Pyraclostrobin induces developmental toxicity and cardiotoxicity through oxidative stress and inflammation in zebrafish embryos.

Pyraclostrobin, a typical representative of strobilurin fungicides, is extensively used in agriculture to control fungi and is often detected in water bodies and food. However, the comprehensive toxicological molecular mechanism of pyraclostrobin requires further study. To assess the toxic effects and underlying mechanisms of pyraclostrobin on aquatic organisms, zebrafish embryos were exposed to pyraclostrobin (20, 40, and 60 µg/L) until 96 h post fertilization (hpf). These results indicated that exposure to pyraclostrobin induces morphological alterations, including spinal curvature, shortened body length, and smaller eyes. Furthermore, heart developmental malformations, such as pericardial edema and bradycardia, were observed. This indicated severe cardiotoxicity induced by pyraclostrobin in zebrafish embryos, which was confirmed by the dysregulation of genes related to heart development. Besides, our findings also demonstrated that pyraclostrobin enhanced the contents of reactive oxygen species (ROS) and malondialdehyde (MDA), up-regulated catalase (CAT) activity, but inhibited superoxide dismutase (SOD) activity. Subsequently, the NF-κb signaling pathway was further studied, and the results indicated that the up-regulation of tnf-α, tlr-4, and myd88 activated the NF-κb signaling pathway and up-regulated the relative expression level of pro-inflammatory cytokines, such as cc-chemokine, ifn-γ, and cxcl-clc. Collectively, this study revealed that pyraclostrobin exposure induces developmental toxicity and cardiotoxicity, which may result from a combination of oxidative stress and inflammatory responses. These findings provide a basis for continued evaluation of the effects and ecological risks of pyraclostrobin on the early development of aquatic organisms.

[Research progress on the developmental toxicity and mechanism of brominated flame retardants during pregnancy exposure on offspring].

Brominated flame retardants (BFRs) are a kind of brominated compounds widely used in electronic and electrical appliances, textiles, construction materials and other industrial products to improve the flame retardant property. Because of its strong chemical stability, environmental persistence, long-distance transmission, biological accumulation, the exposure of humans and organisms in the ecosystem is increasing, and its potential biological effects are of great concern. Now BFRs can be detected in breast milk, serum, placenta and cord blood. Studies have shown that exposure to BFRs during pregnancy can lead to adverse birth outcomes such as low birth weight, malformation, gestational age changes and impairment of neurobehavioral development. This article summarizes the pollution and population exposure of three traditional BFRs, polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA), as well as the impact and mechanism of prenatal exposure on offspring birth outcomes and growth and development. It explores the harm of prenatal exposure to BFRs to offspring and proposes preventive measures for occupational populations for reference.

Reproductive & Developmental Toxicity of quaternary ammonium compounds.

Quaternary ammonium compounds (QACs) are a class of chemicals commonly used as disinfectants in household and healthcare settings. Their usage has significantly increased in recent years due to the COVID-19 pandemic. In addition, QACs have replaced the recently banned disinfectants triclosan and triclocarban in consumer products. QACs are found in daily antimicrobial and personal care products such as household disinfectants, mouthwash, and hair care products. Due to the pervasiveness of QACs in daily use products, humans are constantly exposed. However, little is known about the health effects of everyday QAC exposure, particularly effects on human reproduction and development. Studies that investigate the harmful effects of QACs on reproduction are largely limited to high-dose studies, which may not be predictive of low dose, daily exposure, especially as QACs may be endocrine disrupting chemicals. This review analyzes recent studies on QAC effects on reproductive health, identifying knowledge gaps, and recommending future directions in QAC-related research.

Protective Role of Ellagic Acid Against Ethanol-Induced Neurodevelopmental Disorders in Newborn Male Rats: Insights into Maintenance of Mitochondrial Function and Inhibition of Oxidative Stress.

