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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (29 March 2022) | Viewed by 43285

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Prof. Dr. Ying-Jan Wang

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Department of Environmental and Occupational Health, National Cheng Kung University | NCKU, Tainan, Taiwan
Interests: nanotoxicology; environmental toxicology; ecotoxicology; nanosafety; alternative testing methods; regulatory toxicology; adverse outcome pathways
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

With the rapid development of nanotechnology, nanomaterials have been widely applied in many industrial sectors, including medicine, consumer products, and electronics. While such technology has brought benefits and convenience into our daily lives, it may also potentially threaten human health and environmental safety. However, knowledge of the adverse health effects of these nanomaterials is still very limited. In this Special Issue, we hope to bring together significant research that advances the knowledge base on the adverse effects of nanomaterials, as well as the regulatory aspects of nanomaterials. In vitro, in vivo, and human studies that contribute to our understanding of human health and environmental impacts are welcome. Of particular interest will be papers that describe studies where modes of action and adverse outcome pathways could be evaluated during nanomaterials intoxication. In addition, alternative testing methods using zebrafish, drosophila, and C. Elegant are also welcome.

This Special Issue “Nanotoxicology and Nanosafety 3.0” will focus on the publication of original manuscripts and critical reviews to advance our understanding of the possible health effects of nanomaterials, as well as the means to protect workers and consumers exposed to them.

Prof. Dr. Ying-Jan Wang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular and cellular mechanisms of nanomaterials intoxication
regulatory toxicology
nanotoxicology
nanosafety
alternative testing methods
ecotoxicity of nanomaterials
adverse effects of nanomaterials in zebrafish
adverse effects of nanomaterials in drosophila
adverse effects of nanomaterials in C. Elegant
risk assessment of engineered nanomaterials
risk management of engineered nanomaterials
biological monitoring of engineered nanomaterials
environmental monitoring of engineered nanomaterials

Related Special Issue

Nanotoxicology and Nanosafety 2.0 in International Journal of Molecular Sciences (16 articles)

Published Papers (12 papers)

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Editorial

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3 pages, 180 KiB

Open AccessEditorial

Mechanisms of Nanotoxicology and the Important Role of Alternative Testing Strategies

by Yuan-Hua Wu, Sheng-Yow Ho, Bour-Jr Wang and Ying-Jan Wang

Int. J. Mol. Sci. 2022, 23(15), 8204; https://doi.org/10.3390/ijms23158204 - 26 Jul 2022

Viewed by 1040

Abstract

Recently, rapid advances in nanotechnology have provided a lot of opportunities for the mass production of engineered nanomaterials of various types of chemicals, including metals and nonmetals, promoting the development of a new generation of industrial and commercial products and the field of [...] Read more.

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

Research

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15 pages, 3560 KiB

Open AccessArticle

Nanoplastics and Arsenic Co-Exposures Exacerbate Oncogenic Biomarkers under an In Vitro Long-Term Exposure Scenario

by Irene Barguilla, Josefa Domenech, Laura Rubio, Ricard Marcos and Alba Hernández

Int. J. Mol. Sci. 2022, 23(6), 2958; https://doi.org/10.3390/ijms23062958 - 09 Mar 2022

Cited by 19 | Viewed by 2621

Abstract

The increasing accumulation of plastic waste and the widespread presence of its derivatives, micro- and nanoplastics (MNPLs), call for an urgent evaluation of their potential health risks. In the environment, MNPLs coexist with other known hazardous contaminants and, thus, an interesting question arises as to whether MNPLs can act as carriers of such pollutants, modulating their uptake and their harmful effects. In this context, we have examined the interaction and joint effects of two relevant water contaminants: arsenic and polystyrene nanoplastics (PSNPLs), the latter being a model of nanoplastics. Since both agents are persistent pollutants, their potential effects have been evaluated under a chronic exposure scenario and measuring different effect biomarkers involved in the cell transformation process. Mouse embryonic fibroblasts deficient for oxidative DNA damage repair mechanisms, and showing a cell transformation status, were used as a sensitive cell model. Such cells were exposed to PSNPLs, arsenic, and a combination PSNPLs/arsenic for 12 weeks. Interestingly, a physical interaction between both pollutants was demonstrated by using TEM/EDX methodologies. Results also indicate that the continuous co-exposure enhances the DNA damage and the aggressive features of the initially transformed phenotype. Remarkably, co-exposed cells present a higher proportion of spindle-like cells within the population, an increased capacity to grow independently of anchorage, as well as enhanced migrating and invading potential when compared to cells exposed to arsenic or PSNPLs alone. This study highlights the need for further studies exploring the long-term effects of contaminants of emerging concern, such as MNPLs, and the importance of considering the behavior of mixtures as part of the hazard and human risk assessment approaches. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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17 pages, 13214 KiB

