utilization of cyprodinil but also presents a novel concept to promote its responsible use. [ABSTRACT FROM AUTHOR]

Microalgae-based water treatments for the removal of different types of pollution have been gaining considerable attention during the last few decades. However, information about microalgae potential in the removal of pharmaceuticals and personal care products (PPCPs) and the ecotoxicological outcomes is still limited. Therefore, in this work, we aimed at investigating salicylic acid removal from water by three different microalgae strains, namely Chlorella sorokiniana, Chlorella vulgaris and Scenedesmus obliquus. For such a purpose, photobioreactors were operated under batch and semi-continuous mode. Apart from determining the reduction in the concentration of salicylic acid attained by each strain, we used zebrafish embryo bioassays to assess the efficiency of microalgae to reduce its toxicity effects. S. obliquus was the strain that achieved the most significant decrease in the concentration and toxic effects of salicylic acid. Indeed, S. obliquus was able to rescue mortality and reduce abnormalities at practically 100%. The efficiency of C. sorokiniana and, especially, that of C. vulgaris were not so remarkable, indicating that the removal of SA and its toxic effects from water by microalgae is markedly strain dependent. The obtained results proved the importance of considering toxic effects for a more comprehensive evaluation of microalgae efficiency in the removal of PPCPs in view of an adequate selection for water treatment. [ABSTRACT FROM AUTHOR]

Neurogenesis is the process by which new brain cells are formed. This crucial event emerges during embryonic life and proceeds in adulthood, and it could be influenced by environmental pollution. Non-combustion-derived magnetite represents a portion of the coarse particulate matter (PM) contributing to air and water pollution in urban settings. Studies on humans have reported that magnetite and other iron oxides have significant damaging effects at a central level, where these particles accumulate and promote oxidative stress. Similarly, magnetite nanoparticles can cross the placenta and damage the embryo brain during development, but the impact on neurogenesis is still unknown. Furthermore, an abnormal Fe cation concentration in cells and tissues might promote reactive oxygen species (ROS) generation and has been associated with multiple neurodegenerative conditions. In the present study, we used zebrafish as an in vivo system to analyze the specific effects of magnetite on embryonic neurogenesis. First, we characterized magnetite using mineralogical and spectroscopic analyses. Embryos treated with magnetite at sub-lethal concentrations showed a dose–response increase in ROS in the brain, which was accompanied by a massive decrease in antioxidant genes (sod2, cat, gsr, and nrf2). In addition, a higher number of apoptotic cells was observed in embryos treated with magnetite. Next, interestingly, embryos exposed to magnetite displayed a decrease in neural staminal progenitors (nestin, sox2, and pcna markers) and a neuronal marker (elavl3). Finally, we observed significative increases in apoeb (specific microglia marker) and interleukin-1b (il1b), confirming a status of inflammation in the brain embryos treated with magnetite. Our study represents the very first in vivo evidence concerning the effects of magnetite on brain development. [ABSTRACT FROM AUTHOR]

The benzophenone (BP) family, including oxybenzone (BP-3), a prevalent sunscreen ingredient and environmental contaminant, has raised concerns since the year 2005. This study investigated oxybenzone toxicity in zebrafish (Danio rerio) eleutheroembryos and brine shrimp (Artemia salina) nauplii, focusing on the LC50 and developmental impacts. Zebrafish embryos (0.100–1.50 mg/L BP-3, 96 h) and A. salina (0.100–5.00 mg/L BP-3, 48 h) were tested with ultrasound-assisted emulsified liquid-phase microextraction (UA-ELPME) used for zebrafish tissue analysis. HPLC-DAD determined BP-3 concentrations (highest: 0.74 ± 0.13 mg/L). Although no significant zebrafish embryo mortality or hatching changes occurred, developmental effects were evident. Lethal concentrations were determined (A. salina LC50 at 24 h = 3.19 ± 2.02 mg/L; D. rerio embryos LC50 at 24 h = 4.19 ± 3.60 mg/L), with malformations indicating potential teratogenic effects. A. salina displayed intestinal tract alterations and D. rerio embryos exhibited pericardial edema and spinal deformities. These findings highlight oxybenzone's environmental risks, posing threats to species and ecosystem health. [ABSTRACT FROM AUTHOR]

Exposure to illumination from LED (light emitting diode) light may be an unsuspecting cause of human health problems, including cellular growth disruptions and cardiovascular issues. Vertebrate hearts comprise multiple chambers that create a rhythm resulting in continuous blood flow, which, if insufficient results in the heart retaining fluid. Here we report a preliminary study of the effect of exposing wild-type Danio rerio (zebrafish) embryos to 6500K, White, LED light on development of pericardial edema. Embryos were exposed to LED light from 12 hours post fertilization for 72 hours in one of the following conditions: (1) no exposure, (2) light/dark cycle of 12 hours/12 hours, and (3) 72 consecutive hours. Results indicated a significant relationship between exposure to LED lighting and pericardial edema; a significant relationship was seen between length of exposure and severity of pericardial edema. Pericardial edema became noticeable after 48 hours of light exposure. Further research should explore the effects of different wavelengths of LEDs on development of pericardial edema. Molecular studies might examine how LED exposure alters transcription factors involved in cardiac development. [ABSTRACT FROM AUTHOR]

Objective: Radiofrequency electromagnetic field (RF-EMF) exposure during the embryonic period can cause defects in the development of the fetus. The study’s aim is to evaluate the effects of RF-EMF on the lipid accumulation, oxidant-antioxidant system parameters, locomotor activities, and gene expressions of insulin and leptin as genes related to insulin resistance in fetal hyperglycemia-induced zebrafish embryos. Materials and Methods: The study exposed zebrafish embryos to RF-EMF (60 min) and glucose (5%) every day until 96 hours post fertilization (hpf). The study measured lipid peroxidation (LPO), superoxide dismutase, nitric oxide (NO), glutathione S-transferase (GST), and glutathione (GSH) levels to observe the oxidative stress status. The study monitored the development of the zebrafish embryos under a microscope, performed a locomotor activity analysis, measured acetylcholinesterase activity, and conducted oil red O staining to determine lipid accumulation. The study used reverse transcription polymerase chain reactions (RT-PCRs) to determine the expressions of ins and lepa by using RT-PCR. Results: Both the glucose and RF-EMF applications decreased locomotor activity and increased the LPO and NO levels as oxidative damage indicators. Applying RF-EMF alone increased GST and GSH levels, while applying RF-EMF and glucose showed a decrease in the antioxidant defense systems. ins expression increased in the glucose and RF-EMF groups, while lepa expression increased in the glucose group and decreased in the RF-EMF group. Conclusion: The harmful effects of hyperglycemia and RF-EMF exposure during the fetal period on embryo development need to be supported by studies to confirm the changes the current study has identified at the gene and protein levels. [ABSTRACT FROM AUTHOR]

