Toward Nano-Specific In Silico NAMs: How to Adjust Nano-QSAR to the Recent Advancements of Nanotoxicology?

The rapid development of engineered nanomaterials (ENMs) causes humans to become increasingly exposed to them. Therefore, a better understanding of the health impact of ENMs is highly demanded. Considering the 3Rs (Replacement, Reduction, and Refinement) principle, in vitro and computational methods are excellent alternatives for testing on animals. Among computational methods, nano-quantitative structure-activity relationship (nano-QSAR), which links the physicochemical and structural properties of EMNs with biological activities, is one of the leading method. The nature of toxicological experiments has evolved over the last decades; currently, one experiment can provide thousands of measurements of the organism's functioning at the molecular level. At the same time, the capacity of the in vitro systems to mimic the human organism is also improving significantly. Hence, the authors would like to discuss whether the nano-QSAR approach follows modern toxicological studies and takes full advantage of the opportunities offered by modern toxicological platforms. Challenges and possibilities for improving data integration are underlined narratively, including the need for a consensus built between the in vitro and the QSAR domains.

Implications of environmental nanoparticles on neurodegeneration.

The ubiquity of nanoparticles, sourced from both natural environments and human activities, presents critical challenges for public health. While offering significant potential for innovative biomedical applications-especially in enhancing drug transport across the blood-brain barrier-these particles also introduce possible hazards due to inadvertent exposure. This concise review explores the paradoxical nature of nanoparticles, emphasizing their promising applications in healthcare juxtaposed with their potential neurotoxic consequences. Through a detailed examination, we delineate the pathways through which nanoparticles can reach the brain and the subsequent health implications. There is growing evidence of a disturbing association between nanoparticle exposure and the onset of neurodegenerative conditions, highlighting the imperative for comprehensive research and strategic interventions. Gaining a deep understanding of these mechanisms and enacting protective policies are crucial steps toward reducing the health threats of nanoparticles, thereby maximizing their therapeutic advantages.

Exploring the interplay between the TGF-ßpathway and SLN-mediated transfection: implications for gene delivery efficiency in prostate cancer and non-cancer cells.

Solid lipid nanoparticles (SLN) are widely recognized for their biocompatibility, scalability, and long-term stability, making them versatile formulations for drug and gene delivery. Cellular interactions, governed by complex endocytic and signaling pathways, are pivotal for successfully applying SLN as a therapeutic agent. This study aims to enhance our understanding of the intricate interplay between SLN and cells by investigating the influence of specific endocytic and cell signaling pathways, with a focus on the impact of the TGF-ßpathway on SLN-mediated cell transfection in both cancerous and non-cancerous prostate cells. Here, we systematically explored the intricate mechanisms governing the interactions between solid lipid nanoparticles and cells. By pharmacologically manipulating endocytic and signaling pathways, we analyzed alterations in SLNplex internalization, intracellular traffic, and cell transfection dynamics. Our findings highlight the significant role of macropinocytosis in the internalization and transfection processes of SLNplex in both cancer and non-cancer prostate cells. Moreover, we demonstrated that the TGF-ßpathway is an important factor influencing endosomal release, potentially impacting gene expression and modulating cell transfection efficiency. This study provides novel insights into the dynamic mechanisms governing the interaction between cells and SLN, emphasizing the pivotal role of TGF-ßsignaling in SLN-mediated transfection, affecting internalization, intracellular transport, and release of the genetic cargo. These findings provide valuable insight for the optimization of SLN-based therapeutic strategies in prostate-related applications.

Lowering the pH leads to the disaggregation of NiO and ZnO nanoparticles and modifies the mutagenic response.

