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The mechanism of cellular uptake of nanoparticles (NPs) is critical for both bio-application and risk evaluation of NPs, but is still not fully understood due to many influencing factors, among which particle size is a major one. Recent studies show that there is an unusual interplay among differently-sized NPs when they simultaneously interact with cells, e.g., 100 nm silica NPs (SNP100) can promote the cellular uptake of 50 nm silica NPs (SNP50). However, the underlying mechanism is still unclear. Herein, we manage to capture individual endocytosis events in HeLa and A549 cells after co-exposure to SNP50 and SNP100 for 2 hours, using transmission electron microscopy (TEM). TEM images clearly show that there is a size threshold for SNPs to trigger clathrin-mediated endocytosis: One single SNP100 can efficiently trigger it, while it needs about 6 SNP50 to do so. Remarkably, TEM also captures how SNP100 triggers the endocytosis and carries nearby SNP50 into cells, and statistical data show that the average number of SNP50 carried by one SNP100 could be up to about 6. In addition, the mechanism was further verified by using mixed 60 nm SNPs (SNP60) and SNP100. This mechanism has an immediate implication for the design of drug-deliver nanocarriers, and as a proof-of-concept, more catalase functionalized SNP50 (CAT@SNP50) was delivered into HeLa cells by adding some SNP100, resulting in a more severe cell damage compared to CAT@SNP50 alone under same conditions. The findings have general impact on the nanotoxicity study of NP products that commonly have certain distributions in size, and provide new insights on designing efficient drug delivery systems by deliberately control the combinations of NPs of different sizes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exposure to different types of nanoparticles (NPs) results in their deposition in human bodies. While most studies have examined the cellular uptake of only one type of NP at a time, how the dynamics of NP uptake may change in the presence of other types of NPs remains unclear. We therefore investigated the interplay of two differently sized SiO 2 NPs during their uptake by A549 human lung carcinoma cells. Both NPs contained a CdSeTe core, which was labeled with different Cd isotopes to differentiate between them. Our study showed that the uptake of one size of SiO 2 NPs either increased or decreased with the concentration of the other size of SiO 2 NPs. This variation in uptake was attributable to the concentration-dependent aggregation of SiO 2 NPs, as determined by the amount of cell-excreted proteins adsorbed on the NP surface. Further, the effects of the protein corona on the attachment of SiO 2 NPs to the cell surface and uptake competition between differently sized SiO 2 NPs also played important roles. Cell-excreted proteins were then analyzed by proteomics. Overall, the complex interactions between coexisting NPs of different physicochemical properties and cell-excreted proteins should be considered during bio-applications and bio-safety evaluations of NPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Both dichlorodiphenyltrichloroethane (DDT) and titanium dioxide nanoparticle (TiO 2 NP) have worldwide-scale commercial applications, resulting in their co-pollution in the ecosystems and posing combined health risks. However, there is a lack of toxicity studies for the interactions of DDT and TiO 2 NP in the environmental relevant concentrations. In this study, we characterized the coexposures using a zebrafish waterborne exposure approach and evaluated the neurotoxicity response of the treated embryos or adults. Our results showed that DDT/TiO 2 NP coexposure enhanced the DDT accumulation in vivo and increased the larval locomotor. The chronic DDT/TiO 2 NP coexposure did not affect the overall survival rate, sex ratio and growth. However, DDT/TiO 2 NP coexposure severely affected the adult locomotor activity, social contact, shoaling and aggressive behaviors compared to single treatment groups or controls. These adult behavioral deficits were accompanied by changes in neurotransmitter acetylcholine (ACH) level in the brain and muscle tissues, as well as neural development genes expression activation of growth-associated protein 43 (gap43) and synaptic vesicle glycoprotein 2 (sv2) in the brain. The significantly increased ACH level and the activated neural genes expression in the DDT/TiO 2 NP co-exposed fish may account for the observed hyperactivity and social deficits., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Aquatic environments are complicated systems that contain different types of nanoparticles (NPs). Nevertheless, recent studies of NP toxicity, and especially those that have focused on bioaccumulation have mostly investigated only a single type of NPs. Assessments of the environmental risks of NPs that do not consider co-exposure regimes may lead to inaccurate conclusions and ineffective environmental regulation. Thus, the present study examined the effects of differently sized silica NPs (SiO 2 NPs) on the uptake of iron oxide NPs (Fe 2 O 3 NPs) by the zooplankton Daphnia magna . Both SiO 2 NPs and Fe 2 O 3 NPs were well dispersed in the experimental medium without significant heteroaggregation. Although all three sizes of SiO 2 NPs inhibited the uptake of Fe 2 O 3 NPs, the underlying mechanisms differed. SiO 2 NPs smaller than the average mesh size (∼200 nm) of the filtering apparatus of D. magna reduced the accumulation of Fe 2 O 3 NPs through uptake competition, whereas larger SiO 2 NPs inhibited the uptake of Fe 2 O 3 NPs mainly by reducing the water filtration rate of the daphnids. Overall, in evaluations of the risks of NPs in the natural environment, the different mechanisms underlying the effects of NPs of different sizes on the uptake of dissimilar NPs should be considered.