Esketamine is a widely used intravenous general anesthetic. However, its safety, particularly its effects on the heart, is not fully understood. In this study, we investigated the effects of esketamine exposure on zebrafish embryonic heart development. Zebrafish embryos were exposed to esketamine at concentrations of 1, 10, and 100 mg/L from 48 h post-fertilization (hpf) to 72 hpf. We found that after exposure, zebrafish embryos had an increased hatching rate, decreased heart rate, stroke volume, and cardiac output. When we exposed transgenic zebrafish of the Tg(cmlc2:EGFP) strain to esketamine, we observed ventricular dilation and thickening of atrial walls in developing embryos. Additionally, we further discovered the abnormal expression of genes associated with cardiac development, including nkx2.5, gata4, tbx5, and myh6, calcium signaling pathways, namely ryr2a, ryr2b, atp2a2a, atp2a2b, slc8a3, slc8a4a, and cacna1aa, as well as an increase in acetylcholine concentration. In conclusion, our findings suggest that esketamine may impair zebrafish larvae's cardiac development and function by affecting acetylcholine concentration, resulting in weakened cardiac neural regulation and subsequent effects on cardiac function. The insights garnered from this research advocate for a comprehensive safety assessment of esketamine in clinical applications. [ABSTRACT FROM AUTHOR]

Rare earth elements are a group of chemicals widely utilized in industry, leading to ecosystem contamination. Due to the lack of regulatory measures, there exists a considerable gap in knowledge concerning their potential to induce adverse effects in organisms. Zebrafish serve as a species utilized in evaluating the risk of potentially toxic substances in the aquatic ecosystem. Our objective was to evaluate the acute toxicity in zebrafish embryos induced by two of the most used rare earth elements, neodymium, categorized as a light element, and yttrium, as a heavy element. We followed OECD guideline n°. 236 "Fish Embryo Acute Toxicity Test", exposing embryos to concentrations of 6.4, 16, 40, 100, and 250 mg/L, and calculated the LC50. Our study revealed comparable LC50 values for both elements (55.58 mg/L for Nd, and 45.61 mg/L for Y), suggesting a probable similarity in toxicity. These concentrations values have previously been identified in various contaminated regions globally, presenting a cause for concern. [ABSTRACT FROM AUTHOR]

Background: Oxygen deprivation (OD) is a critical condition that can lead to brain damage and even death. Current hypoxia management approaches are limited in effectiveness. Centella asiatica (CA), known for its neuroprotective properties, offers a potential alternative for OD treatment. Aims: This study aims to investigate the neuroprotective effects of CA on the expression of brain-derived neurotrophic factor (BDNF) and vesicular glutamate transporter 1 (VGLUT1) in zebrafish larvae under oxygen-deficient conditions. Methods: Zebrafish embryos were subjected to low oxygen levels (1.5 mg/l) 0-2 hours post-fertilization (hpf) until 3 days post-fertilization (dpf), simulating the early stages of OD. Subsequent treatment involved varying concentrations of CA (1.25-5 µg/ml) up to 9 days post-fertilization. The expression levels of BDNF and VGLUT1 were measured using PCR methods. Statistical analysis was conducted using a two-way analysis of variance to evaluate the impact of CA on the expression of BDNF and VGLUT1 in zebrafish larvae aged 3 and 9 dpf in oxygen-deprived conditions. Results: CA significantly influenced the expression of BDNF and VGLUT1 under OD (p < 0.001). An increase in BDNF expression (p < 0.001) and a decrease in VGLUT1 (p < 0.01) were observed in zebrafish larvae experiencing OD and treated with CA. There was no significant difference in BDNF and VGLUT1 expression across age variations in zebrafish larvae at 3 dpf and 9 dpf in the treatment groups (p > 0.05). CA concentration of 2.5 µg/ml effectively enhanced BDNF and reduced VGLUT1 in 3-9 dpf zebrafish larvae. Conclusion: CA demonstrates potential as a neuroprotective agent, modulating increased BDNF expression and reduced VGLUT1 under OD conditions. These findings lay a foundation for further research in developing therapies for oxygen deficiency. [ABSTRACT FROM AUTHOR]

The amount of Sargassum spp. arriving in the Caribbean Sea has increased steadily in the last few years, producing a profound environmental impact on the ecological dynamics of the coasts of the Yucatan Peninsula. We characterized the toxicological effects of an ethanolic extract of Sargassum spp. on zebrafish (Danio rerio) embryos (ZFEs) in a 96‐h static bioassay using T1 (0.01 mg/L), T2 (0.1 mg/L), T3 (1 mg/L), T4 (10 mg/L), T5 (25 mg/L), T6 (50 mg/L), T7 (75 mg/L), T8 (100 mg/L), T9 (200 mg/L), and T10 (400 mg/L). In this extract, we detected 74 compounds by gas chromatography‐mass spectrometry (GC‐MS), of which hexadecanoic acid methyl ester, and 2‐pentanone 4‐hydroxy‐4‐methyl, were the most abundant. In ZFEs, a median lethal concentration of 251 mg/L was estimated. Exposed embryos exhibited extensive morphological changes, including edema in the yolk sac, scoliosis, and loss of pigmentation, as well as malformations of the head, tail, and eyes. By integrating these abnormalities using the Integrated Biological Response (IBRv2) and General Morphological Score (GMS) indices, we were able to determine that ZFEs exposed to 200 mg/L (T9) exhibited the most pronounced biological response in comparison with the other groups. In the comparative transcriptomic analysis, 66 genes were upregulated, and 246 genes were downregulated in the group exposed to 200 mg/L compared with the control group. In the upregulated genes, we identified several gene ontology‐enriched terms, such as response to xenobiotic stimuli, cellular response to chemical stimulus, transcriptional regulation, pigment metabolic process, erythrocyte differentiation and embryonic hemopoiesis, extracellular matrix organization, and chondrocyte differentiation involved in endochondral bone morphogenesis, among others. In the down‐regulated genes, we found many genes associated with nervous system processes, sensory and visual perception, response to abiotic stimulus, and the nucleoside phosphate biosynthetic process. The probable connections among the morphological changes observed in the transcriptome are thoroughly discussed. Our findings suggest that Sargassum spp. exposure can induce a wide negative impact on zebrafish embryos. Environ Toxicol Chem 2024;43:1075–1089. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Background: The fish embryo acute toxicity (FET) test with the zebrafish (Danio rerio) was developed to assess the acute fish toxicity of chemicals or environmental samples as a replacement for the Acute Fish Test (AFT) with juvenile fish. However, the FET is not yet established in the regulatory context. One reason is the (postulated) difference between the biotransformation capacities of embryos and juvenile fish. The present study was designed to develop a procedure for external metabolization of test substances prior to testing in the FET. The workflow allows simultaneous exposure of the embryos to the maternal substances and their potential metabolites throughout the entire exposure period. After a 2 h incubation of the samples at 37 °C with non-toxic concentrations of a rat liver S9 homogenate or an animal-free (ewoS9R) metabolization system, freshly fertilized zebrafish embryos are added and incubated up to 120 h post-fertilization at 26 °C. Five biotransformable model substances (allyl alcohol, benzo[a]pyrene (B[a]P), chlorpyrifos (CP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and bisphenol A (BPA)) were evaluated for embryotoxicity with and without external metabolization. Results: Only for allyl alcohol, external metabolization with both rat S9 and ewoS9R resulted in significantly higher embryotoxicity than under non-premetabolized conditions and, thus, in a better correlation of FET and AFT data. For B[a]P, CP, TDCPP and BPA, there was no relevant difference between data derived from the FET (with and without pre-metabolization) and literature AFT data; even though the FET results with and without pre-metabolization differed significantly for BPA (with rat S9 and ewoS9R) and TDCPP (rat S9 only). Conclusions: External pre-metabolization appears a promising add-on to the FET protocol to improve the correlation with AFT data of certain biotransformable substances and might help to strengthen the FET as an alternative to the AFT and finally to reduce or replace sentient animals used for acute fish toxicity data in the regulatory context. [ABSTRACT FROM AUTHOR]