OBJECTIVE: Ellagic acid (EA) exerts, neuroprotective, mitoprotective, anti-oxidative and anti-inflammatory effects. We evaluated protective effect of EA on ethanol-induced fetal alcohol spectrum disorders (FASD). METHODS: A total of 35 newborn male rats were used, divided into five groups, including; control (normal saline), ethanol (5.25 g/kg per day), ethanol (5.25 g/kg per day) + EA (10 mg/kg), ethanol (5.25 g/kg per day) + EA (20 mg/kg) and ethanol (5.25 g/kg per day) + EA (40 mg/kg). Thirty-six days after birth behavioral tests (Morris water maze and Elevated Plus Maze), tumor necrosis factor-α (TNF-α) levels, oxidative markers (malondialdehyde, glutathione and superoxide dismutase), mitochondrial examination such as succinate dehydrogenases (SDH) activity, mitochondrial swelling, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) formation were analyzed. RESULTS: The results revealed that ethanol exposure adversely affected cognitive and mitochondrial functions and as well as induced oxidative stress and inflammation in brain tissue. However, EA (20 and 40 mg/kg) administration effectively prevented the toxic effects of ethanol in FASD model. CONCLUSIONS: These findings demonstrate that ethanol application significantly impairs the brain development via mitochondrial dysfunction and induction of oxidative stress. These data indicate that EA might be a useful compound for prevention of alcohol-induced FASD.

Developmental toxicity of the neonicotinoid pesticide clothianidin to the larvae of the crustacean Decapoda, Penaeus vannamei.

The developmental toxicity effects of neonicotinoid pesticides such as clothianidin have not been fully explored in agricultural applications. This is particularly noteworthy because such pesticides significantly impact the survival rates of invertebrates, with arthropod larvae being particularly vulnerable. This study aimed to address this research gap by specifically investigating the toxicological effects of clothianidin on the developmental stages of the larvae of the economically important aquaculture species Penaeus vannamei. In these experiments, shrimp eggs were exposed to seawater containing different concentrations of clothianidin beginning at N1, and each phase was observed and analyzed to determine its toxic impact on larval development. These results revealed that clothianidin induces an increase in deformity rates and triggers abnormal cell apoptosis. It also significantly reduced survival rates and markedly decreased body length and heart rate in the later stages of larval development (P3). Transcriptomic analysis revealed disruptions in larval DNA integrity, protein synthesis, and signal transduction caused by clothianidin. To survive prolonged exposure, larvae may attempt to maintain their viability by repairing cell structures and enhancing signal transduction mechanisms. This study offers the first empirical evidence of the toxicity of clothianidin to arthropod larvae, underscoring the impact of environmental pollution on aquatic health.

Esketamine Exposure Impairs Cardiac Development and Function in Zebrafish Larvae.

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.

Differential Analysis of Cereblon Neosubstrates in Rabbit Embryos Using Targeted Proteomics.

Targeted protein degradation is the selective removal of a protein of interest through hijacking intracellular protein cleanup machinery. This rapidly growing field currently relies heavily on the use of the E3 ligase cereblon (CRBN) to target proteins for degradation, including the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide which work through a molecular glue mechanism of action with CRBN. While CRBN recruitment can result in degradation of a specific protein of interest (e.g., efficacy), degradation of other proteins (called CRBN neosubstrates) also occurs. Degradation of one or more of these CRBN neosubstrates is believed to play an important role in thalidomide-related developmental toxicity observed in rabbits and primates. We identified a set of 25 proteins of interest associated with CRBN-related protein homeostasis and/or embryo/fetal development. We developed a targeted assay for these proteins combining peptide immunoaffinity enrichment and high-resolution mass spectrometry and successfully applied this assay to rabbit embryo samples from pregnant rabbits dosed with three IMiDs. We confirmed previously reported in vivo decreases in neosubstrates like SALL4, as well as provided evidence of neosubstrate changes for proteins only examined in vitro previously. While there were many proteins that were similarly decreased by all three IMiDs, no compound had the exact same neosubstrate degradation profile as another. We compared our data to previous literature reports of IMiD-induced degradation and known developmental biology associations. Based on our observations, we recommend monitoring at least a major subset of these neosubstrates in a developmental test system to improve CRBN-binding compound-specific risk assessment. A strength of our assay is that it is configurable, and the target list can be readily adapted to focus on only a subset of proteins of interest or expanded to incorporate new findings as additional information about CRBN biology is discovered.