In a changing environmental scenario, acid rain can have a significant impact on aquatic ecosystems. Acidification is known to produce corrosion in metals, hence increasing their harmful effects on the environment, organisms and human health. The prevalent use of metallic nanoparticles (NPs) in everyday products raises concerns regarding exposure and nanotoxicity even in these acidified conditions. We thus report on the cytotoxic and genotoxic potential of nickel oxide (NiO-NP) and zinc oxide (ZnO-NP) NPs when suspended in aqueous media in light of pH variations (7.5 and 5). A modified microsuspension method of the Salmonella/microsome assay was adopted, and strains (TA97a, TA98, TA100, TA102) were exposed to NPs (10-1280 µg/plate) with and without a metabolization fraction. The acidic condition favored disaggregation and caused a decrease in NPs size. Mutagenicity was observed in all samples and different strains, with greater DNA base pair substitution damage (TA100 and TA102), but extrinsic conditions (pH) suggest different action mechanisms of NiO-NP and ZnO-NP on genetic content. Mutagenic activity was found to increase upon metabolic activation (TA98, TA100, and TA102) demonstrating the bioactivity of NiO-NP and ZnO-NP in relation to metabolites generated by the mammalian p450 system in vitro. Modifications in the Salmonella assay methodology increased cell exposure time. The observed responses recommend this modified assay as one of the methodologies of choice for nanoecotoxicological evaluation. These findings emphasize the significance of incorporating the environmental context when evaluating the toxicity of metal-based NPs.

Molecular characterization and transcriptional response of Lactuca sativa seedlings to co-exposure to graphene nanoplatelets and titanium dioxide nanoparticles.

The widespread use of nanomaterials in agriculture may introduce multiple engineered nanoparticles (ENPs) into the environment, posing a combined risk to crops. However, the precise molecular mechanisms explaining how plant tissues respond to mixtures of individual ENPs remain unclear, despite indications that their combined toxicity differs from the summed toxicity of the individual ENPs. Here, we used a variety of methods including physicochemical, biochemical, and transcriptional analyses to examine the combined effects of graphene nanoplatelets (GNPs) and titanium dioxide nanoparticles (TiO2 NPs) on hydroponically exposed lettuce (Lactuca sativa) seedlings. Results indicated that the presence of GNPs facilitated the accumulation of Ti as TiO2 NPs in the seedling roots. Combined exposure to GNPs and TiO2 NPs caused less severe oxidative damage in the roots compared to individual exposures. Yet, GNPs and TiO2 NPs alone and in combination did not cause oxidative damage in the shoots. RNA sequencing data showed that the mixture of GNPs and TiO2 NPs led to a higher number of differentially expressed genes (DEGs) in the seedlings compared to exposure to the individual ENPs. Moreover, the majority of the DEGs encoding superoxide dismutase displayed heightened expression levels in the seedlings exposed to the combination of GNPs and TiO2 NPs. The level of gene ontology (GO) enrichment in the seedlings exposed to the mixture of GNPs and TiO2 NPs was found to be greater than the level of GO enrichment observed after exposure to isolated GNPs or TiO2 NPs. Furthermore, the signaling pathways, specifically the "MAPK signaling pathway-plant" and "phenylpropanoid biosynthesis," exhibited a close association with oxidative stress. This study has provided valuable insights into the molecular mechanisms underlying plant resistance against multiple ENPs.

Zinc oxide nanoparticles disrupt the mammary epithelial barrier via Z-DNA binding protein 1-triggered PANoptosis.

Lactation women, a highly concerned demographic in society, face health risks that deserve attention. Zinc oxide nanoparticles (ZnO NPs) are widely utilized in food and daily products due to their excellent physicochemical properties, leading to the potential exposure of lactating women to ZnO NPs. Hence, assessing the potential risks associated with ZnO NP exposure during lactation is critical. While studies have confirmed that exposure to ZnO NPs during lactation can induce toxic responses in multiple organs through blood circulation, the effects of lactational exposure on mammary tissue remain unclear. This research investigated the impairment of mammary tissue induced by ZnO NPs and its potential mechanisms. Through administering multiple injections of ZnO NPs into the tail vein of lactating ICR mice, our study revealed that ZnO NPs can deposit in the mammary tissues, downregulating key components of mammary epithelial barrier such as ZO-1, occludin, and claudin-3. In vivo, we also found that ZnO NPs can simultaneously induce apoptosis, necroptosis, and pyroptosis, called PANoptosis. Additionally, using EpH4-Ev cells to simulate an in vitro mammary epithelial barrier model, we observed that ZnO NPs effectively disrupted the integrity of mammary epithelial barrier and induced PANoptosis. Furthermore, we confirmed that PANoptosis was responsible for the mammary epithelial barrier disruption induced by ZnO NPs. Moreover, we identified that ZBP1 was the primary mechanism of ZnO NPs inducing PANoptosis. These discoveries are designed to enhance our comprehension of the mechanisms underlying mammary epithelial barrier disruption caused by ZnO NPs, and we aim to highlight the potential hazards associated with daily usage and therapeutic exposure to ZnO NPs during lactation.