Tolfenpyrad, a highly effective and broad‐spectrum insecticide and acaricide extensively utilized in agriculture, presents a potential hazard to nontarget organisms. This study was designed to explore the toxic mechanisms of tolfenpyrad on zebrafish embryos. Between 24 and 96 h after exposure of the fertilized embryos to tolfenpyrad at concentrations ranging from 0.001 to 0.016 mg/L (96 h‐LC50 = 0.017 mg/L), lethal effects were apparent, accompanied with notable anomalies including pericardial edema, increased pericardial area, diminished heart rate, and an elongated distance between the venous sinus and the arterial bulb. Tolfenpyrad elicited noteworthy alterations in the expression of genes pertinent to cardiac development and apoptosis, with the most pronounced changes observed in the cardiac development‐related genes of bone morphogenetic protein 2b (bmp2b) and p53 upregulated modulator of apoptosis (puma). The findings underscore that tolfenpyrad induces severe cardiac toxicity and mitochondrial damage in zebrafish embryos. This data is imperative for a comprehensive assessment of tolfenpyrad risks to aquatic ecosystems, particularly considering the limited knowledge regarding its detrimental impact on aquatic vertebrates. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonate (PFOS) is a ubiquitous pollutant in global aquatic ecosystems with increasing concern for its toxicity to aquatic wildlife through inadvertent exposures. To assess the likely adverse effects of PFOS exposure on aquatic wildlife inhabiting polluted ecosystems, there is a need to identify biomarkers of its exposure and toxicity. We used an integrated systems toxicological framework to identify physiologically relevant biomarkers of PFOS toxicity in fish. An in silico stoichiometric metabolism model of zebrafish (Danio rerio) was used to integrate available (published by other authors) metabolomics and transcriptomics datasets from in vivo toxicological studies with 5 days post fertilized embryo-larval life stage of zebrafish. The experimentally derived omics datasets were used as constraints to parameterize an in silico mathematical model of zebrafish metabolism. In silico simulations using flux balance analysis (FBA) and its extensions showed prominent effects of PFOS exposure on the carnitine shuttle and fatty acid oxidation. Further analysis of metabolites comprising the impacted metabolic reactions indicated carnitine to be the most highly represented cofactor metabolite. Flux simulations also showed a near dose-responsive increase in the pools for fatty acids and acyl-CoAs under PFOS exposure. Taken together, our integrative in silico results showed dyslipidemia effects under PFOS exposure and uniquely identified carnitine as a candidate metabolite biomarker. The verification of this prediction was sought in a subsequent in vivo environmental monitoring study by the authors which showed carnitine to be a modal biomarker of PFOS exposure in wild-caught fish and marine mammals sampled from the northern Gulf of Mexico. Therefore, we highlight the efficacy of FBA to study the properties of large-scale metabolic networks and to identify biomarkers of pollutant exposure in aquatic wildlife. [ABSTRACT FROM AUTHOR]

The present study compares sugarcane-wax purified policosanols sourced from Cuba (Raydel®) and China (BOC Sciences) and utilized following the synthesis of reconstituted high-density lipoproteins (rHDL). The two policosanols exhibited distinctly different ingredient ratios of long-chain aliphatic alcohols, particularly 1-octacosanol (C28) and 1-tetratriacotanol (C34). After synthesizing rHDL with apolipoprotein A-I (apoA-I), the two policosanols bound well with phospholipid and apoA-I to form the discoidal rHDL. Notably, rHDL-1, containing Cuban policosanol, displayed the largest particle diameter at approximately 78 ± 3 nm. In contrast, both control rHDL (rHDL-0) and rHDL containing Chinese policosanol (rHDL-2) exhibited smaller particles, with diameters of approximately 58 ± 3 nm and 61 ± 2 nm, respectively. Furthermore, rHDL-1 demonstrated enhanced anti-glycation activity, safeguarding apoA-I from degradation within HDL, and displayed the antioxidant ability to inhibit LDL oxidation. A microinjection of each rHDL into zebrafish embryos in the presence of carboxymethyllysine (CML) revealed rHDL-1 to have the strongest antioxidant activity with the highest embryo survivability and normal developmental morphology. Dermal application to recover the wound revealed rHDL-1 to have the highest wound-healing activity (75%) and survivability (92%) in the cutaneous wound area in the presence of CML. In adult zebrafish, injecting CML (250 μg) caused acute death and hyperinflammation, marked by heightened neutrophil infiltration and interleukin (IL)-6 production in liver. However, co-administering rHDL-1 notably increased survival (85%) and exhibited strong anti-inflammatory properties, reducing IL-6 production while improving the blood lipid profile. However, a co-injection of rHDL-2 resulted in the lowest survivability (47%) with more hepatic inflammation. In conclusion, Cuban policosanol (Raydel®) has more desirable properties for the in vitro synthesis of rHDL with stronger anti-glycation and antioxidant activities than those of Chinese policosanol (BOC Sciences). Moreover, Raydel-policosanol-integrated rHDL demonstrates a noteworthy effect on accelerated wound healing and robust anti-inflammatory properties, leading to increased survivability in zebrafish embryos and adults by effectively suppressing CML-induced hyperinflammation. [ABSTRACT FROM AUTHOR]

Known for their high stability and surfactant properties, per‐ and polyfluoroalkyl substances (PFAS) have been widely used in a range of manufactured products. Despite being largely phased out due to concerns regarding their persistence, bioaccumulation, and toxicity, legacy PFAS such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid continue to persist at high levels in the environment, posing risks to aquatic organisms. We used high‐resolution magic angle spinning nuclear magnetic resonance spectroscopy in intact zebrafish (Danio rerio) embryos to investigate the metabolic pathways altered by PFOS both before and after hatching (i.e., 24 and 72 h post fertilization [hpf], respectively). Assessment of embryotoxicity found embryo lethality in the parts‐per‐million range with no significant difference in mortality between the 24‐ and 72‐hpf exposure groups. Metabolic profiling revealed mostly consistent changes between the two exposure groups, with altered metabolites generally associated with oxidative stress, lipid metabolism, energy production, and mitochondrial function, as well as specific targeting of the liver and central nervous system as key systems. These metabolic changes were further supported by analyses of tissue‐specific production of reactive oxygen species, as well as nontargeted mass spectrometric lipid profiling. Our findings suggest that PFOS‐induced metabolic changes in zebrafish embryos may be mediated through previously described interactions with regulatory and transcription factors leading to disruption of mitochondrial function and energy metabolism. The present study proposes a systems‐level model of PFOS toxicity in early life stages of zebrafish, and also identifies potential biomarkers of effect and exposure for improved environmental biomonitoring. Environ Toxicol Chem 2024;43:896–914. © 2024 SETAC [ABSTRACT FROM AUTHOR]