Urtica dioica Extract Abrogates Chlorpyrifos-Induced Toxicity in Zebrafish Larvae.

Chlorpyrifos (CPF) is a widely used organophosphate insecticide, though its excessive use causes environmental contamination, raising concerns about its adverse effects on human health. In this regard, Urtica dioica stands out as a promising candidate for counteracting chemical 'contaminant' toxicity thanks to its therapeutic properties. Therefore, our study aimed to investigate the potential of an Urtica dioica ethanolic extract (UDE) to mitigate chlorpyrifos-induced toxicity. Eight compounds in the Urtica dioica ethanolic extract have been identified, most of which present significant potential as antioxidant, anti-inflammatory, and neuroprotective agents. Chlorpyrifos exposure altered hatching rates, increased the incidence of teratogenic effects, and upregulated the expression of brain-derived neurotrophic factor (Bdnf) in zebrafish larvae telencephalon. On the other hand, UDE demonstrated a preventive effect against CPF-induced teratogenicity, which is expressed by a lower morphological deformity rate. Moreover, the UDE showed a rather protective effect, maintaining the physiological condition of the telencephalon. Additionally, CPF altered the locomotor behavior of larvae, which was characterized by irregular swimming and increased activity. This defective behavioral pattern was slightly attenuated by the UDE. Our findings suggest that the UDE possesses significant protective properties against CPF-induced toxicity, probably conferred by its natural antioxidant and anti-inflammatory contents. Still, further research is needed to elucidate the recruited mechanisms and implicated pathways on UDE's protective effects.

Prenatal prednisone exposure disturbs fetal kidney development and its characteristics.

Prednisone is a synthetic glucocorticoid that is commonly used in both human and veterinary medication. Now, it is also recognized as an emerging environmental contaminant. Pregnant women may be exposed to prednisone actively or passively through multiple pathways and cause developmental toxicity to the fetus. However, the impact of prenatal prednisone exposure (PPE) on fetal kidney development remains unclear. In this study, pregnant mice were administered prednisone intragastrically during full-term pregnancy with different doses (0.25, 0.5, or 1 mg/(kg·day)), or at the dose of 1 mg/(kg·day) in different gestational days (GD) (GD0-9, GD10-18, or GD0-18). The pregnant mice were euthanized on GD18. HE staining revealed fetal kidney dysplasia, with an enlarged glomerular Bowman's capsule space and a reduced capillary network in the PPE groups. The expression of the podocyte and the mesangial cell marker genes was significantly reduced in the PPE groups. However, overall gene expression in renal tubules and collecting ducts were markedly increased. All of the above effects were more pronounced in high-dose, full-term pregnancy, and female fetuses. Studies on the mechanism of the female fetal kidney have revealed that PPE reduced the expression of Six2, increased the expression of Hnf1ß, Hnf4α, and Wnt9b, and inhibited the expression of glial cell line-derived neurotrophic factor (GDNF) and Notch signaling pathways. In conclusion, this study demonstrated that there is a sex difference in the developmental toxicity of PPE to the fetal kidney, and the time effect is manifested as full-term pregnancy > early pregnancy > mid-late pregnancy.

Effects of Metabolic Disruption on Lipid Metabolism and Yolk Retention in Zebrafish Embryos.

A subgroup of endocrine-disrupting chemicals have the ability to disrupt metabolism. These metabolism-disrupting chemicals (MDCs) can end up in aquatic environments and lead to adverse outcomes in fish. Although molecular and physiological effects of MDCs have been studied in adult fish, few studies have investigated the consequences of metabolic disruption in fish during the earliest life stages. To investigate the processes affected by metabolic disruption, zebrafish embryos were exposed to peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the PPARγ antagonist T0070907, and the well-known environmentally relevant MDC bisphenol A. Decreased apolipoprotein Ea transcript levels indicated disrupted lipid transport, which was likely related to the observed dose-dependent increases in yolk size across all compounds. Increased yolk size and decreased swimming activity indicate decreased energy usage, which could lead to adverse outcomes because the availability of energy reserves is essential for embryo survival and growth. Exposure to T0070907 resulted in a darkened yolk. This was likely related to reduced transcript levels of genes involved in lipid transport and fatty acid oxidation, a combination of responses that was specific to exposure to this compound, possibly leading to lipid accumulation and cell death in the yolk. Paraoxonase 1 (Pon1) transcript levels were increased by rosiglitazone and T0070907, but this was not reflected in PON1 enzyme activities. The present study shows how exposure to MDCs can influence biochemical and molecular processes involved in early lipid metabolism and may lead to adverse outcomes in the earliest life stages of fish. Environ Toxicol Chem 2024;00:1-14. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Engineering a Computable Epiblast for in silico Modeling of Developmental Toxicity.

Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals result from complex chemical-biological interactions, and while New Approach Methods (NAMs) based on in vitro bioactivity profiles of human cells offer promising alternatives to animal testing, most of these assays lack cellular positional information, physical constraints, and regional organization of the intact embryo. Here, we engineered a fully computable model of the embryonic disc in the CompuCell3D.org modeling environment to simulate epithelial-mesenchymal transition (EMT) of epiblast cells and self-organization of mesodermal domains (chordamesoderm, paraxial, lateral plate, posterior/extraembryonic). Mesodermal fate is modeled by synthetic activity of the BMP4-NODAL-WNT signaling axis. Cell position in the epiblast determines timing with respect to EMT for 988 computational cells in the computer model. An autonomous homeobox (Hox) clock hidden in the epiblast is driven by WNT-FGF4-CDX signaling. Executing the model renders a quantitative cell-level computation of mesodermal fate and consequences of perturbation based on known biology. For example, synthetic perturbation of the control network rendered altered phenotypes (cybermorphs) mirroring some aspects of experimental mouse embryology, with electronic knockouts, under-activation (hypermorphs) or over-activation (hypermorphs) particularly affecting the size and specification of the posterior mesoderm. This foundational model is trained on embryology but capable of performing a wide variety of toxicological tasks conversing through anatomical simulation to integrate in vitro chemical bioactivity data with known embryology. It is amenable to quantitative simulation for probabilistic prediction of early developmental toxicity.

From molecular descriptors to the developmental toxicity prediction of pesticides/veterinary drugs/bio-pesticides against zebrafish embryo: Dual computational toxicological approaches for prioritization.

The escalating introduction of pesticides/veterinary drugs into the environment has necessitated a rapid evaluation of their potential risks to ecosystems and human health. The developmental toxicity of pesticides/veterinary drugs was less explored, and much less the large-scale predictions for untested pesticides, veterinary drugs and bio-pesticides. Alternative methods like quantitative structure-activity relationship (QSAR) are promising because their potential to ensure the sustainable and safe use of these chemicals. We collected 133 pesticides and veterinary drugs with half-maximal active concentration (AC50) as the zebrafish embryo developmental toxicity endpoint. The QSAR model development adhered to rigorous OECD principles, ensuring that the model possessed good internal robustness (R2 > 0.6 and QLOO2 > 0.6) and external predictivity (Rtest2 > 0.7, QFn2 >0.7, and CCCtest > 0.85). To further enhance the predictive performance of the model, a quantitative read-across structure-activity relationship (q-RASAR) model was established using the combined set of RASAR and 2D descriptors. Mechanistic interpretation revealed that dipole moment, the presence of C-O fragment at 10 topological distance, molecular size, lipophilicity, and Euclidean distance (ED)-based RA function were main factors influencing toxicity. For the first time, the established QSAR and q-RASAR models were combined to prioritize the developmental toxicity of a vast array of true external compounds (pesticides/veterinary drugs/bio-pesticides) lacking experimental values. The prediction reliability of each query molecule was evaluated by leverage approach and prediction reliability indicator. Overall, the dual computational toxicology models can inform decision-making and guide the design of new pesticides/veterinary drugs with improved safety profiles.

Induction of oxidative stress and cardiac developmental toxicity in zebrafish embryos by arsenate at environmentally relevant concentrations.