The size-dependent in vivo toxicity of amorphous silica nanoparticles: A systematic review.

The extensive application of amorphous silica nanoparticles (aSiNPs) in recent years has resulted in unavoidable human exposure in daily life, thus raising widespread concerns regarding the safety of aSiNPs on human health. The particle size is one of the important characteristics of nanomaterials that could influence their toxicity. For the reason that particles with smaller sizes possess larger surface area, which may lead to higher surface activity and biological reactivity. However, due to the complexity of experimental conditions and biological systems, the relationship between the particle size and the toxic effect of aSiNPs remains unclear. Therefore, this systematic review aims to investigate how particle size influences the toxic effect of aSiNPs in vivo and to analyze the relevant experimental factors affecting the size-dependent toxicity of aSiNPs in vivo. We found that 83.8% of 35 papers included in the present review came to the conclusion that smaller-sized aSiNPs exhibited stronger toxicity, though a few papers (6 papers) put forward different opinions. The reasons for smaller aSiNPs manifested greater toxicity were summarized. In addition, certain important experimental factors could influence the size-dependent effects and in vivo toxicity of aSiNPs, such as the synthesis method of aSiNPs, disperse medium of aSiNPs, administration route of aSiNPs, species or strain of experimental animals, sex of experimental animals, aggregation/agglomeration and protein corona of aSiNPs.

Titanium Dioxide Nanoparticle (TiO2 NP) Induces Toxic Effects on LA-9 Mouse Fibroblast Cell Line.

BACKGROUND/AIMS: Titanium dioxide nanoparticles (TiO2 NPs) are extensively applied in the industry due to their photocatalytic potential, low cost, and considerably low toxicity. However, new unrelated physicochemical properties and the wide use of nanoparticles brought concern about their toxic effects. Thereby, we evaluated the cytotoxicity of a TiO2 NP composed of anatase and functionalized with sodium carboxylate ligands in a murine fibroblast cell line (LA-9). METHODS: Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), and ATR-FTIR spectroscopy were applied to determine nanoparticle physicochemical properties. The cell viability (MTT assay) and clonogenic survival were analyzed in fibroblasts exposed to TiO2 NP (50, 150, and 250 µg/mL) after 24h. Moreover, oxidative stress, proinflammatory state, and apoptosis were evaluated after 24h. RESULTS: TiO2 NP characterization showed an increased hydrodynamic size (3.57 to 7.62 nm) due to solvent composition and a heterogeneity dispersion in water and cell culture media. Also, we observed a zeta potential increased from -20 to -11 mV in function of protein adsorption. TiO2 NP reduced fibroblast cell viability and induced ROS production at the highest concentrations (150 and 250 µg/mL). Moreover, TiO2 NP reduced the fibroblasts clonogenic survival at the highest concentration (250 µg/mL) on the 7th day after the 24h exposure. Nevertheless, TiO2 NP did not affect the fibroblast proinflammatory cytokines (IL-6 and TNF) secretion at any condition. Early and late apoptotic fibroblast cells were detected only at 150 µg/mL TiO2 NP after 24h. CONCLUSION: Probably, TiO2 NP photocatalytic activity unbalanced ROS production which induced apoptosis and consequently reduced cell viability and metabolic activity at higher concentrations.

Synchrotron XRF and Histological Analyses Identify Damage to Digestive Tract of Uranium NP-Exposed Daphnia magna.