The environmental risks of silica nanoparticles (SiNP) reported in the literature are contradictory and bring into question its safety for use in consumer applications. Organisms are never exposed to NPs alone in the real environment, while studies of the combined toxicity of SiNP are limited. To address this, we compared the acute toxicity of fluorescent core-shell SiNPs alone and in mixtures with Cd 2+ to Ceriodaphnia dubia in the absence and presence of NOM. We identified biodistribution and feeding behaviour in addition to the traditional endpoints. NOM increased the colloidal stability of SiNPs in reconstituted water. In immobility tests, no significant effects were observed from Cd 2+ exposure with NOM and varying concentrations of SiNPs. A similar pattern of curve dose-response was observed for varying concentrations of SiNPs and increasing Cd 2+ concentration and constant NOM. Fluorescence microscopy verified a dose-dependent bioaccumulation of SiNPs in C. dubia. Co-exposure to 10 mg L -1 SiNP with NOM and Cd 2+ resulted in a stimulated stress feeding response at the lower Cd 2+ concentrations which declined at the higher dose due to a functional impairment of the digestive tract. Alterations in feeding behaviour and the increasing bioaccumulation of SiNP indicate a potential ecological risk for Ceriodaphnia dubia from the mixture exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The wide use of carbon-based materials for various purposes leads to their discharge in the aquatic systems, and simultaneous occurrence with other environmental contaminants, such as pharmaceutical drugs. This co-occurrence can adversely affect exposed aquatic organisms. Up to now, few studies have considered the simultaneous toxicity of nanomaterials, and organic contaminants, including pharmaceutical drugs, towards aquatic plants. Thus, this study aimed to assess the toxic effects of the co-exposure of propranolol (PRO), and nanomaterials based on cellulose nanocrystal, and graphene oxide in the aquatic macrophyte Lemna minor. The observed effects included reduction of growth rate in 13% in co-exposure 1 (nanomaterials + PRO 5 μg L -1 ), and 52-64% in co-exposure 2 (nanomaterials + PRO 51.3 mg L -1 ), fresh weight reduction of 94-97% in co-exposure 2 compared to control group, and increased pigment production caused by co-exposure treatments. The analysis of PCA showed that co-exposure 1 (nanomaterials + PRO 5 μg L -1 ) positively affected growth, and fresh weight, and co-exposure 2 positively affected pigments content. The results suggested that the presence of nanomaterials enhanced the overall toxicity of PRO, exerting deleterious effects in the freshwater plant L. minor, suggesting that this higher toxicity resulting from co-exposure was a consequence of the interaction between nanomaterials and PRO., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Several nano-toxicological studies have assessed the prospective health risks of engineered nanostructures. Still, nanoscale ingredients from food products are not explored well, and only a few have attended to the possible effects of food additive-based nanoparticles in food. The physicochemical properties of food additives and their fate on human health are still unknown. To fill this knowledge gap, we examined the physicochemical characteristics of food product isolate E341/E551. Additionally, we assessed the consequence of these nanoscale E341 and E551 as co-exposure on human mesenchymal stem cells (hMSCs). The transmission electron microscope (TEM) images revealed that food product isolate (E341/E551) consists of nanoscale particles. The E551 and E341 have 20-50 nm and 70-200 nm diameters, respectively. Co-exposure of food additives SiO2 (E551) and Tricalcium phosphate (E341) effect on the cell viability, morphology, mitochondrial membrane potential, and reactive oxygen species (ROS) level of hMSCs were studied. The cell viability reduction, mitochondrial membrane potential loss, and ROS generation in E341/E551 co-exposed cells were observed. Our study suggests that E341/E551 co-exposure elevated the ROS level and mitochondrial membrane potential depletion at a high dose. The oxidative stress-related genes MDM3, TNFSF10, and POR have exhibited significant upregulation in the E341/E551 treatment group. These results conclude that long-term over-exposure to E341/E551 may be triggers health risks in a human. Further in vivo studies are required for food industry implications due to nanoscale ingredients in E341 and E551., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Silicon dioxide nanoparticles (n-SiO 2 ) absorb tetrabromobisphenol A (TBBPA) and modify its bioavailability and toxicity in the aquatic phase; embryonic chorion is an efficient barrier against nanoparticles (e.g., SiO 2 ) and influences their toxicity. However, few studies have investigated developmental neurotoxicity in fish after co-exposure to TBBPA and n-SiO 2 , especially considering the barrier function of the chorion. In the present study, zebrafish embryos were exposed to TBBPA (50, 100, and 200 μg/L) alone or in combination with n-SiO 2 (25 mg/L) until 24 or 120 h post fertilization (hpf), in the presence and absence of the chorion. The results confirmed that TBBPA exposure alone significantly downregulated the expression of neurodevelopment marker genes (mbp, alpha-tubulin, shha, and gfap), altered acetylcholinesterase activity and acetylcholine content, and affected locomotor behavior at different developmental stages. Moreover, the results indicated that n-SiO 2 promoted TBBPA-induced neurotoxic effects in zebrafish larvae at 120 hpf, including further repression of the transcription of CNS-related genes, disruption of the cholinergic system, and decrease in the average swimming speed under dark/light stimulation. However, scanning electron microscopy/energy dispersive spectroscopy analysis revealed that at 24 hpf, the embryonic chorion efficiently blocked n-SiO 2 and consequently decreased the bioaccumulation of TBBPA and TBBPA-induced neurotoxicity in dechorionated zebrafish embryos. Taken together, the results demonstrate that n-SiO 2 affected the bioavailability and neurodevelopmental toxicity of TBBPA, and their combined toxicity to zebrafish embryos was mitigated by embryonic chorion, which will facilitate risk assessment on n-SiO 2 and TBBPA and improve understanding the function of the fish embryonic chorion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Human gastrointestinal cells can be exposed to different xenobiotics present in food or drinking water. In this work, we assessed the cytotoxicity of polystyrene nanoparticles (PS-NPs) and how it is impacted by fluoride (F - ) presence. We decided to examine PS-NPs and F - which can be easily found in drinking water and food. Commercially available amine-modified 100 nm PS-NPs were used in the study. Scanning Electron Microscopy with Electron Dispersive Spectroscopy (SEM-EDS) and Dynamic Light Scattering (DLS) were used to characterize PS-NPs. The colon cell lines (HT-29, Caco-2, CCD 841 CoN) were used. Cytotoxicity of PS-NPs and F - alone or in co-exposition were assessed with MTT assay in a time- and concentration-dependent manner. Flow cytometry was used to measure reactive oxygen species (ROS) production, cell cycle distribution, and apoptosis analysis. Transmission electron microscopy (TEM) was used to determine whether PS-NPs and/or F - can cause ultrastructure changes in the cells. We have shown that PS-NPs are cytotoxic to human colon cells in a time- and concentration-dependent manner. PS-NPs did not impact neither intracellular ROS production nor the cells cell cycle distribution. However, if HT-29 cells were co-exposed to PS-NPs and F - , an increased number of cells in G0/G1 phase and decreased number of cells in G2/M were observed. PS-NPs can cause apoptosis in HT-29 cells, this effect was enhanced if cells were co-exposed to PS-NP and F - . PS-NPs were internalised by the cells and caused ultrastructure changes. Fluoride itself (1 mM) was not cytotoxic to the cells and did not cause any changes in the ultrastructure of the cells. We have proven that polystyrene nanoparticles can be cytotoxic to human gastrointestinal cells and this effect is enhanced by fluoride., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Combined exposure of chronic stress and alumina nanoparticles (AlNPs) aggravates hippocampal injury, but the pathogenesis is unevaluated. This study aimed to investigate the effect and mechanism of co-exposure to chronic stress and AlNPs on hippocampal microglia pyroptosis. In this study, chronic restraint stress (CRS) alone caused NLRP3-mediated hippocampal microglia pyroptosis, but AlNPs did not. Moreover, co-exposure to CRS and AlNPs exacerbated hippocampal microglia pyroptosis, resulting in more severe hippocampal damage and behavioral deficits in rats. Protein-protein interaction network predicted that cathepsin B was a potential regulatory protein of NLRP3. CRS up-regulated cathepsin B expression which had a more pronounced increase in co-exposure group. Whereas, caspase-1 inhibitor VX-765 alleviated hippocampal microglia pyroptosis and behavioral deficits in rats. Consistent with in vivo results, co-exposure of corticosterone and AlNPs aggravated NLRP3-mediated pyroptosis and cathepsin B expression in HAPI cells. Nevertheless, the pyroptosis of HAPI cells was inhibited by cathepsin B inhibitor CA-074Me and NLRP3 knockout, respectively. NLRP3 agonist nigericin failed to promote the pyroptosis of HAPI cells in the presence of cathepsin B inhibition. These results demonstrated that co-exposure to chronic stress and AlNPs could aggravate hippocampal microglia pyroptosis by activating cathepsin B/NLRP3 signaling pathway, resulting in hippocampal damage and behavioral deficits., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Considering the increasing emergence of new contaminants, such as nanomaterials, mixing with legacy contaminants, including metal(loid)s, it becomes imperative to understand the toxic profile resulting from these interactions. This work aimed at assessing and comparing the individual and combined hepatotoxic and neurotoxic potential of titanium dioxide nanoparticles (TiO 2 NPs 0.75-75 mg/L), cerium oxide nanoparticles (CeO 2 NPs 0.075-10 μg/L), arsenic (As 0.01-2.5 mg/L), and mercury (Hg 0.5-100 mg/L) on human hepatoma (HepG2) and neuroblastoma (SH-SY5Y) cells. Viability was assessed through WST-1 (24 h) and clonogenic (7 days) assays and it was affected in a dose-, time- and cell-dependent manner. Higher concentrations caused greater toxicity, while prolonged exposure caused inhibition of cell proliferation, even at low concentrations, for both cell lines. Cell cycle progression, explored by flow cytometry 24 h post-exposure, revealed that TiO 2 NPs, As and Hg but not CeO 2 NPs, changed the profiles of SH-SY5Y and HepG2 cells in a dose-dependent manner, and that the cell cycle was, overall, more affected by exposure to mixtures. Exposure to binary mixtures revealed either potentiation or antagonistic effects depending on the composition, cell type and time of exposure. These findings prove that joint toxicity of contaminants cannot be disregarded and must be further explored.