The contamination of water by arsenic (As) has emerged as a significant environmental concern due to its well-documented toxicity. Environmentally relevant concentrations of As have been reported to pose a considerable threat to fish. However, previous studies mainly focused on the impacts of As at environmentally relevant concentrations on adult fish, and limited information is available regarding its impacts on fish at early life stage. In this study, zebrafish embryos were employed to evaluate the environmental risks following exposure to different concentrations (0, 25, 50, 75 and 150 µg/L) of pentavalent arsenate (AsV) for 120 hours post fertilization. Our findings indicated that concentrations ≤ 150 µg/L AsV did not exert significant effects on survival or aberration; however, it conspicuously inhibited heart rate of zebrafish larvae. Furthermore, exposure to AsV significantly disrupted mRNA transcription of genes associated with cardiac development, and elongated the distance between the sinus venosus and bulbus arteriosus at 75 µg/L and 150 µg/L treatments. Additionally, AsV exposure enhanced superoxide dismutase (SOD) activity at 50, 75 and 150 µg/L treatments, and increased mRNA transcriptional levels of Cu/ZnSOD and MnSOD at 75 and 150 µg/L treatments. Concurrently, AsV suppressed metallothionein1 (MT1) and MT2 mRNA transcriptions while elevating heat shock protein70 mRNA transcription levels in zebrafish larvae resulting in elevated malondialdehyde (MDA) levels. These findings provide novel insights into the toxic effects exerted by low concentrations of AsV on fish at early life stage, thereby contributing to an exploration into the environmental risks associated with environmentally relevant concentrations.

Effects of polystyrene nanoplastic size on zebrafish embryo development.

Polystyrene nanoplastics (PS) require a comprehensive evaluation of their toxicity and potential risks to humans and the environment. The zebrafish model, a well-established animal model increasingly utilized for nanotoxicity assessments, was employed in this study. Our research aimed to explore the toxic effects of PS with sizes of 30, 100, 200, and 450 nm on zebrafish embryos. Exposure experiments were conducted on embryos at 4 h post-fertilization (hpf) using various concentrations of nanoparticles (20, 40, 60, 80, and 100 mg/L) until 96 hpf. Notably, PS ranging from 100 to 450 nm did not adversely affect zebrafish embryo development. However, PS with a size of 30 nm at a concentration of 100 mg/L resulted in embryo mortality but not embryonic malformations. Furthermore, our investigation confirmed the uptake of these nanoparticles by zebrafish larvae following the opening of their mouths, with the particles being found predominantly in the digestive system of the larvae. Additionally, 30 nm PS were found to significantly modulate the expression levels of genes associated with oxidative stress and apoptosis. These findings highlight the developmental impacts of 30 nm PS on zebrafish embryos, raising concerns about potential similar consequences in humans. Considering our findings, it is essential to encourage further research into the management and regulation of PS to mitigate their potential environmental and health impacts.

Co-exposure to microplastic and plastic additives causes development impairment in zebrafish embryos.

Since the run off of microplastic and plastic additives into the aquatic environment through the disposal of plastic products, we investigated the adverse effects of co-exposure to microplastics and plastic additives on zebrafish embryonic development. To elucidate the combined effects between microplastic mixtures composed of microplastics and plastic additives in zebrafish embryonic development, polystyrene (PS), bisphenol S (BPS), and mono-(2-ethylhexyl) phthalate (MEHP) were chosen as a target contaminant. Based on non-toxic concentration of each contaminant in zebrafish embryos, microplastic mixtures which is consisted of binary and ternary mixed forms were prepared. A strong phenotypic toxicity to zebrafish embryos was observed in the mixtures composed with non-toxic concentration of each contaminant. In particular, the mixture combination with ≤ EC10 values for BPS and MEHP showed a with a strong synergistic effect. Based on phenotypic toxicity to zebrafish embryos, change of transcription levels for target genes related to cell damage and thyroid hormone synthesis were analyzed in the ternary mixtures with low concentrations that were observed non-toxicity. Compared with the control group, cell damage genes linked to the oxidative stress response and thyroid hormone transcription factors were remarkably down-regulated in the ternary mixture-exposed groups, whereas the transcriptional levels of cyp1a1 and p53 were significantly up-regulated in the ternary mixture-exposed groups (P < 0.05). These results demonstrate that even at low concentrations, exposure to microplastic mixtures can cause embryonic damage and developmental malformations in zebrafish, depending on the mixed concentration-combination. Consequently, our findings will provide data to examine the action mode of zebrafish developmental toxicity caused by microplastic mixtures exposure composed with microplastics and plastic additives.