The present study investigated the reproductive and developmental effects of sex-specific chronic exposure to dietary arsenic in zebrafish. Adult zebrafish (Danio rerio) were exposed to environmentally realistic doses of arsenic via diet [0 (control; no added arsenic), 30 (low), 60 (medium), and 100 (high) μg/g dry weight, as arsenite] for 90 days. Following exposure, arsenic-exposed females from each dietary treatment were mated with control males, and similarly, arsenic-exposed males from each dietary treatment were mated with control females. In females, arsenic exposure resulted in a dose-dependent decrease in reproductive performance (fecundity, fertilization success, and hatching success). Moreover, a dose-dependent increase in developmental toxicity (larval deformities and larval mortality) was observed with maternal exposure to arsenic. In contrast, in males, arsenic exposure also induced similar reproductive and developmental toxicity; however, the adverse effects were mainly evident only in the medium and high dietary arsenic treatment groups. We also examined the sex-specific effects of dietary arsenic exposure on the expression of genes that regulate the hypothalamus–pituitary–gonadal–liver (HPG-L) axis in fish. The gene expression results indicated the downregulation of HPG-L axis genes in females irrespective of the arsenic treatment dose; however, the reduced expression of HPG-L axis genes in males was recorded only in the medium and high arsenic treatment groups. These observations suggest that chronic arsenic exposure in either females or males causes reproductive and developmental toxicity in zebrafish. However, these toxic effects are markedly higher in females than in males. Our results also suggest that arsenic can act as an endocrine disruptor and mediate reproductive and developmental toxicity by disrupting the HPG-L axis in zebrafish. [ABSTRACT FROM AUTHOR]

Simple Summary: The unsurmountable diversity of marine life is an invaluable reservoir of natural compounds for drug discovery, amongst which toxins and other bioactive molecules in venoms and poisons are prized targets. Cnidarians are some of the best-studied marine venomous animals, yet most venom components remain unidentified. This study focuses on the sea anemone Actinia equina from Portuguese intertidal zones, comparing two common morphotypes, "green" and "red", ultimately aiming to explore its potential as a source of bioactive compounds. We provide detailed examinations of A. equina's anatomy and microanatomy, a proteomics analysis to identify proteinaceous toxins in its tentacles and toxicity testing on zebrafish embryos. The study confirms the presence of venom-injecting cells (nematocysts) in the tentacles but finds no differences between green and red varieties. Various toxins, including neurotoxins and pore-forming proteins, were discovered. Both green and red extracts exhibit toxicity to zebrafish embryos, with green anemones appearing more potent. Overall, this study unveils proteinaceous toxins in A. equina and demonstrates that different varieties harbour distinct bioactive compounds. Besides ecological considerations, these findings bring further promise to bioprospecting A. equina for novel toxins with potential biotechnological and biomedical interest. The current study investigates the venom-delivery system of green and red morphotypes of the sea anemone Actinia equina to disclose its potential as a source of bioactive compounds. We compared the two morphotypes using electron and optical microscopy, proteomics, and toxicity assessment on zebrafish embryos. Specialized venom-injecting cells (nematocysts) are equally distributed and found in the tentacles of both varieties. Proteomics revealed proteins of interest in both red and green Actinia, yielding the three most abundant Gene Ontology (GO) terms related to the biological processes "proteolysis", "hemolysis in another organism" and "lipid catabolic process". Neurotoxins and cytolytic toxins similar to known cnidarian toxins like PsTX-60A and AvTX-60A, for instance, were identified in both types. Extracts from green and red anemones were toxic to zebrafish embryos, with green anemone venom appearing to be more potent. The findings highlight the presence of proteinaceous toxins in A. equina and the potential for different varieties to possess distinct bioactive compounds. Notably, pore-forming toxins are suggested for molecular probes and immunotoxins, making them valuable assets for potential biotechnological and biomedical purposes. [ABSTRACT FROM AUTHOR]

Fenoxaprop-p-ethyl (FEN) is an aryloxy phenoxy propionate herbicide that has been widely used in paddy fields. Previous studies have indicated that FEN is highly toxic to aquatic organisms, but little is known about the developmental effects of FEN. This study investigated acute and developmental toxicity, malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and metabolomic analyses in zebrafish embryos after 96 h of exposure. FEN exhibited high acute toxicity to zebrafish embryos and larvae. Exposure to FEN could reduce heartbeat and hatching rates and increase malformation rates in embryos. Oxidative damage was also caused in embryos. The results of metabolomics analysis showed that 102 differentially abundant metabolites were found in zebrafish embryos in the 0.05 mg/L FEN treatment group, and 60 differentially abundant metabolites were found in the 0.20 mg/L FEN treatment group. These differentially abundant metabolites mainly belonged to 9 metabolic pathways, of which folate pathways and ABC transport protein pathways had the greatest impact. These results suggested that FEN induced high acute and developmental toxicity in zebrafish embryos. [ABSTRACT FROM AUTHOR]

Environmentally cued hatching is prevalent, diverse, and crucial to many animals' survival. Fish embryos use a variety of chemical cues to initiate hatching to avoid potential predators, yet the function of chemical cues released from the predatory consumption of heterospecific prey is largely unknown. Zebra cichlids (Metriaclima estherae) are ferocious predators that can feed on medaka (Oryzias latipes), though it is impossible for this to occur in their natural habitat. Zebrafish (Danio rerio) embryos have been employed as experimental subjects due to their sensitivity to a variety of chemical signals. In this study, zebrafish embryos were subjected to three types of chemical signals: predator cues (PCs, released from cichlids), heterospecific cues (HCs, released from medaka), and heterospecific dietary cues (HDCs, released from cichlids that have ingested medaka). As a result, the hatching times of zebrafish embryos were accelerated by 6.8% and 12.6% by PCs and HDCs, respectively. PCs and HDCs cause significantly reduced morphology in zebrafish embryos, including regarding total length, eye length, dorsal fin length, trunk height, caudal fin height, and body cavity, and increase yolk sac height. The PCs and HDCs diminished the larvae's motion at 120 and 144 h post fertilization (hpf), which could be attributed to non-developmental embryogenesis. Overall, the impacts of HDCs on embryonic hatching, developmental morphology, and locomotor were more pronounced in comparison with PCs. Our findings demonstrate that predators' dietary cues, even those released after predation on heterospecific prey, can modify embryogenesis, highlighting the critical functions of chemical signals in predation risk assessment using embryos. [ABSTRACT FROM AUTHOR]