The continuous release of manufactured nanomaterials (MNMs) to environments raised concerns on their combined toxicological risks with co-existing contaminants, since MNMs might severely alter the environmental behavior and fate of the contaminants. In this study, the combined toxicity of nano-sized titanium dioxide (nTiO 2 ) and cadmium (Cd 2+ ) to the green alga Scenedesmus obliquus and the underlying physicochemical mechanisms were investigated for the first time at different concentration ratios of Cd 2+ to nTiO 2 to closely mimic the realistic environment scenarios where the concentration ratios of nTiO 2 to other contaminants are constantly changing. Our results suggested that under the co-exposure to different concentration ratios of Cd 2+ to nTiO 2 , the co-exposure contaminants exhibited three different combined toxicity modes (antagonistic, partially additive, and synergistic). Specifically, antagonistic combined toxicity was observed under co-exposure to a low concentration ratio of nTiO 2 to Cd 2+ as the absorption by nTiO 2 decreased the bioavailability of Cd 2+ . However, the partially additive and synergistic combined toxicity occurred when the proportion of nTiO 2 in the co-exposure system was relatively high, which would mechanically and/or oxidatively damage the alga cell structures. Even worse, as a carrier of Cd 2+ , nTiO 2 enhanced the amount of Cd 2+ entering cells, which significantly enhanced the toxicity of Cd 2+ to algae. Overall, we demonstrated that concentration ratios of nTiO 2 to Cd 2+ play an important role in determining the combined toxicity mode, which would provide a novel reference to environmental and health risk assessment of co-exposure to conventional pollutants and MNMs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The increasing use and disposal of plastics has become a persistent problem in the marine environment, calling for studies that refer to realistic scenarios to understand their effects on biota. Particularly, the understanding about the effects of co-exposure with nanoplastic particles and metals on aquatic organisms is still limited. The present work aimed to investigate the acute toxicity of amino-functionalized polystyrene nanoparticles (PS-NH 2 ; 50 nm) as proxy for nanoplastics on brine shrimp Artemia franciscana larvae under different culture conditions and at different stages of development, as well as the combined effect with two reference toxicants - potassium dichromate (K 2 Cr 2 O 7 ) and copper sulfate (CuSO 4 ). Nauplii (instar II or III larval stages) were exposed to different concentrations of PS-NH 2 (0.005 to 5 μg mL -1 ) for up to 48 h, with or without agitation in order to mimic a more realistic environmental scenario. Larval mobility and PS-NH 2 accumulation were monitored under microscopy. PS-NH 2 alone showed toxicity only at the highest concentration tested (5 μg mL -1 ) regardless the incubation method used (61.2 + 3.1% and 65.0 + 4.5% with and without agitation, respectively). Moreover, instar III stage was the most sensitive to PS-NH 2 exposure (38.2% immobility in 24 h of exposure; 5 μg mL -1 ). Evidence of PS-NH 2 retention in the gastrointestinal tract in a concentration- and time-dependent manner was also obtained. Mixtures of PS-NH 2 (0.005 and 5 μg mL -1 ) with different concentrations of K 2 Cr 2 O 7 increased the immobilization rate of the larvae after 48 h of exposure, when compared to the K 2 Cr 2 O 7 alone. Similar results were observed for CuSO 4 in the co-exposure conditions at different concentrations. However, exposing nauplii to a mixture of PS-NH 2 (0.005 μg mL -1 ) and CuSO 4 decreased immobilization rate, in comparison to the group exposed to CuSO 4 alone. The present work highlights the potential risk posed by nanoplastics to zooplanktonic species through their interaction with other toxicants., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The wide applications of titanium dioxide nanoparticles (TNP) and ubiquitous cadmium (Cd) pollution increase the chances of their co-existence in the environment and also pose potential health risks to humans. However, toxicological understanding of effects of co-exposures of TNP and Cd to mammals is still lacking. In this study, non-lethal doses of TNP and CdCl 2 were intravenously co-administered to healthy or Concanavalin A (ConA)-induced acute hepatitis mice. Co-exposures of TNP and CdCl 2 increased the accumulation of Cd 2+ in the liver of hepatitis mice, which was 1.42-fold higher than that of healthy mice. Co-exposures also caused liver damage only in hepatitis mice on the basis of histopathological and biochemical evidence. Further study showed that co-exposure upregulated hepatic oxidative stress, which further induced autophagy and apoptosis only in the liver of hepatitis mice. This finding underlines the potential toxicological consequences of co-exposures of TNP and CdCl 2 in hepatitis sufferers., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Air pollution is considered as a major public health issue worldwide. It consists of a complex mixture of pollutants including nanoparticles to which we are increasingly exposed to due to the dramatic development of the nanotechnologies and their incidental or intentional release in the environment. Consequently, some concerns have raised about the combined toxicity of air particulates and other air pollutants on human health. However, the interactions between the contaminants and their resulting combined toxicity are often overlooked. Indeed, the biological effects triggered by nanoparticles are usually assessed focusing on individual nanoparticles, while their interaction with co-contaminants can deeply impact, either positively or negatively, their biodistribution, fate in the organism and toxicological profile (additive, synergistic or antagonistic responses). This paper presents a bibliographic review on the combined toxicity of nanoparticles and co-pollutants and discusses the underlying mechanisms. It also highlights the scarcity of data in the current literature, arguing for an urgent need to take into account the mixture effects to be more representative of real-life conditions for a better and accurate human health risk assessment and management., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recent attention has been focused on reproductive toxicity of nanoscale materials in combination with pre-existing environmental pollutants. Due to its unique characteristics, bismuth (III) oxide (Bi 2 O 3 ) nanoparticles (BONPs) are being used in diverse fields including cosmetics and biomedicine. Benzo[a]pyrene (BaP) is a known endocrine disruptor that most common sources of BaP exposure to humans are cigarette smoke and well-cooked barbecued meat. Hence, joint exposure of BONPs and BaP in humans is common. There is scarcity of information on toxicity of BONPs in combination with BaP in human reproductive system. In this work, combined effects of BONPs and BaP in mouse spermatogonia (GC-1 spg) cells were assessed. Results showed that combined exposure of BONPs and BaP synergistically induced cell viability reduction, lactate dehydrogenase leakage, induction of caspases (-3 and -9) and mitochondrial membrane potential loss in GC-1 spg cells. Co-exposure of BONPs and BaP also synergistically induced production of pro-oxidants (reactive oxygen species and hydrogen peroxide) and reduction of antioxidants (glutathione and several antioxidant enzymes). Experiments with N-acetyl-cysteine (NAC, a reactive oxygen species scavenger) indicated that oxidative stress was a plausible mechanism of synergistic toxicity of BONPs and BaP in GC-1 spg cells. Present data could be helpful for future in vivo research and risk assessment of human reproductive system co-exposed to BONPs and BaP.