Micro- and nanoscopic X-ray techniques were used to investigate the relationship between uranium (U) tissue distributions and adverse effects to the digestive tract of aquatic model organism Daphnia magna following uranium nanoparticle (UNP) exposure. X-ray absorption computed tomography measurements of intact daphnids exposed to sublethal concentrations of UNPs or a U reference solution (URef) showed adverse morphological changes to the midgut and the hepatic ceca. Histological analyses of exposed organisms revealed a high proportion of abnormal and irregularly shaped intestinal epithelial cells. Disruption of the hepatic ceca and midgut epithelial tissues implied digestive functions and intestinal barriers were compromised. Synchrotron-based micro X-ray fluorescence (XRF) elemental mapping identified U co-localized with morphological changes, with substantial accumulation of U in the lumen as well as in the epithelial tissues. Utilizing high-resolution nano-XRF, 400-1000 nm sized U particulates could be identified throughout the midgut and within hepatic ceca cells, coinciding with tissue damages. The results highlight disruption of intestinal function as an important mode of action of acute U toxicity in D. magna and that midgut epithelial cells as well as the hepatic ceca are key target organs.

A Nano-QSTR model to predict nano-cytotoxicity: an approach using human lung cells data.

BACKGROUND: The widespread use of new engineered nanomaterials (ENMs) in industries such as cosmetics, electronics, and diagnostic nanodevices, has been revolutionizing our society. However, emerging studies suggest that ENMs present potentially toxic effects on the human lung. In this regard, we developed a machine learning (ML) nano-quantitative-structure-toxicity relationship (QSTR) model to predict the potential human lung nano-cytotoxicity induced by exposure to ENMs based on metal oxide nanoparticles. RESULTS: Tree-based learning algorithms (e.g., decision tree (DT), random forest (RF), and extra-trees (ET)) were able to predict ENMs' cytotoxic risk in an efficient, robust, and interpretable way. The best-ranked ET nano-QSTR model showed excellent statistical performance with R2 and Q2-based metrics of 0.95, 0.80, and 0.79 for training, internal validation, and external validation subsets, respectively. Several nano-descriptors linked to the core-type and surface coating reactivity properties were identified as the most relevant characteristics to predict human lung nano-cytotoxicity. CONCLUSIONS: The proposed model suggests that a decrease in the ENMs diameter could significantly increase their potential ability to access lung subcellular compartments (e.g., mitochondria and nuclei), promoting strong nano-cytotoxicity and epithelial barrier dysfunction. Additionally, the presence of polyethylene glycol (PEG) as a surface coating could prevent the potential release of cytotoxic metal ions, promoting lung cytoprotection. Overall, the current work could pave the way for efficient decision-making, prediction, and mitigation of the potential occupational and environmental ENMs risks.

In vivo toxicity evaluation of tumor targeted glycol chitosan nanoparticles in healthy mice: repeated high-dose of glycol chitosan nanoparticles potentially induce cardiotoxicity.

BACKGROUND: Glycol chitosan nanoparticles (CNPs) have emerged as an effective drug delivery system for cancer diagnosis and treatment. Although they have great biocompatibility owing to biodegradable chemical structure and low immunogenicity, sufficient information on in vivo toxicity to understand the potential risks depending on the repeated high-dose have not been adequately studied. Herein, we report the results of in vivo toxicity evaluation for CNPs focused on the number and dose of administration in healthy mice to provide a toxicological guideline for a better clinical application of CNPs. RESULTS: The CNPs were prepared by conjugating hydrophilic glycol chitosan with hydrophobic 5ß-cholanic acid and the amphiphilic glycol chitosan-5ß-cholanic acid formed self-assembled nanoparticles with its concentration-dependent homogeneous size distributions (265.36-288.3 nm) in aqueous condition. In cell cultured system, they showed significantly high cellular uptake in breast cancer cells (4T1) and cardiomyocytes (H9C2) than in fibroblasts (L929) and macrophages (Raw264.7) in a dose- and time-dependent manners, resulting in severe necrotic cell death in H9C2 at a clinically relevant highly concentrated condition. In particular, when the high-dose (90 mg/kg) of CNPs were intravenously injected into the healthy mice, considerable amount was non-specifically accumulated in major organs (liver, lung, spleen, kidney and heart) after 6 h of injection and sustainably retained for 72 h. Finally, repeated high-dose of CNPs (90 mg/kg, three times) induced severe cardiotoxicity accompanying inflammatory responses, tissue damages, fibrotic changes and organ dysfunction. CONCLUSIONS: This study demonstrates that repeated high-dose CNPs induce severe cardiotoxicity in vivo. Through the series of toxicological assessments in the healthy mice, this study provides a toxicological guideline that may expedite the application of CNPs in the clinical settings.