Houttuyniae herba has a long history of medicinal and edible homology in China. It has the functions of clearing heat and detoxifying, reducing swelling and purulent discharge, diuresis, and relieving gonorrhea. It is mainly distributed in the central, southeastern, and southwestern provinces of China. Houttuyniae herba has been designated by the National Ministry of Health of China as a dual-use plant for both food and medicine. Comprising volatile oils, flavonoids, and alkaloids as its primary constituents, Houttuyniae herba harbors aristolactams, a prominent subclass of alkaloids. Notably, the structural affinity of aristolactams to aristolochic acids is discernible, the latter known for its explicit toxicological effects. Additionally, the safety study on Houttuyniae herba mainly focused on the ethanol, methanol, or aqueous extract. In this study, both zebrafish and mice were used to evaluate the acute toxicity of the total alkaloids extracts from Houttuyniae herba (HHTAE). The zebrafish experiment showed that a high concentration (0.1 mg/mL) of HHTAE had a lethal effect on zebrafish embryos. Furthermore, the mice experiment results showed that, even at a higher dose of 2000 mg/kg, HHTAE was not toxic. In conclusion, HHTAE was of low safety risk. [ABSTRACT FROM AUTHOR]

Angiogenesis is a key process in embryonic development, a disruption of this process can lead to severe developmental defects, such as limb malformations. The identification of molecular perturbations representative of antiangiogenesis in zebrafish embryo (ZFE) may guide the assessment of developmental toxicity from an endpoint- to a mechanism-based approach, thereby improving the extrapolation of findings to humans. Thus, the aim of the study was to discover molecular changes characteristic of antiangiogenesis and developmental toxicity. We exposed ZFEs to two antiangiogenic drugs (SU4312, sorafenib) and two developmental toxicants (methotrexate, rotenone) with putative antiangiogenic action. Molecular changes were measured by performing untargeted metabolomics in single embryos. The metabolome response was accompanied by the occurrence of morphological alterations. Two distinct metabolic effect patterns were observed. The first pattern comprised common effects of two specific angiogenesis inhibitors and the known teratogen methotrexate, strongly suggesting a shared mode of action of antiangiogenesis and developmental toxicity. The second pattern involved joint effects of methotrexate and rotenone, likely related to disturbances in energy metabolism. The metabolites of the first pattern, such as phosphatidylserines, pterines, retinol, or coenzyme Q precursors, represented potential links to antiangiogenesis and related developmental toxicity. The metabolic effect pattern can contribute to biomarker identification for a mechanism-based toxicological testing. [ABSTRACT FROM AUTHOR]

The presence of per- and polyfluoroalkyl substances (PFASs) in aquatic environments is often persistent and widespread. Understanding the potential adverse effects from this group of chemicals on aquatic communities allows for better hazard characterization. This study examines impacts on zebrafish (Danio rerio) embryo physiology, behavior, and lipid levels from exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and heptadecafluorooctanesulfonic acid (PFOS). Embryos were exposed to lethal and sublethal levels of each chemical and monitored for alterations in physiological malformations, mortality, lipid levels, and behavior (only PFOA and PFHxS). The predicted 50% lethal concentrations for 120 hpf embryos were 528.6 ppm PFOA, 14.28 ppm PFHxS, and 2.14 ppm PFOS. Spine curvature and the inability of the 120 hpf embryos to maintain a dorsal-up orientation was significantly increased at 10.2 ppm PFHxS and 1.9 ppm PFOS exposure. All measured 120 hpf embryo behaviors were significantly altered starting at the lowest levels tested, 188 ppm PFOA and 6.4 ppm PFHxS. Lipid levels decreased at the highest PFAS levels tested (375 PFOA ppm, 14.4 PFHxS ppm, 2.42 ppm PFOS). In general, the PFAS chemicals, at the levels examined in this study, increased morphological deformities, embryo activity, and startle response time, as well as decreased lipid levels in 120 hpf zebrafish embryos. [ABSTRACT FROM AUTHOR]

Narcissin is a natural flavonoid from some edible and traditional medicinal plants. It has been proven to have multiple biological functions and exhibits potential therapeutic effects on hypertension, cancer, and Alzheimer's disease. However, the toxicity of narcissin is largely unknown. Here, we revealed that narcissin treatment led to reduced hatchability, increased malformation rate, shorter body length, and slowed blood flow in zebrafish. Furthermore, bradycardia, pericardial edema, increased SV‐BA distance, diminished stroke volume, ejection fraction, and ventricular short‐axis shortening rate were also found. A large accumulation of ROS, increased apoptotic cells, and histopathological changes were detected in the heart region. Moreover, the gene expression profiles and molecular docking analysis indicated that Nrf2/HO‐1 and calcium signaling pathways were involved in narcissin‐induced toxicity. In conclusion, here we provide the first evidence that demonstrates narcissin‐induced developmental toxicity and cardiotoxicity in zebrafish via Nrf2/HO‐1 and calcium signaling pathways for the first time. Narcissin is a natural flavonoid from some edible and traditional medicinal plants, while its toxicity is largely unknown. Here, we revealed that narcissin treatment led to reduced hatchability, increased malformation rate, shorter body length, slowed blood flow, and cardiodevelopmental toxicity in zebrafish. A large accumulation of ROS, increased apoptotic cells, and histopathological changes were detected in the heart region. Nrf2/HO‐1 and calcium signaling pathways were involved in narcissin‐induced toxicity. [ABSTRACT FROM AUTHOR]

Among nanoparticles (NPs), titanium dioxide is one of the most highly manufactured worldwide and widely used in multiple products for both industrial use and personal care products. This increases the probability of release into aquatic environments, potentially affecting these ecosystems. The present study aimed to evaluate TiO2 P25 NP toxicity in zebrafish embryos and eleutheroembryos by evaluating LC50, hatching rate, embryo development, and chemical analysis of the TiO2 concentration accumulated in eleutheroembryo tissues. Zebrafish embryos ~2 h post-fertilization (hpf) were exposed to 75, 100, 150, 200, and 250 mg/L TiO2 P25 NPs for 48 and 96 h. A total of 40–60 embryos were placed in each Petri dish for the respective treatments. Three replicates were used for each treatment group. Ti4+ concentrations were determined by inductively coupled plasma optical emission spectrometry (ICP-OES), and a conversion factor was used to calculate the TiO2 concentrations in the tissues. The highest calculated concentrations of TiO2 in zebrafish larvae were 1.0199 mg/L after 48 h and 1.2679 mg/L after 96 h of exposure. The toxicological results indicated that these NPs did not have a significant effect on the mortality and hatching of zebrafish embryos but did have an effect on their development. LC20 and LC30 were determined experimentally, and LC50 and LC80 were estimated using four different methods. Up to 11% of embryos also presented physical malformations. These effects can be detrimental to a species and affect ecosystems. Physical malformations were observed in all treatments, indicating teratogenic effects. [ABSTRACT FROM AUTHOR]