The coexistence of nanoparticles and organic toxicants in the environment modifies pollutant bioavailability and toxicity. This study investigated the influence of silicon dioxide nanoparticles (n-SiO 2 ) on the uptake of tetrabromobisphenol A (TBBPA) and its impact on the thyroid endocrine system in zebrafish larvae. Zebrafish (Danio rerio) embryos were exposed to TBBPA at different concentrations (50, 100, and 200 μg/L) alone or in combination with n-SiO 2 (25 mg/L) until 120 h post-fertilization (hpf). Chemical measurements showed that both TBBPA and n-SiO 2 were bioconcentrated in zebrafish larvae, and the uptake of TBBPA was enhanced by n-SiO 2 . Furthermore, zebrafish larvae exposed to 200 μg/L TBBPA alone exhibited significantly increased T4 contents and decreased T3 contents, whereas n-SiO 2 treatment alone did not have a detectable effect. Furthermore, the thyroid hormone levels changed more upon treatment with 200 μg/L TBBPA combined with 25 mg/L n-SiO 2 than upon TBBPA treatment alone. Alterations in gene transcription along the related hypothalamic-pituitary-thyroid (HPT) axis were observed, and expression of the binding and transport protein transthyretin (TTR) was significantly decreased for both TBBPA alone and co-exposure with n-SiO 2 . Thus, the current study demonstrates that n-SiO 2 , even at the nontoxic concentrations, increases thyroid hormone disruption in zebrafish larvae co-exposed to TBBPA by promoting its bioaccumulation and bioavailability., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The aquatic environment is the major recipient of wastes containing nanoparticles and other contaminants. Titanium dioxide nanoparticles (NPTiO 2 ) are one of the most produced and used nanoparticle worldwide. This study investigated the toxicity of NPTiO 2 , as well as the toxicity interaction between NPTiO 2 and lead (Pb), in response to genetic and biochemical biomarkers using freshwater fish Rhamdia quelen, as an animal model. The results showed genotoxicity in blood and kidney tissues. No effect of NPTiO 2 alone or in co-exposure with Pb on liver genotoxicity were observed. Alterations in the antioxidant hepatic enzymes activities, as well as alterations in glutathione levels indicated that NPTiO 2 alone or in co-exposure with Pb can cause antioxidant imbalance. The lipid peroxidation was also raised after exposure to NPTiO 2 . In general, the results of this study indicated that both NPTiO 2 alone and their co-exposure with Pb are capable of producing significant toxic effects in short-term exposure., (Copyright © 2020. Published by Elsevier B.V.)

The co-existence of organic pollutants and nanoparticles in the environment may lead to combined biological effects. The joint toxicity of pollutants and nanoparticles has been receiving increasing attention from researchers, but few studies have focused on soil biota due to the complexity of soil matrices. This study investigated the effects of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) at 0, 5, and 25 mg/kg and nanoparticulate TiO 2 (nTiO 2 ) at 0, 500, and 2500 mg/kg in a 3 × 3 factorial arrangement of treatments for 28 days (d) on Eisenia fetida (earthworm). Compared with the control group (the 0 mg/kg TDCIPP + 0 mg/kg nTiO 2 treatment), all other single (TDCIPP or nTiO 2 ) and binary (TDCIPP + nTiO 2 ) treatments except for the single 500 mg/kg nTiO 2 treatment significantly reduced the weight gain rate of E. fetida. The binary treatments had significantly greater such effect than their corresponding single treatments, exhibiting a synergistic toxicity between TDCIPP and nTiO2 on the growth of E. fetida. Since TDCIPP and nTiO 2 had no significant effect on their concentrations in the soil or in E. fetida during binary exposure, the synergistic toxicity could be a result of the superimposition of the toxicity pathways of TDCIPP and nTiO 2 . Transcriptomic analysis of E. fetida intestinal region revealed that exposure to 25 mg/kg TDCIPP or 2500 mg/kg nTiO 2 affected nutrient-related or cell apoptosis and DNA damage related genes, respectively; their co-exposure greatly inhibited genes related to nutrient digestion and absorption, while causing abnormal transcription of genes related to the development and maintenance of E. fetida's muscles, leading to synergistic toxicity. These findings provide new insights into the environmental risks of organophosphorus flame retardants, nanoparticles, and their co-exposure., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Silica nanoparticles (NPs) are widely used in various industrial and biomedical applications. Little is known about the cellular uptake of co-exposed silica particles, as can be expected in our daily life. In addition, an inflamed microenvironment might affect a NP's uptake and a cell's physiological response. Herein, prestimulated mouse J774A.1 macrophages with bacterial lipopolysaccharide were post-exposed to micron- and nanosized silica particles, either alone or together, i.e., simultaneously or sequentially, for different time points. The results indicated a morphological change and increased expression of tumor necrosis factor alpha in lipopolysaccharide prestimulated cells, suggesting a M1-polarization phenotype. Confocal laser scanning microscopy revealed the intracellular accumulation and uptake of both particle types for all exposure conditions. A flow cytometry analysis showed an increased particle uptake in lipopolysaccharide prestimulated macrophages. However, no differences were observed in particle uptakes between single- and co-exposure conditions. We did not observe any colocalization between the two silica (SiO 2 ) particles. However, there was a positive colocalization between lysosomes and nanosized silica but only a few colocalized events with micro-sized silica particles. This suggests differential intracellular localizations of silica particles in macrophages and a possible activation of distinct endocytic pathways. The results demonstrate that the cellular uptake of NPs is modulated in inflamed macrophages but not in the presence of micron-sized particles.