Insights into the toxicological effects of nanomaterials on atherosclerosis: mechanisms involved and influence factors.

Atherosclerosis is one of the most common types of cardiovascular disease and is driven by lipid accumulation and chronic inflammation in the arteries, which leads to stenosis and thrombosis. Researchers have been working to design multifunctional nanomedicines with the ability to target, diagnose, and treat atherosclerosis, but recent studies have also identified that nanomaterials can cause atherosclerosis. Therefore, this review aims to outline the molecular mechanisms and physicochemical properties of nanomaterials that promote atherosclerosis. By analyzing the toxicological effects of nanomaterials on cells involved in the pathogenesis of atherosclerosis such as vascular endothelial cells, vascular smooth muscle cells and immune cells, we aim to provide new perspectives for the prevention and treatment of atherosclerosis, and raise awareness of nanotoxicology to advance the clinical translation and sustainable development of nanomaterials.

Artificial intelligence and machine learning disciplines with the potential to improve the nanotoxicology and nanomedicine fields: a comprehensive review.

The use of nanomaterials in medicine depends largely on nanotoxicological evaluation in order to ensure safe application on living organisms. Artificial intelligence (AI) and machine learning (MI) can be used to analyze and interpret large amounts of data in the field of toxicology, such as data from toxicological databases and high-content image-based screening data. Physiologically based pharmacokinetic (PBPK) models and nano-quantitative structure-activity relationship (QSAR) models can be used to predict the behavior and toxic effects of nanomaterials, respectively. PBPK and Nano-QSAR are prominent ML tool for harmful event analysis that is used to understand the mechanisms by which chemical compounds can cause toxic effects, while toxicogenomics is the study of the genetic basis of toxic responses in living organisms. Despite the potential of these methods, there are still many challenges and uncertainties that need to be addressed in the field. In this review, we provide an overview of artificial intelligence (AI) and machine learning (ML) techniques in nanomedicine and nanotoxicology to better understand the potential toxic effects of these materials at the nanoscale.

Biopharmaceutical and nanotoxicological aspects of cyclodextrins for non-invasive topical treatments: A critical review.

Cyclodextrins are nanometric cyclic oligosaccharides with amphiphilic characteristics that increase the stability of drugs in pharmaceutical forms and bioavailability, in addition to protecting them against oxidation and UV radiation. Some of their characteristics are low toxicity, biodegradability, and biocompatibility. They are divided into α-, ß-, and γ-cyclodextrins, each with its own particularities. They can undergo surface modifications to improve their performances. Furthermore, their drug inclusion complexes can be made by various methods, including lyophilization, spray drying, magnetic stirring, kneading, and others. Cyclodextrins can solve several problems in drug stability when incorporated into dosage forms (including tablets, gels, films, nanoparticles, and suppositories) and allow better topical biological effects of drugs at administration sites such as skin, eyeballs, and oral, nasal, vaginal, and rectal cavities. However, as they are nanostructured systems and some of them can cause mild toxicity depending on the application site, they must be evaluated for their nanotoxicology and nanosafety aspects. Moreover, there is evidence that they can cause severe ototoxicity, killing cells from the ear canal even when applied by other administration routes. Therefore, they should be avoided in otologic administration and should have their permeation/penetration profiles and the in vivo hearing system integrity evaluated to certify that they will be safe and will not cause hearing loss.

Potential issues specific to cytotoxicity tests of cellulose nanofibrils.

Cellulose nanofibrils (also called cellulose nanofibers or nanofibrillated cellulose [CNFs]) are novel polymers derived from biomass with excellent physicochemical properties and various potential applications. However, the introduction of such new materials into the market requires thorough safety studies to be conducted. Recently, toxicity testing using cultured cells has attracted attention as a safety assessment that does not rely on experimental animals. This article reviews recent information regarding the cytotoxicity testing of CNFs and highlights the issues relevant to evaluating tests. In the literature, we found that a variety of cell lines and CNF exposure concentrations was evaluated. Furthermore, the results of cytotoxicity results tests differed and were not necessarily consistent. Numerous reports that we examined had not evaluated endotoxin/microbial contamination or the interaction of CNFs with the culture medium used in the tests. The following potential specific issues involved in CNF in vitro testing, were discussed: (1) endotoxin contamination, (2) microbial contamination, (3) adsorption of culture medium components to CNFs, and (4) changes in aggregation/agglomeration and dispersion states of CNFs resulting from culture medium components. In this review, the available measurement methods and solutions for these issues are also discussed. Addressing these points will lead to a better understanding of the cellular effects of CNFs and the development of safer CNFs.