Biological models with genetic similarities to humans are used for exploratory research to develop behavioral screening tools and understand sensory–motor interactions. Their small, often mm-sized appearance raises challenges in the straightforward quantification of their subtle behavioral responses and calls for new, customisable research tools. 3D printing provides an attractive approach for the manufacture of custom designs at low cost; however, challenges remain in the integration of functional materials like porous membranes. Nanoporous membranes have been integrated with resin exchange using purpose-designed resins by digital light projection 3D printing to yield functionally integrated devices using a simple, economical and semi-automated process. Here, the impact of the layer thickness and layer number on the porous properties – parameters unique for 3D printing – are investigated, showing decreases in mean pore diameter and porosity with increasing layer height and layer number. From the same resin formulation, materials with average pore size between 200 and 600 nm and porosity between 45% and 61% were printed. Membrane-integrated devices were used to study the chemoattractant induced behavioural response of zebrafish embryos and planarians, both demonstrating a predominant behavioral response towards the chemoattractant, spending >85% of experiment time in the attractant side of the observation chamber. The presented 3D printing method can be used for printing custom designed membrane-integrated devices using affordable 3D printers and enable fine-tuning of porous properties through adjustment of layer height and number. This accessible approach is expected to be adopted for applications including behavioural studies, early-stage pre-clinical drug discovery and (environmental) toxicology. [ABSTRACT FROM AUTHOR]

CIGB-258 is a 3 kDa altered peptide ligand from heat shock protein (HSP) 60 that exhibits anti-inflammatory activity against the acute toxicity of carboxymethyllysine (CML) with antioxidant and anti-glycation activities via protection of high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I). It is necessary to test a synergistic interaction between apoA-I and CIGB-258 in reconstituted high-density lipoproteins (rHDL). Several rHDLs were synthesized containing palmitoyloleoyl phosphatidylcholine (POPC), cholesterol, apoA-I, and CIGB-258 at molar ratios of 95:5:1:0, 95:5:1:0.1, 95:5:1:0.5, and 95:5:1:1 for rHDL-(1:0), rHDL-(1:0.1), rHDL-(1:0.5), and rHDL-(1:1), respectively. As the CIGB-258 content in rHDL was increased, the particle size of rHDL was 1.4-times higher than rHDL-(1:0) to rHDL-(1:1), from 60 nm to 83 nm, respectively. As the CIGB-258 content was increased, the rHDL showed the most resistance to isothermal denaturation by a urea treatment, and rHDL-(1:1) exhibited the highest structural stability and the strongest antioxidant ability against LDL oxidation. Co-treatment of rHDL-(1:0), rHDL-(1:0.5), and rHDL-(1:1) resulted in up to 10%, 24%, and 34% inhibition of HDL glycation, inhibition of HDL glycation, which was caused by the CML, with protection of apoA-I. Microinjection of each rHDL into zebrafish embryos in the presence of CML showed that a higher CIGB-258 content in rHDL was associated with higher survivability with the least inflammation and apoptosis. Furthermore, an intraperitoneal injection of rHDL and CML showed that a higher CIGB-258 content in rHDL was also associated with higher survivability of zebrafish and faster recovery of swimming ability. The rHDL-(1:1) group showed the lowest triglyceride, AST, and ALT serum levels with the least production of interleukin-6, oxidized product, and neutrophil infiltration in hepatic tissue. In conclusion, CIGB-258 could bind well to phospholipids and cholesterol to stabilize apoA-I in the rHDL structure against denaturation stress and larger particle sizes. The rHDL containing CIGB-258 enhanced the in vitro antioxidant ability against LDL oxidation, the anti-glycation activity to protect HDL, and the in vivo anti-inflammatory activity against CML toxicity in zebrafish adults and embryos. Overall, incorporating apoA-I and CIGB-258 in rHDL resulted in a synergistic interaction to enhance the structural and functional correlations in a dose-dependent manner of CIGB-258. [ABSTRACT FROM AUTHOR]

Cefaclor represents second-generation cephalosporin antibiotics that act by inhibiting bacterial cell wall synthesis. Systematic studies on the toxicological effects of cefaclor on aquatic organisms are scarce. In the present study, the toxicity of cefaclor in terms of LC50, teratogenicity, histopathology, and genotoxicity was assessed in zebrafish embryos (between 4 and 128 cell stages). In a definitive test, the embryos were exposed to different test concentrations of cefaclor ranging from 45 to 3000 mg/L. Using the probit analysis, the LC50 of cefaclor was estimated to be 7020, 3189, 1464, and 775 mg/L respectively, at 24, 48, 72, and 96 h. As regards the teratogenic effects, zebrafish embryos exhibited slight to severe defects at different test concentrations of the antibiotic. The histological examination of embryos showed morphological alterations like yolk sac edema, abnormal muscle fibers, and body curvature at LC20 concentration. The genotoxicity of cefaclor was significantly higher at LC20 concentration compared to the negative and positive control. Although significant toxic effects were not evident in zebrafish embryos at lower concentrations of cefaclor, adverse effects were more pronounced at the higher concentrations for all the endpoints. However, chronic exposure studies may be needed to validate and elucidate the long-term adverse impact of cefaclor antibiotic in aquatic organisms. [ABSTRACT FROM AUTHOR]

In order to investigate the chronic toxicity of strobilurins to the early life stage of aquatic organisms, the sublethal effect of kresoxim-methyl on the early development of zebrafish after long-term exposure was determined. After continuous exposure of zebrafish embryos to different concentrations of kresoxim-methyl (0.000750 ~0.180 mg·L-1) for 34 d, the median lethal concentrations (LC50) of kresoxim-methyl for 144 h and 34 d of zebrafish early life stage was 0.141 mg·L-1 and 0.0106 mg·L-1, respectively. It was found that 0.00460 mg·L-1, 0.0115 mg ·L-1 and 0.0288 mg·L-1 kresoxim-methyl significantly decreased the body weight of larvae after 34 d exposure, 0.0115 mg·L-1 and 0.0288 mg·L-1 kresoxim-methyl decreased the body length of larvae, and 0.180 mg·L-1 kresoxim-methyl increased the body length and body weight of larvae. The 34 d-NOEC and 34 d-LOEC of kresoxim-methyl was 0.00460 mg·L-1 and 0.0115 mg·L-1 for body length, and was 0.00185 mg·L-1 and 0.00460 mg·L-1 for body weight during zebrafish early life development, respectively. During the 34 d exposure, the activities and levels of factors related to mitochondrial energy metabolism and oxidative stress in zebrafish embryos/larvae were measured at 1, 3, 7, 14, 21 and 34 d. Results showed that long-term exposure of kresoxim-methyl could increase the catalase (CAT) activity, the peroxide (POD) activity increased then decreased and then increased, the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content decreased first then increased during zebrafish early life development. It was found that the calcium ion (Ca2+) level and the activity of calcium ion adenosine triphosphatase (Ca2+-ATPase) was inhibited during the 34 d exposure of kresoxim-methyl, and the adenosine triphosphate (ATP) level was increased first then decreased. The results suggested long-term exposure to kresoxim-methyl caused negative effects on the growth indexes and antioxidant system during zebrafish early life development, kresoxim-methyl might interfere with mitochondrial energy metabolism by regulating the ATP and Ca2+ levels, and Ca2+-ATPase activity, then induced oxidative stress during the early life stage of zebrafish. [ABSTRACT FROM AUTHOR]