Widespread application of titanium dioxide nanoparticles (nTiO 2 ) and ubiquitous cadmium (Cd) pollution may increase their chance of co-existence in the natural environment. Toxicological information on co-exposure of nTiO 2 and Cd in mammalian models is largely lacking. Hence, we studied the combined effects of nTiO 2 and Cd in human liver (HepG2) and breast cancer (MCF-7) cells. We observed that nTiO 2 did not produce toxicity to HepG2 and MCF-7 cells. However, moderate concentration of Cd exposure caused cytotoxicity to both cells. Interestingly, non-cytotoxic concentration of nTiO 2 effectively enhanced the oxidative stress response of Cd indicated by pro-oxidants generation (reactive oxygen species, hydrogen peroxide, and lipid peroxidation) and antioxidants depletion (glutathione level and glutathione reductase, superoxide dismutase, and catalase enzymes). Moreover, nTiO 2 potentiated the Cd-induced apoptosis in both cells suggested by altered expression of p53, bax, and bcl-2 genes along with low mitochondrial membrane potential. Cellular uptake results demonstrated that nTiO 2 facilitates the internalization of Cd into the cells. Overall, this study demonstrated that non-cytotoxic concentration of nTiO 2 enhanced the toxicological potential of Cd in human cells. Therefore, more attention should be paid on the combine effects of nTiO 2 and Cd on human health.

The size effect on the cellular uptake of nanoparticles (NPs) has been extensively studied, but it is still not well understood. Herein, a reductionist approach is used to minimize all influencing factors except the particle size, and co-exposure of different-sized silica nanoparticles (SNPs) is adopted instead of the common single exposure. SNPs are found being internalized by Hela cells in serum-free medium mainly via clathrin-dependent endocytosis, thus simplifying the data analysis for reliable attribution to size effects. Remarkably, even though at conditions that the size effects seem very small or even undetectable in the common single exposure experiments, the co-exposure experiments reveal significant size effects due to an unexpected interplay between two different-sized SNPs. Namely, the bigger SNPs significantly promote the cellular uptake of the smaller ones, while the smaller SNPs inhibit the internalization of the bigger ones, with a total uptake increase of the particle number of SNPs in the cells. This strong interplay between different-sized NPs might unavoidably exist within most "single-sized" NP products, whose sizes actually distribute in certain ranges, thus urging reconsideration of the size effect on the cellular uptake of NPs, for the benefits of both bioapplications and safety assessment of nanomaterials., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Wide application of TiO 2 nanoparticles (nTiO 2 ) and ubiquitous lead (Pb) pollution in natural environment enhance the chance of co-exposure of humans to Pb and nTiO 2 . We investigated the effects of nTiO 2 on Pb-induced toxicity in human lung epithelial (A549) cells. Results showed that nTiO 2 was not toxic to A549 cells. Conversely, Pb-induced cytotoxicity and oxidative stress in A549 cells were evidenced by cell viability reduction, cell membrane damage, reactive oxygen species generation and depletion of antioxidants. The Pb was also found to alter the regulation of apoptotic genes and cell cycle. Interestingly, in co-exposure group (nTiO 2  + Pb), nTiO 2 effectively attenuated the cytotoxicity, oxidative stress and apoptotic responses of Pb in A549 cells. Cellular uptake experiments demonstrated that nTiO 2 increased the bioaccumulation of Pb in cells. However, due to strong adsorption of Pb on nTiO 2 , free Pb ions were not available even inside the cells. Hence, nTiO 2 significantly prevented the bioavailability and toxicity of Pb in A549 cells. This is the first report providing insight into understanding the mechanism of nTiO 2 mediated prevention against Pb-induced toxicity in human cells. This study warranted further research on co-exposure effects of nTiO 2 and Pb at in vivo mammalian models., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Humans are potentially exposed to multiple nanoparticles kinds through nanotechnology-based consumer products. There is insufficient data on the in vivo toxicity of nanotechnology products, as well as no data on the possible toxicity, including genotoxicity and reproductive toxicity of co-exposure to different kind of nanoparticles. In this work, solid lipid nanoparticles (SLNs) and superparamagnetic iron oxide nanoparticles (SPIONs) were selected for evaluation of a hypothetical condition of in vivo co-exposure. Genotoxicity of SPIONs and SLNs was performed separately and in 1:1 mixture in mice. Bone marrow micronucleus assay, sperm morphology test, and sperm count were carried out. Also, the serum ALT and AST activities; and hematological parameters of the treated mice were analyzed. The results showed a significant increase (p < 0.05) in micronucleated polychromatic erythrocytes (MNPCE) and nuclear abnormalities (NA) in SPIONs, SLNs and their mixture treated mice. The mixture induced the highest frequency of MNPCE and NA. A similar result was observed in the sperm morphology test, with the mixture inducing the highest sperm abnormalities, followed by SLNs and the least by SPIONs. Significant alteration to RDW, MCHC, MCV, GRAN, and platelets, as well as increased activities of serum AST were observed in the mice treated with a mixture of the two kinds of nanoparticles. Calculation of interaction factor showed a possible synergistic effect between SPIONs and SLNs in MNPCE, NA and sperm morphology studied. Even as a hypothetical scenario of co-exposure to SLNs and SPIONs, this study showed, for the first time, that co-exposure to SPIONs and SLNs is more genotoxic to somatic and germ cells than their individual exposure., (Copyright © 2019. Published by Elsevier B.V.)