Hepatic effect of subacute Fe2 O3 nanoparticles exposure in Sprague-Dawley rats by LC-MS/MS based lipidomics.

Fe2 O3 nanoparticles (Fe2 O3 NPs) are one of the components of food additives numbered E172 and have been widely used as food pigments to color sweets. Although a large number of studies have reported that Fe2 O3 NPs could induce hepatotoxicity, the pathogenesis is still unclear, especially the subacute effects on the metabolic network after oral exposure. Therefore, it is necessary to define a highly sensitive strategy to investigate the potential effects of Fe2 O3 NPs and the mechanism. In this study, an animal experiment showed that Fe2 O3 NPs had no obvious toxic effects on body weight, histopathology and oxide stress. In order to further investigate the potential effects of Fe2 O3 NPs in vivo, a more sensitive LC-MS/MS-based lipidomic study was performed. The results of multivariate statistical analysis and western blot analysis showed that Fe2 O3 NP exposure significantly affects the hepatic glycerophospholipid metabolism, decreasing triacylglycerol, diglyceride, lysophosphatidylethanolamine and free fatty acids, and increasing phosphatidylcholine, lysophosphatidylinositol and coenzyme Q9. These data provide further insight into the hepatic subacute effects of Fe2 O3 NPs obtained by conventional toxicology methods.

The influence of size and surface chemistry on the bioavailability, tissue distribution and toxicity of gold nanoparticles in zebrafish (Danio rerio).

Gold nanoparticles (AuNPs) are widely used in biomedicine and their specific properties including, size, geometrics, and surface coating, will affect their fate and behaviour in biological systems. These properties are well studied for their intended biological targets, but there is a lack of understanding on the mechanisms by which AuNPs interact in non-target organisms when they enter the environment. We investigated the effects of size and surface chemistry of AuNPs on their bioavailability, tissue distribution and potential toxicity using zebrafish (Danio rerio) as an experimental model. Larval zebrafish were exposed to fluorescently tagged AuNPs of different sizes (10-100 nm) and surface modifications (TNFα, NHS/PAMAM and PEG), and uptake, tissue distribution and depuration rates were measured using selective-plane illumination microscopy (SPIM). The gut and pronephric tubules were found to contain detectable levels of AuNPs, and the concentration-dependent accumulation was related to the particle size. Surface addition of PEG and TNFα appeared to enhance particle accumulation in the pronephric tubules compared to uncoated particles. Depuration studies showed a gradual removal of particles from the gut and pronephric tubules, although fluorescence indicating the presence of the AuNPs remained in the pronephros 96 h after exposure. Toxicity assessment using two transgenic zebrafish reporter lines, however, revealed no AuNP-related renal injury or cellular oxidative stress. Collectively, our data show that AuNPs used in medical applications across the size range 40-80 nm, are bioavailable to larval zebrafish and some may persist in renal tissue, although their presence did not result in measurable toxicity with respect to pronephric organ function or cellular oxidative stress for short term exposures.

Toxicological effects and transcriptome mechanisms of rice (Oryza sativa L.) under stress of quinclorac and polystyrene nanoplastics.