Electronic waste (E-waste) has been increasing in recent years, and the pollution around E-waste dismantling plants is a serious problem. The organophosphorus flame retardants tris (2-chloroisopropyl) phosphate (TCPP) and lead (Pb) are the two primary pollutants in E-waste dismantling plants, which adversely affect both human health and the surrounding environment. There are no studies on the effects of combined exposure to TCPP and Pb on aquatic organisms and human development. In this study, the zebrafish was selected to investigate the effects of Pb (190 μg·L-1), TCPP (200, 2 000, and 6 000 μg·L-1) and their co-exposure on the development of zebrafish embryos. The results showed that exposure to Pb and low, medium, and high doses of TCPP alone and in combination had no significant effect on zebrafish survival and hatching rates. Meanwhile, individual and co-exposure to Pb and low and medium doses of TCPP had no significant effect on zebrafish spinal curvature rate and behavior. Compared with TCPP and Pb exposure alone, the high-dose combined exposure (Pb 190 μg·L-1 + TCPP 6 000 μg·L-1) inhibited spontaneous locomotion in zebrafish (P<0.01), decreased the body length (P<0.01) and the heart rate at 96 hpf and 120 hpf ( <0.001). In addition, the high-dose combined exposure down-regulated the ex- pression of spinal development-related genes (col8a1a, ngs, bmp2a, bmp2b, runx2b) and neurodevelopment-related genes (mbp, elavl3, gfap, gap43) (P<0.05). These findings suggest that high-dose combined exposure to TCPP and Pb disrupts the expression of key genes involved in spinal and neural development, thereby adversely affecting these crucial developmental processes in zebrafish embryos. [ABSTRACT FROM AUTHOR]

Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is a conductive polymer commonly used in various technological applications. However, its impact on aquatic ecosystems remains largely unexplored. In this study, we investigated the toxicity effects of PEDOT:PSS on zebrafish. We first determined the lethal concentration (LC50) of PEDOT:PSS in zebrafish and then exposed AB-type zebrafish embryos to different concentrations of PEDOT:PSS for 120 h. Our investigation elucidated the toxicity effects of zebrafish development, including morphological assessments, heart rate measurements, behavioral analysis, transcriptome profiling, and histopathological analysis. We discovered that PEDOT:PSS exhibited detrimental effects on the early developmental stages of zebrafish, exacerbating the oxidative stress level, suppressing zebrafish activity, impairing cardiac development, and causing intestinal cell damage. This study adds a new dimension to the developmental toxicity of PEDOT:PSS in zebrafish. Our findings contribute to our understanding of the ecological repercussions of PEDOT:PSS and highlight the importance of responsible development and application of novel materials in our rapidly evolving technological landscape. [ABSTRACT FROM AUTHOR]

Featured Application: C10 massoia lactone possessed developmental toxicity on cardiac formation of zebrafish embryos. C10 massoia lactone (C10) is the main component of massoia essential oil derived from Cryptocarya massoia plant bark, which is used as natural flavoring agent of "generally recognized as safe" status. In this study, the developmental toxicity of C10 was evaluated on zebrafish (Danio rerio) embryos at an exposure level of 0–2000 µg·L−1, and acute toxicity was determined with respect to lethal effects, hatching rates, and morphological changes. Additionally, morphological changes were determined for the endpoints as the occurrence of yolk edema, pericardial edema, spine curvature, and shortened body length after treatment until 96 h post-fertilization (hpf). The complete lethality of C10 was achieved with embryos treated at 2000 µg·L−1, and most embryos treated at 1000 µg·L−1 developed pericardial edemas with some spine curvature. Some embryos exhibited delayed development with shortened body length when compared with the control. Hatchability was completely accomplished at the tested dose of 1000 µg·L−1, and cardiac malformation was observed using a transgenic zebrafish line Tg(cmlc:EGFP), with a lower heartbeat rate in embryos treated with C10 for 72 hpf. After 96 hpf, heartbeat rates were normalized when compared with the control group, and two cardiac development-related genes such as nppa and canca1 were differently expressed in C10-treated embryos by 2.3-fold and 0.4-fold, respectively. Therefore, C10 must be studied further in other higher organisms for its risk. [ABSTRACT FROM AUTHOR]

This work is aimed at studying the effect of saturated stearic acid (SA) under in vitro culture conditions on the embryos of the domestic cat (Felis silvestris catus) and at estimating how a change in the composition of intracellular lipids is reflected in the results of cryopreservation. The addition of SA to the culture medium had no effect on the development of cat embryos in vitro before cryopreservation. There were also no changes by the total amount of lipids in the embryos after the effect of SA. Meanwhile, the degree of lipid unsaturation was reduced in the embryos after in vitro cultivation with SA. Moreover, the temperature of lipid phase transition onset (T*) was higher in the embryos exposed to the effect of SA as compared with the control. A decrease in the efficiency of embryo cryopreservation during the cultivation with SA was associated with a decrease in the degree of unsaturation of intracellular lipids and a increase in T *. The results can be important for the conservation of genetic resources of the species from the subfamily Felinae. [ABSTRACT FROM AUTHOR]

We aimed to evaluate how different types of toothpaste (TP) for children affected molecular mechanisms of odontogenesis in zebrafish embryos. Commercially available TPs were selected according to their detergent contents as the cocamidopropyl betaine (CAPB) containing TP (TP1) and sodium lauryl sulfate (SLS) containing TP (TP2). TP3 contained no detergent. Effects of SLS, and CAPB alone were also examined. TP and detergent concentrations affecting development were determined as 750 mg/L and 4 mg/L, respectively. Embryos were exposed to TP1, TP2, TP3, SLS, CAPB, and embryo medium (control) for 72 h post fertilization. Acetylcholinesterase (AChE) activity and oxidant–antioxidant parameters were analyzed spectrophotometrically. Expressions of tooth development genes were evaluated by reverse transcription PCR (RT-PCR). Intraocular distance, lower jaw, and ceratohyal cartilage length were displayed using Alcian Blue staining. axin2 and wnt10a expressions increased in SLS and TP2 groups. igf2a and eve1 expressions decreased in all groups except TP3. nrOb1 expression decreased in TP1, SLS, and CAPB groups. Oxidant–antioxidant balance was disturbed in all groups except TP3, evidenced by increased lipid peroxidation, nitric oxide. SLS, and CAPB groups were more affected in terms of AChE, glutathione-S-transferase, and superoxide dismutase; perturbations were observed in cartilage structures. Altered expression of tooth development gene axin2 correlated with wnt10a, and with changes in cartilage structures in SLS and TP2 groups. TP3 group presented no disruptions in oxidant–antioxidant balance. Our study shows the availability of externally developing zebrafish embryos in examining the effects of TP' contents on embryogenesis. [ABSTRACT FROM AUTHOR]