It was hypothesized that interactions between emerging contaminants such as decabromodiphenyl ether (BDE-209) and nanoparticles (NPs) such as nano-SiO 2 (nSiO 2 ), can affect contaminant transport in the aquatic environment and its ecotoxicity. This study assessed the influence of nSiO 2 on the uptake of BDE-209 by zebrafish embryo. The distribution of BDE-209 and nSiO 2 on the external chorion and the internal embryo mass (i.e., dechorionated embryo) was measured. For single exposure of nSiO 2 to zebrafish embryo, separately, results showed that nSiO 2 accumulation on the chorion surface was higher than that in the dechorionated embryo. The nSiO 2 accumulation on the chorion surface was 129-200 mg-nSiO 2 /g-chorion at 48 h post fertilization, hpf, of exposure time, whereas the equilibrium adsorption of nSiO 2 on the dechorionated embryo was ca. 0.42-0.54 mg-nSiO 2 /g-embryo at 6 hpf. Results showed that the formation of nSiO 2 -BDE-209 associates promoted both extracellular and intracellular uptake of BDE-209 by zebrafish embryo, thereby increasing the bioconcentration of BDE-209 on the chorion surface and in embryo. The results also revealed that the accumulation of BDE-209 on the chorion was remarkably greater than that on the dechorionated embryo at 48 hpf. The uptake of BDE-209 was 17.2 ± 0.45 mg/g-chorion (or 86 ng-BDE-209/chorionated embryo) and 0.37 ± 0.01 mg/g-embryo (or 18.6 ng-BDE-209/dechorionated embryo), respectively, when co-exposure of zebrafish embryos to BDE-209 and nSiO 2 . Results from the SEM and EDS analysis revealed that nSiO 2 already passed through the chorion and adhered to the embryo surface/mass., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In aquatic environment, the presence of nanoparticles (NPs) has been reported to modify the bioavailability and toxicity of the organic toxicants. Nevertheless, the combined toxicity of NPs and the pesticides that were used world-widely still remains unclear. Cypermethrin (CYP), a synthetic pyrethroid insecticide, is commonly used for controlling agricultural and indoor pests. Therefore, the effects of titanium dioxide NPs (nTiO 2 ) on CYP bioconcentration and its effects on the neuronal development in zebrafish were investigated in our study. Zebrafish embryos (2- hour-post-fertilization, hpf) were exposed to CYP (0, 0.4, 2 and 10 μg/L) alone or co-exposed with nTiO 2 (1 mg/L) until 120-hpf. nTiO 2 is taken up by zebrafish larvae and also it can adsorb CYP. The zebrafish body burdens of CYP was observed and CYP uptake was increased by nTiO 2 , indicating that the nTiO 2 could accelerate the bioaccumulation of CYP in larvae. Co-exposure of nTiO 2 and CYP induced the generation of reactive oxygen species. Exposure to CYP alone significantly decreased the mRNA expression of genes, including glial fibrillary acidic protein (gfap), α1-tubulin, myelin basic protein (mbp) and growth associated protein (gap-43). Besides, reductions of serotonin, dopamine and GABA concentrations were observed in zebrafish and the larval locomotion was significantly decreased in response to the lower level of the neurotransmitters. Moreover, co-exposure of nTiO 2 and CYP caused further significantly decreased in the locomotion activity, and enhanced the down-regulation of the mRNA expression of specific genes and the neurotransmitters levels. The results demonstrated that nTiO 2 increased CYP accumulation and enhanced CYP-induced developmental neurotoxicity in zebrafish., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Titanium dioxide nanoparticles (TiO 2 NPs) are the most risk assessed nanoparticles in the aquatic environment due to their increased usage in the various sectors from electronics to consumer products. The natural aquatic system also comprises of numerous toxicants like antibiotics, whose impact on the toxicity of nanoparticles are less assessed. Hence, it is essential to determine the effect of other toxicants on the TiO 2 NP toxicity. In the current study, the impact of antibiotic (tetracycline, TC) on the toxic effect of TiO 2 NPs was studied on a freshwater alga, Scenedesmus obliquus. The median effective concentrations (EC 50 ) of TiO 2 NPs and TC were noted to be 136.88±2.30μM and 0.63±0.02μM, respectively. Based on the EC 50 obtained, three different concentrations of TC, such as 0.34, 0.68, and 1.36μM have been selected to evaluate their effect on the toxicity of 18.75, 37.5, and 75μM of TiO 2 NPs. Existence of TC provoked the growth inhibition of TiO 2 NPs at their lower concentrations. In contrast, a reduction in the growth inhibition was noted as the concentrations of TC and TiO 2 NPs were increased. Abbott modeling confirmed the additive and antagonistic effects noted. The stability profile of TiO 2 NPs elucidated the aggregation of NPs with an increase in time. Even though a similar trend has been followed for TiO 2 NPs+TC, a significant difference in the aggregation has not been observed in most cases when compared with TiO 2 NPs alone. The presence of TC lowered the Ti uptake by the algal cells, which portrayed the dominance of TC in the toxic effect of TiO 2 NPs to be either additive or antagonistic. The SEM images of the algal cells upon exposure to TiO 2 NPs, TC, and their mixture elucidated the aggregation of algal cells, cellular deformations like compromised cell membrane, and vacuole formation, etc. In addition, the release of algal exudates was also noticed as a protective layer over the cells to counteract the stress. EPS secretion in response to TiO 2 NPs along with TC is found to be in corroboration with the toxicity patterns observed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Both ultrafine particles (UFP) and polycyclic aromatic hydrocarbons (PAHs) are widely present in the environment, thus increasing their chances of exposure to human in the daily life. However, the study on the combined toxicity of UFP and PAHs on respiratory system is still limited. In this study, we examined the potential interactive effects of silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P) in bronchial epithelial cells (BEAS-2B). Cells were exposed to SiNPs and B[a]P alone or in combination for 24 h. Co-exposure to SiNPs and B[a]P enhanced the malondialdehyde (MDA) contents and reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities significantly, while the reactive oxygen species (ROS) generation had a slight increase in the exposed groups compared to the control but not statistically significant. Cell cycle arrest induced by the co-exposure showed a significant percentage increase in G2/M phase cells and a decrease in G0/G1 phase cells. In addition, there was a significant increase in BEAS-2B cells multinucleation as well as DNA damage. Cellular apoptosis was markedly increased even at the low-level co-exposure. Our results suggest that co-exposure to SiNPs and B[a]P exerts synergistic and additive cytotoxic and genotoxic effects.

Given the severe situation of world-wide particulate matter air pollution, it is urgent to explore the combined effects of particulate matter components on cardiovascular system. Using zebrafish model, this study was aimed to determine whether the low level co-exposure to silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P) had a pronounced cardiovascular toxicity than the single exposure to either SiNPs or B[a]P alone. The FTIR and TGA analysis showed that the co-exposure system possessed of high absorption and thermal stability. Embryos exposed to SiNPs or B[a]P alone did not show cardiac toxicity phenotype at the NOAEL level. However, embryos co-exposed to SiNPs and B[a]P exhibited pericardial edema and bradycardia. While ROS generation remained unaffected, the co-exposure induced significant neutrophil-mediated inflammation and caused erythrocyte aggregation in caudal vein of embryos. Microarray analysis and STC analysis were performed to screen the cardiovascular-related differential expression genes and the expression trend of genes in each group. The co-exposure of SiNPs and B[a]P significantly enhanced the expression of proinflammatory and procoagulant genes. Moreover, the co-exposure markedly increased the phosphorylated AP-1/c-Jun and induced TF expression, but not NF-κB p65. This study for the first time demonstrated the inflammatory response and blood hypercoagulable state were triggered by the combination of SiNPs and B[a]P at low level exposure., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

ZnO nanoparticles (ZnONPs) and carbon nanotubes (CNTs) are frequently used nanoparticles with unique features. Aquatic organisms are exposed to a combination of contaminants in natural water systems, so the combination effect of two or more nanomaterials has caused much concern. In this study, the toxicity to the liver of common carp was explored under four weeks of exposure to single ZnONPs or in combination with multi-walled CNTs (MWCNTs). The results demonstrated that ZnONPs induced pathological changes and apoptosis in the liver. In combination, decreased pathological changes were observed in the LSC-ZnONPs group (50 mg L-1 ZnONPs and 0.25 mg L-1 MWCNTs) at the microscopic level and ultrastructural level, and increased pathological changes in the HSC-ZnONPs group (50 mg L-1 ZnONPs and 2.5 mg L-1 MWCNTs). A 52% reduction in the percentage of TUNEL-positive nuclei in the LSC-ZnONPs group and a 33% increase in the HSC-ZnONPs group were observed compared to the ZnONPs group. The mRNA expression of apoptosis-related genes, including caspase3, BAX, and XBP1, were significantly up-regulated in the exposure groups, confirming the occurrence of apoptosis. Significantly decreased caspase 3 and BAX mRNA levels in the co-exposure groups were detected compared to the ZnONPs group. Nevertheless, the XBP1 mRNA level was significantly upregulated in the LSC-ZnONPs group, but downregulated in the HSC-ZnONPs group, indicating multiple signal pathways involved in the apoptosis. In conclusion, a low concentration of MWCNTs (0.25 mg L-1) decreased the toxic effect of ZnONPs on common carp, but a high concentration of MWCNTs (2.5 mg L-1) enhanced it. This study will contribute to developing future risk assessment and management strategies for nanomaterials. [ABSTRACT FROM AUTHOR]