The absorption and accumulation of nanoplastics (NPs) by plants is currently attracting considerable attention. NPs also tend to adsorb surrounding organic pollutants, such as pesticides, which can damage plants. However, molecular mechanisms underlying the phytotoxicity of NPs are not sufficiently researched. Therefore, we analyzed the toxicological effects of 50 mg/L polystyrene NPs (PS 50 nm) and 5 mg/L the herbicide quinolinic (QNC) on rice (Oryza sativa L.) using 7-day hydroponic experiments, explaining the corresponding mechanisms by transcriptome analysis. The main conclusion is that all treatments inhibit rice growth and activate the antioxidant level. Compared with CK, the inhibition rates of PS, QNC, and PS+QNC on rice shoot length were 3.95%, 6.68%, and 11.43%, respectively. The gene ontology (GO) term photosynthesis was significantly enriched by QNC, and the combination PS+QNC significantly enriched the GO terms of amino sugar and nucleotide sugar metabolisms. The chemicals QNC and PS+QNC significantly affected the Kyoto Encyclopedia of Genes and Genomes (KEGG) of the MAPK signaling pathway, plant hormone signal transduction, and plant-pathogen interaction. Our findings provide a new understanding of the phytotoxic mechanisms and environmental impacts of the interactions between NPs and pesticides. It also provides insights into the impact of NPs and pesticides on plants in the agricultural system.

Ultrastructural characteristics of the accumulation of iron nanoparticles in the intestine of Cyprinus carpio (Linnaeus, 1758) under aquaculture.

During the development of nanotechnology, the production of many substances containing nanoparticles leads to the release of various nanoparticles into the environment, including the water ecosystem. The main goal of the current research was to study the ultrastructural characteristics of the entry and bioaccumulation of Fe3O4 nanoparticles in the small intestine of Cyprinus carpio (Linnaeus, 1758), as well as the pathomorphological changes in the fish organism. Two different doses (10 and 100 mg) of Fe3O4 nanoparticles were fed to fingerlings for 7 days and then intestinal samples were taken and studied. It was found that the extent of damages was boosted within the increment of nanoparticle concentration. The sequence and bioaccumulation of Fe3O4 nanoparticles in the small intestine of fish occurred as below: firstly, the nanoparticles passed into microvilli located in the apical part of enterocytes in the mucosa layer, from there into the cytoplasm of the epithelial cells, including cytoplasmatic organelles (nucleus, mitochondria, lysosomes, fat granules), and then into a lamina propria of the mucosa of the small intestine and passed into the endothelium of the blood vessels and to the erythrocytes of the vessels which located in the lumen. It was determined that although the nanoparticles were up to 30 nm in size, only particles with a maximum size of 20 nm could penetrate the intestinal wall. Thus, the release of Fe3O4 nanoparticles into the environment in high doses has a negative effect on the living ecosystem, including the body of fish living in the water.

Toxic and bioaccumulative effects of zinc nanoparticle exposure to goldfish, Carassius auratus (Linnaeus, 1758).

The widespread use of produced metal oxide nanoparticles (NPs) has increased major concerns about their impact on human as well as aquatic animal health. The present study shows that exposure to different concentrations of zinc oxide (ZnO) NPs led to high accumulations of Zn ions in the metabolic organs of fish (liver and gills), resulting in severe oxidative stress in Carassius auratus. The goldfish (C. auratus) was chosen as an aquatic species for the evaluation of the potential toxicity of aqueous ZnO-NPs (Treatments of hemoglobin and neutrophils (0, 0.5, 1, and 1.5 mg L- 1) following 14 days of exposure. A range of histological and hematological factors were examined. Exposure to the NPs produced significant reduction of red blood cell and white blood cell counts, hematocrit) were found to produce no significant differences in lymphocyte, monocyte, and eosinophil counts; as well as the mean corpuscular hemoglobin concentrations index (P > 0.05). Moreover, the results revealed significant alterations in serum biochemical parameters, hepatic enzyme levels, and immune and antioxidant responses; except for total protein and superoxide dismutase (SOD) of C. auratus exposed to ZnO-NPs, particularly at the 1 and 1.5 mg L- 1 concentrations. Fish exposed to 1 and 1.5 mg L-1 ZnO-NPs displayed a significant reduction in alternative complement pathway activity, lysozyme, and total protein contents of mucus compared to those in the control group. The results showed that hepatic SOD and catalase, and gill catalase activity were significantly decreased, and their malondialdehyde levels increased at 1 and 1.5 mg L-1 ZnO-NPs compared to the control group (P < 0.05). Significant accumulations of ZnO-NPs were observed in the liver, kidney, and gill tissues of fish leading to severe histopathological alterations in these organs. These results suggest that water-borne ZnO-NPs can easily accumulate in metabolic organs and lead to oxidative stress and destructive effects on the physiological features of C. auratus.