Lignin-derivable alternatives to bisphenol A with potentially undetectable estrogenic activity and minimal developmental toxicity.

Lignin-derivable bisguaiacols/bissyringols are viable alternatives to commercial bisphenols; however, many bisguaiacols/bissyringols (e.g., bisguaiacol F [BGF]) have unsubstituted bridging carbons between the aromatic rings, making them more structurally similar to bisphenol F (BPF) than bisphenol A (BPA) - both of which are suspected endocrine disruptors. Herein, we investigated the estrogenic activity (EA) and developmental toxicity of dimethyl-substituted bridging carbon-based lignin-derivable bisphenols (bisguaiacol A [BGA] and bissyringol A [BSA]). Notably, BSA showed undetectable EA at seven test concentrations (from 10-12 M to 10-6 M) in the MCF-7 cell proliferation assay, whereas BPA had detectable EA at five concentrations (from 10-10 M to 10-6 M). In silico results indicated that BSA had the lowest binding affinity with estrogen receptors. Moreover, in vivo chicken embryonic assay results revealed that lignin-derivable monomers had minimal developmental toxicity vs. BPA at environmentally relevant test concentrations (8.7-116 µg/kg). Additionally, all lignin-derivable compounds showed significantly lower expression fold changes (from ∼1.81 to ∼4.41) in chicken fetal liver tests for an estrogen-response gene (apolipoprotein II) in comparison to BPA (fold change of ∼11.51), which was indicative of significantly reduced estrogenic response. Altogether, the methoxy substituents on lignin-derivable bisphenols appeared to be a positive factor in reducing the EA of BPA alternatives.

Developmental toxicity assay of xanthatin in zebrafish embryos.

Xanthatin (XAN), a xanthanolide sesquiterpene lactone, isolated from Chinese herb, Xanthium strumarium L, has various pharmacological activities, such as antitumor activity and anti-inflammatory. However, little is known about its potential toxicity and the mechanism. Here, zebrafish model was used to study the developmental toxicity in vivo. Our results indicated that xanthatin increased the mortality and led to the morphological abnormalities including pericardial edema, yolk sac edema, curved body shape and hatching delay. Furthermore, xanthatin damaged the normal structure and/or function of heart, liver, immune and nervous system. ROS elevation and much more apoptosis cells were observed after xanthatin exposure. Gene expression results showed that oxidative stress-related genes nrf2 was inhibited, while oxidative stress-related genes (keap1 and nqo1) and apoptotic genes (caspase3, caspase9 and p53) were increased after xanthatin exposure. Mitophagy related genes pink1 and parkin, and wnt pathway (ß-catenin, wnt8a and wnt11) were significantly increased after xanthatin exposure. Taken together, our finding indicated that xanthatin induced developmental toxicity, and the ROS elevation, apoptosis activation, dysregulation of mitophagy and wnt pathways were involved in the toxicity caused by xanthatin.

Toxicological inhalation studies in rats to substantiate grouping of zinc oxide nanoforms.

BACKGROUND: Significant variations exist in the forms of ZnO, making it impossible to test all forms in in vivo inhalation studies. Hence, grouping and read-across is a common approach under REACH to evaluate the toxicological profile of familiar substances. The objective of this paper is to investigate the potential role of dissolution, size, or coating in grouping ZnO (nano)forms for the purpose of hazard assessment. We performed a 90-day inhalation study (OECD test guideline no. (TG) 413) in rats combined with a reproduction/developmental (neuro)toxicity screening test (TG 421/424/426) with coated and uncoated ZnO nanoforms in comparison with microscale ZnO particles and soluble zinc sulfate. In addition, genotoxicity in the nasal cavity, lungs, liver, and bone marrow was examined via comet assay (TG 489) after 14-day inhalation exposure. RESULTS: ZnO nanoparticles caused local toxicity in the respiratory tract. Systemic effects that were not related to the local irritation were not observed. There was no indication of impaired fertility, developmental toxicity, or developmental neurotoxicity. No indication for genotoxicity of any of the test substances was observed. Local effects were similar across the different ZnO test substances and were reversible after the end of the exposure. CONCLUSION: With exception of local toxicity, this study could not confirm the occasional findings in some of the previous studies regarding the above-mentioned toxicological endpoints. The two representative ZnO nanoforms and the microscale particles showed similar local effects. The ZnO nanoforms most likely exhibit their effects by zinc ions as no particles could be detected after the end of the exposure, and exposure to rapidly soluble zinc sulfate had similar effects. Obviously, material differences between the ZnO particles do not substantially alter their toxicokinetics and toxicodynamics. The grouping of ZnO nanoforms into a set of similar nanoforms is justified by these observations.