The co-occurrence of heavy metals and microplastics (MPs) is an emerging issue that has attracted considerable attention. However, the interaction of nickel oxide nanoparticle (nano-NiO) combined with MPs in soil was poorly researched. Here, experiments were conducted to study the influence of nano-NiO (200 mg/kg) and polyethylene (PE) MPs with different concentrations (0.1, 1, and 10%) and sizes (13, 50, and 500 µm) on earthworms for 28 days. Compared to control, the damage was induced by PE and nano-NiO, which was evaluated by biomarker Integrated Biomarker Response index: version 2 (IBRv2) based on six biomarkers including SOD, POD, CAT, MDA, AChE, Na+/K+-ATPase and cellulase. The majority of the chosen biomarkers showed significant but complicated responses with increasing contaminant concentrations after 28 days of exposure. Moreover, the joint effect was assessed as antagonism by the effect addition index (EAI). Overall, this work expands our understanding of the combined toxicity of PE and nano-NiO in soil ecosystems. [ABSTRACT FROM AUTHOR]

The effects of combined exposure to microplastics and contaminants are still not completely understood. To fill this gap, we assessed the effects of polyethylene terephthalate microplastic fibers (100 mg/L; 360 µm average length) on the toxicity of silver nanoparticles (AgNPs; 32 nm) and silver nitrate (AgNO3; 0.1–10 µg Ag/L) to Daphnia magna. Acute immobilization (median effect concentration [EC50]) and cellular energy allocation (CEA; ratio between available energy and energy consumption) were determined in neonates (<24 h old) and juveniles (7 d old), respectively. The 48‐h EC50 for AgNP and AgNO3 (2.6 and 0.67 µg Ag/L, respectively) was not affected by the presence of microplastic fibers (2.2 and 0.85 µg Ag/L, respectively). No decrease in the available energy was observed: lipid, carbohydrate, and protein contents were unaffected. However, a significant increase in energy consumption was observed in animals exposed to AgNO3 (250% compared with control) and to the combination of microplastic fibers with AgNP (170%) and AgNO3 (260%). The exposure to microplastic fibers alone or in combination with both Ag forms decreased the CEA (values were 55–75% of control values). Our results show that after short‐term exposure (48 h), microplastic fibers increased Ag toxicity at a subcellular level (i.e., CEA), but not at the individual level (i.e., immobilization). These results highlight the importance of combining different levels of biological organization to fully assess the ecotoxicological effects of plastics in association with environmental contaminants. Environ Toxicol Chem 2022;41:896–904. © 2021 SETAC [ABSTRACT FROM AUTHOR]

Increased production and use of different types of nanoparticles (NPs) in the last decades has led to increased environmental release of these NPs with potential detrimental effects on both the environment and public health. Information is scarce in the literature on the cytotoxic effect of co-exposure to many NPs as this concern is relatively recent. Thus, in this study, we hypothesized scenarios of cell's co-exposure to two kinds of NPs, solid lipid nanoparticles (SLNs) and superparamagnetic iron oxide nanoparticles (SPIONs), to assess the potential cytotoxicity of exposure to NPs combination. Cytotoxicity of SPIONs, SLNs, and their 1:1 mixture (MIX) in six tumor and six non-tumor cell lines was investigated. The mechanisms underlining the induced cytotoxicity were studied through cell cycle analysis, detection of reactive oxygen species (ROS), and alterations in mitochondrial membrane potential (ΔΨM). Double staining with acridine orange and ethidium bromide was also used to confirm cell morphology alterations. The results showed that SPIONs induced low cytotoxicity compared to SLNs. However, the mixture of SPIONs and SLNs showed synergistic, antagonistic, and additive effects based on distinct tests such as viability assay, ROS generation, ΔΨM, and DNA damage, depending on the cell line. Apoptosis triggered by ROS and disturbances in ΔΨM are the most probable related mechanisms of action. As was postulated, there is possible cytotoxic interaction between the two kinds of NPs. [ABSTRACT FROM AUTHOR]

In recent years, carbon nanotubes (CNTs) have gained tremendous attention due to their widespread application. Previous research indicated that carbon nanomaterials can affect the toxicity of some pollutants. In this study, we investigated the influence of multi-walled CNTs (MWCNTs) on the toxicity of ZnO nanoparticles (ZnONPs) in the intestine of common carp (Cyprinus carpio). After four-week exposure, histopathological observation and TUNEL assay showed concentration ratio-dependent intestinal lesions and apoptosis, with the most severe in the HSC-ZnONPs group (50 mg L−1 ZnONPs and 2.5 mg L−1 MWCNTs), less severe in the ZnONPs group (50 mg L−1 ZnONPs) and the least in the LSC-ZnONPs group (50 mg L−1 ZnONPs and 0.25 mg L−1 MWCNTs). Furthermore, ICP-OES indicated that intercellular zinc accumulation was significantly decreased by the presence of the MWCNTs, which suggested the varied contribution of ZnONPs to intestine injury in different groups. Moreover, 16 s rDNA sequencing revealed that ZnONPs alone and in combination with MWCNTs significantly altered the microbial community diversity and composition of the gut microbiota compared with controls. In addition, the predominant phylum, class, order, family, and genus were significantly different among these groups. In conclusion, the influence of MWCNTs on the toxicity of ZnONPs was related to the concentration and concentration ratio of the mixture. [Display omitted] • ZnONPs exposure induced histological alterations and apoptosis in the intestine. • Low level of MWCNTs have an antagonism effect on toxicity of ZnONPs to common carp. • High level of MWCNTs have a synergy effect on toxicity of ZnONPs to common carp. • MWCNTs significantly decreased ZnONPs accumulation in the intestine after four weeks exposure. • Single ZnONPs exposure or co-exposure with MWCNTs and ZnONPs alterated gut microbiota. [ABSTRACT FROM AUTHOR]

Little is known about the simultaneous uptake of different engineered nanoparticle types, as it can be expected in our daily life. In order to test such co-exposure effects, murine macrophages (J774A.1 cell line) were incubated with gold (AuNPs) and iron oxide nanoparticles (FeOxNPs) either alone or combined. Environmental scanning electron microscopy revealed that single NPs of both types bound within minutes on the cell surface but with a distinctive difference between FeOxNPs and AuNPs. Uptake analysis studies based on laser scanning microscopy, transmission electron microscopy, and inductively coupled plasma optical emission spectrometry revealed intracellular appearance of both NP types in all exposure scenarios and a time-dependent increase. This increase was higher for both AuNPs and FeOxNPs during co-exposure. Cells treated with endocytotic inhibitors recovered after co-exposure, which additionally hinted that two uptake mechanisms are involved. Cross-talk between uptake pathways is relevant for toxicological studies: Co-exposure acts as an uptake accelerant. If the goal is to maximize the cellular uptake, e.g., for the delivery of pharmaceutical agents, this can be beneficial. However, co-exposure should also be taken into account in the case of risk assessment of occupational settings. The demonstration of co-exposure-invoked pathway interactions reveals that synergetic nanoparticle effects, either positive or negative, must be considered for nanotechnology and nanomedicine in particular to develop to its full potential.