Perfluorohexanesulfonic acid (PFHxS) is a highly prevalent environmental pollutant, often considered to be less toxic than other poly- and perfluoroalkyl substances (PFASs). Despite its relatively lower environmental impact compared to other PFASs, several studies have suggested that exposure to PFHxS may be associated with disruptions of liver function in humans. Nevertheless, the precise pathomechanisms underlying PFHxS-induced non-alcoholic fatty liver disease (NAFLD) remain relatively unclear. Therefore, this study applied our previously published transcriptome dataset to explore the effects of PFHxS exposure on the susceptibility to NAFLD and to identify potential mechanisms responsible for PFHxS-induced NAFLD through transcriptomic analysis conducted on zebrafish embryos. Results showed that exposure to PFHxS markedly aggravated hepatic symptoms resembling NAFLD and other metabolic syndromes (MetS) in fish. Transcriptomic analysis unveiled 17 genes consistently observed in both NAFLD and insulin resistance (IR), along with an additional 28 genes identified in both the adipocytokine signaling pathway and IR. These shared genes were also found within the NAFLD dataset, suggesting that hepatic IR may play a prominent role in the development of PFHxS-induced NAFLD. In conclusion, our study suggests that environmental exposure to PFHxS could be a potential risk factor for the development of NAFLD, challenging the earlier notion of PFHxS being safer as previously claimed. [ABSTRACT FROM AUTHOR]

Emamectin benzoate (EMB) is an insecticide for the control of agricultural lepidoptera pests, and also an anti‐parasiticide for the control of exoparasites in aquaculture industry. Increased studies suggest that EMB could cause toxicity to non‐targeted organisms, but its immunotoxicity to human remains unclear. In this study, zebrafish were used to investigate the immunotoxic effects induced by environmentally relevant doses of EMB. We observed that EMB exposure led to embryo mortality and delayed hatching, as well as increased malformations. Meanwhile, zebrafish exposed to EMB exhibited a significant decrease in the number of neutrophils and macrophages. In addition, untargeted metabolomics approach was developed to elucidate the mechanism of EMB‐induced immunotoxicity. We found that a total of 10 shared biomarkers were identified in response to EMB exposure. Furthermore, pathway analysis identified glycerophospholipid metabolism was the most relevant pathway. Within this pathway, it was observed abnormal increases in glycerol 3‐phosphate content, which could be attributed to the increased expression of GK5 and decreased expression of GPAT3. Our study provided novel and robust perspectives, which showed that EMB exposure to zebrafish embryos could cause metabolic disturbances that adversely affected development and immune system. [ABSTRACT FROM AUTHOR]

Embryonic zebrafish represent a useful test system to screen substances for their ability to perturb development. The exposure scenarios, endpoints captured, and data analysis vary among the laboratories who conduct screening. A lack of harmonization impedes the comparison of the substance potency and toxicity outcomes across laboratories and may hinder the broader adoption of this model for regulatory use. The Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT) initiative was developed to investigate the sources of variability in toxicity testing. This initiative involved an interlaboratory study to determine whether experimental parameters altered the developmental toxicity of a set of 42 substances (3 tested in duplicate) in three diverse laboratories. An initial dose-range-finding study using in-house protocols was followed by a definitive study using four experimental conditions: chorion-on and chorion-off using both static and static renewal exposures. We observed reasonable agreement across the three laboratories as 33 of 42 test substances (78.6%) had the same activity call. However, the differences in potency seen using variable in-house protocols emphasizes the importance of harmonization of the exposure variables under evaluation in the second phase of this study. The outcome of the Def will facilitate future practical discussions on harmonization within the zebrafish research community. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) can cause human diseases, particularly respiratory diseases. Since eyes are directly exposed to the air, they might be directly adversely affected by PM. Therefore, we determined the toxicity caused to eye development by PM using zebrafish (Danio rerio) embryos. The PM-induced embryo toxicity was dependent on dose and time and caused significant morphological defects, reducing the total body length and the total eye area. Reactive oxygen species (ROS) overproduction was confirmed in the PM treatment group, and antioxidant genes (cat and sod2), photoreceptor cell development, pigmentation genes (atoh8, vsx1, and rho), eye-embryogenesis genes (pax6a and pax6b), and eye-lens-development genes (cryaa) were downregulated, while eye-development genes (crybb1) were upregulated. In conclusion, PM had a direct adverse effect on the eyes, and zebrafish embryos can be used as a model to evaluate PM-induced eye toxicity in vivo. [ABSTRACT FROM AUTHOR]

The coexistence of polystyrene (PS) and polypropylene (PVC) microplastics (MPs) and methamphetamine (METH) in aquatic systems is evident. However, the joint toxicity is unclear. Here, zebrafish larvae were exposed to single PS and PVC MPs (20 mg L−1) and combined with METH (250 and 500 μg L−1) for 10 days. The results indicated that acute exposure to PS and PVC MPs induced lethal effects on zebrafish larvae (10–20%). Treatment with MPs markedly suppressed the locomotion of zebrafish, showing as the lengthy immobility (51–74%) and lower velocity (0.09–0.55 cm s−1) compared with the control (1.07 cm s−1). Meanwhile, histopathological analysis revealed pronounced depositions of MPs particles in fish's intestinal tract, triggering inflammatory responses (histological scores: 1.6–2.0). In the coexposure groups, obviously inflammatory responses were found. Furthermore, the up-regulations of the genes involved in the oxidative kinase gene and inflammation related genes implied that oxidative stress triggered by MPs on zebrafish larvae might be responsible for the mortality and locomotion retardant. The antagonistic and stimulatory effects of METH on the expression changes of genes found in PVC and PS groups implied the contrary combined toxicity of PS/PVC MPs and METH. This study for the first time estimated the different toxicity of PS and PVC MPs on fish and the joint effects with METH at high environmental levels. The results suggested PS showed stronger toxicity than PVC for fish larvae. The addition of METH stimulated the effects of PS but antagonized the effects of PVC, promoting control strategy development on MPs and METH in aquatic environments. [ABSTRACT FROM AUTHOR]

Gelidium spinosum is an edible red seaweed from the family Gelidiaceae with possibility to be developed. The potential medical benefits of G. spinosum have been established, yet adequate empirical research on its toxicity is still lacking. Hence, the present work was aimed to examine the toxicity of G. spinosum methanol extract (GsME) on zebrafish (Danio rerio) embryos and to identify the phytoconstituents using gas chromatography-mass spectrometry (GC-MS) analysis. Results of this study showed that GsME induced morphological defects in zebrafish embryos, including reduction in eye size and body length. Moreover, yolk sac size and mortality were increased in zebrafish embryos exposed to GsME in a dose-dependent manner. GsME at high concentrations triggered teratogenic effects in zebrafish embryos such as decrease in heartbeat/minute, lack of pigmentation, lack of somite, structural deformity, pericardial oedema, and yolk oedema. The LC50 and EC50 of GsME were < 100 mg/L, which classified as a harmful category. The teratogenic index of GsME was found to be > 1, indicating its teratogenic attribute. Additionally, GsME exerted behavioral effects i.e. significantly lower total distance of movement and slower swimming speed of zebrafish embryos. GC-MS analysis of GsME was confirmed the presence of amino acid, phenolics, carboxylic acids, reducing sugars, saturated fatty acids and brominated saturated fatty acid in the extract. It suggesting that compounds of 13-bromotetradecanoic acid, palmitic acid, and stearic acid containing in GsME were contributed to the toxic effects. [ABSTRACT FROM AUTHOR]