Chitosan-TPP encapsulated quercetin nanoparticles: amplified protection mechanisms unveiled against Ethion-induced developmental toxicity through comprehensive in-vivo and in-silico elucidation.

Aim: The study investigated Ethion-induced developmental toxicity in Wistar albino rats and the potential ameliorative effects of quercetin and nano-quercetin co-administration. Further, In-silico docking of Ethion and quercetin with MCL-1 was conducted. Methodology: Quercetin nanoparticles were synthesized by ionic-gelation method. The encapsulated quercetin nanoparticles were characterized for Zeta size, UV-Vis spectroscopy, encapsulation efficiency, and TEM studies. Male rats were administered Ethion (high/low dose), quercetin, and nano-quercetin alone or in combination for 60 days. Female rats were introduced for mating on the 61st day, and pregnant females were observed for 20 gestational days. On GD 20, rats were sacrificed and evaluated for body/organ weight, reproductive indices, fetal morphology, skeletal, and visceral deformities.In silico binding energies of ethion and quercetin with MCL-1 were determined. Results: Nanoparticle size was 363.2 ± 1.23 nm on day 0 and 385.63 ± 1.53 nm on day 60, with PDI of 0.247 and charge of 22.9 mV. Absorbance maxima were at 374 nm, with encapsulation efficacy of 85.16 ± 0.33%. EHD male crossed females showed decreased body/organ weights, reduced fertility, hematoma, cleft palate, tail curling, and absence of extremity. Nano-quercetin co-administration normalized parameters comparable to controls. Both Ethion and quercetin interacted with MCL-1, with quercetin exhibiting stronger binding energy. Conclusion: Nano-quercetin demonstrated stronger antioxidant properties than quercetin, counteracting ethion-induced maternal/fetal abnormalities.

Abnormal eyes and spine development in zebrafish (Danio rerio) embryos and larvae induced by triphenyltin.

Triphenyltin (TPT) is widely used in crop pest control and ship antifouling coatings, which leads to its entry into aquatic environment and poses a threat to aquatic organisms. However, the effects of TPT on the early life stages of wild fish in natural water environments remains unclear. The aim of this study was to assess the toxic effects of TPT on the early life stages of fish under two different environments: field investigation and laboratory experiment. The occurrence of deformities in wild fish embryos and larvae in the Three Gorges Reservoir (TGR) and the developmental toxicity of TPT at different concentrations (0, 0.15, 1.5 and 15 µg Sn/L) to zebrafish embryos and larvae were observed. The results showed that TPT content was higher in wild larvae, reaching 27.21 ng Sn/g w, and the malformation of wild fish larvae mainly occurred in the eyes and spine under natural water environment. Controlled experiment exposure of zebrafish larvae to TPT also resulted in eye and spinal deformities. Gene expression analysis showed that compared with the control group, the expression levels of genes related to eye development (sox2, otx2, stra6 and rx1) and spine development (sox9a and bmp2b) were significantly up-regulated in the 15 µg Sn/L exposure group, which may be the main cause of eye and spine deformity in the early development stage of fish. In addition, the molecular docking results further elucidate that the strong hydrophobic and electrostatic interactions between TPT and protein residues are the main mechanism of TPT induced abnormal gene expression. Based on these results, it can be inferred that TPT is one of the teratogenic factors of abnormal eye and spine development in the early life stage of fish in the TGR. These findings have important implications for understanding the toxicity of TPT on fish.