Abstract A huge variety of organic microcontaminants are presently detected in freshwater ecosystems, but there is still a lack of knowledge about their interactions, either with living organisms or with other contaminants. Actually, carbon nanomaterials like fullerenes (C 60) can act as carriers of organic microcontaminants, but their relevance in processes like bioaccumulation and biotransformation of organic microcontaminants by organisms is unknown. In this study, mesocosm experiments were used to assess the bioaccumulation and biotransformation of three organic microcontaminants (venlafaxine, diuron and triclosan) in river biofilms, and to understand how much the concomitant presence of C 60 at environmental relevant concentrations could impact these processes. Results indicated that venlafaxine exhibited the highest bioaccumulation (13% of the initial concentration of venlafaxine in water), while biotransformation was more evident for triclosan (5% of the initial concentration of triclosan in water). Furthermore, biotransformation products such as methyl-triclosan were also present in the biofilm, with levels up to 42% of the concentration of accumulated triclosan. The presence of C 60 did not involve relevant changes in the bioaccumulation and biotransformation of microcontaminants in biofilms, which showed similar patterns. Nevertheless, the study shows that a detailed evaluation of the partition of the organic microcontaminants and their transformation products in freshwater systems are important to better understand the impact of the co-existence of others microcontaminants, like carbon nanomaterials, in their possible routes of bioaccumulation and biotransformation. Highlights • River biofilms are a good model to assess the effect of pollutants at a community level. • Impact of C 60 in bioaccumulation and biotransformation of VLF, DIU and TCS was assessed. • Venlafaxine showed the highest potential to accumulate in river biofilms. • Biotransformation was more evident for triclosan. • Presence of C 60 did not alter bioaccumulation and biotransformation of OMC. [ABSTRACT FROM AUTHOR]

The exposure of habitats to the herbicide diuron, one of the most effective and highly used antifouling agents worldwide, leads to serious environmental toxicity, mainly for marine invertebrates. Moreover, nanoparticles (NPs) act as carriers of organic pollutants in marine ecosystems, thereby influencing their bioaccumulation and toxicity in exposed organisms. This study aimed to investigate the individual and combined toxicity of diuron and two NPs (ZnO NPs and TiO _2 NPs) at sub-lethal doses on the marine mussel Mytilus galloprovincialis .

The potential entry of nanomaterials into the water ecosystems increased following their increasing use. In addition to the direct effects of nanomaterials on aquatic organisms, they also affect the toxicity of other pollutants on aquatic organisms. This study assessed the presence of titanium dioxide nanoparticles (nTiO2) in water on acute toxicity of silver nanoparticles (AgNPs) on zebra fish (Danio rerio). After preliminary tests, we simultaneously exposed the fish for 96 h to different concentrations of each of these nanoparticles so that, in each of the treatments, the concentrations of nTiO2 were ten times the concentration of AgNPs. The results showed that the presence of nTiO2 in water decreased the acute toxicity of AgNPs to more than three times in the zebra fish. The median lethal concentrations of AgNPs increased from 0.014 (in the absence of nTiO2) to 0.044 (in the presence of nTiO2). The reduction in toxicity of AgNps in the presence of TiO2 nanoparticles in this study possibly happened due to decreased bioavailability of AgNPs by binding to the nTiO2 and its deposition in water media.

Technetium-99 (Tc) was used as an isotope tracer to study the biodistribution of oxidized multi-walled carbon nanotubes (oMWCNTs) and /or graphene oxide nanoplatelets (GONP) after intravenous administration (i.v.). The authors also investigated the histological impact of non-radiolabeled oMWCNT or GONP as they passed through systemic circulation and their excretion pathways in comparison to co-exposure groups of both (oMWCNTs and GONP). Results indicated that oMWCNTs were mainly excreted through feces rather than urine. From the blood, oMWCNTs first entered the stomach, then intestines via chyme, and were finally excreted in feces. GONP also followed this pathway, but could also be excreted through urine when co-exposed with oMWCNTs. In summary, the biodistribution patterns and excretion rates of the nanomaterials in vivo depended on their composition and chemical modifications. A new mechanism is proposed to explain how chemical modification groups affect the behavior of nanomaterials in vivo. The behavior and fate of GONP depended strongly on oMWCNTs in mice in vivo, but the GONP did not affect deeply biodistribution and excretion pattern of oMWCNTs in co-exposure. [ABSTRACT FROM AUTHOR]

The co-existence of organic pollutants and nanoparticles in the environment may lead to combined biological effects. The joint toxicity of pollutants and nanoparticles has been receiving increasing attention from researchers, but few studies have focused on soil biota due to the complexity of soil matrices. This study investigated the effects of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) at 0, 5, and 25 mg/kg and nanoparticulate TiO 2 (nTiO 2) at 0, 500, and 2500 mg/kg in a 3 × 3 factorial arrangement of treatments for 28 days (d) on Eisenia fetida (earthworm). Compared with the control group (the 0 mg/kg TDCIPP + 0 mg/kg nTiO 2 treatment), all other single (TDCIPP or nTiO 2) and binary (TDCIPP + nTiO 2) treatments except for the single 500 mg/kg nTiO 2 treatment significantly reduced the weight gain rate of E. fetida. The binary treatments had significantly greater such effect than their corresponding single treatments, exhibiting a synergistic toxicity between TDCIPP and nTiO2 on the growth of E. fetida. Since TDCIPP and nTiO 2 had no significant effect on their concentrations in the soil or in E. fetida during binary exposure, the synergistic toxicity could be a result of the superimposition of the toxicity pathways of TDCIPP and nTiO 2. Transcriptomic analysis of E. fetida intestinal region revealed that exposure to 25 mg/kg TDCIPP or 2500 mg/kg nTiO 2 affected nutrient-related or cell apoptosis and DNA damage related genes, respectively; their co-exposure greatly inhibited genes related to nutrient digestion and absorption, while causing abnormal transcription of genes related to the development and maintenance of E. fetida 's muscles, leading to synergistic toxicity. These findings provide new insights into the environmental risks of organophosphorus flame retardants, nanoparticles, and their co-exposure. ga1 • Co-exposure to TDCIPP and nTiO 2 synergistically inhibited earthworm growth. • The two analytes did not alter the concentration of each other in soil or earthworms. • TDCIPP inhibited expression of genes related to nutrient digestion and absorption. • nTiO 2 affected cell apoptosis and DNA damage related genes. • The synergistic effect could be caused by the superimposition of toxic pathways. [ABSTRACT FROM AUTHOR]