Open AccessArticle

A Transcriptomic Analysis of T98G Human Glioblastoma Cells after Exposure to Cadmium-Selenium Quantum Dots Mainly Reveals Alterations in Neuroinflammation Processes and Hypothalamus Regulation

by Encarnación Fuster, Héctor Candela, Jorge Estévez, Eugenio Vilanova and Miguel A. Sogorb

Int. J. Mol. Sci. 2022, 23(4), 2267; https://doi.org/10.3390/ijms23042267 - 18 Feb 2022

Cited by 6 | Viewed by 1642

Abstract

Quantum dots are nanoparticles with very promising biomedical applications. However, before these applications can be authorized, a complete toxicological assessment of quantum dots toxicity is needed. This work studied the effects of cadmium-selenium quantum dots on the transcriptome of T98G human glioblastoma cells. It was found that 72-h exposure to 40 µg/mL (a dose that reduces cell viability by less than 10%) alters the transcriptome of these cells in biological processes and molecular pathways, which address mainly neuroinflammation and hormonal control of hypothalamus via the gonadotropin-releasing hormone receptor. The biological significance of neuroinflammation alterations is still to be determined because, unlike studies performed with other nanomaterials, the expression of the genes encoding pro-inflammatory interleukins is down-regulated rather than up-regulated. The hormonal control alterations of the hypothalamus pose a new concern about a potential adverse effect of quantum dots on fertility. In any case, more studies are needed to clarify the biological relevance of these findings, and especially to assess the real risk of toxicity derived from quantum dots exposure appearing in physiologically relevant scenarios. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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18 pages, 4420 KiB

Open AccessArticle

Ovarian Accumulation of Nanoemulsions: Impact of Mice Age and Particle Size

by Eike Folker Busmann, Julia Kollan, Karsten Mäder and Henrike Lucas

Int. J. Mol. Sci. 2021, 22(15), 8283; https://doi.org/10.3390/ijms22158283 - 31 Jul 2021

Cited by 2 | Viewed by 3197

Abstract

Nanotechnology in the field of drug delivery comes with great benefits due to the unique physicochemical properties of newly developed nanocarriers. However, they may come as well with severe toxicological side effects because of unwanted accumulation in organs outside of their targeted site of actions. Several studies showed an unintended accumulation of various nanocarriers in female sex organs, especially in the ovaries. Some led to inflammation, fibrosis, or decreasing follicle numbers. However, none of these studies investigated ovarian accumulation in context to both reproductive aging and particle size. Besides the influences of particle size, the biodistribution profile may be altered as well by reproductive aging because of reduced capacities of the reticuloendothelial system (RES), changes in sex steroid hormone levels as well as altering ovarian stromal blood flow. This systematic investigation of the biodistribution of intravenously (i.v) injected nanoemulsions revealed significant dependencies on the two parameters particle size and age starting from juvenile prepubescent to senescent mice. Using fluorescent in vivo and ex vivo imaging, prepubescent mice showed nearly no accumulation of nanoemulsion in their uteri and ovaries, but high accumulations in the organs of the RES liver and spleen independently of the particle size. In fertile adult mice, the accumulation increased significantly in the ovaries with an increased particle size of the nanoemulsions by nearly doubling the portion of the average radiant efficiency (PARE) to ~10% of the total measured signal of all excised organs. With reproductive aging and hence loss of fertility in senescent mice, the accumulation decreased again to moderate levels, again independently of the particle size. In conclusion, the ovarian accumulation of these nanocarriers depended on both the age plus the particle size during maturity. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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15 pages, 4393 KiB

Open AccessArticle

Examination of Surfactant Protein D as a Biomarker for Evaluating Pulmonary Toxicity of Nanomaterials in Rat

by Taisuke Tomonaga, Hiroto Izumi, Yukiko Yoshiura, Chinatsu Nishida, Kazuhiro Yatera and Yasuo Morimoto

Int. J. Mol. Sci. 2021, 22(9), 4635; https://doi.org/10.3390/ijms22094635 - 28 Apr 2021

Cited by 5 | Viewed by 1866

Abstract

This work studies the relationship between lung inflammation caused by nanomaterials and surfactant protein D (SP-D) kinetics and investigates whether SP-D can be a biomarker of the pulmonary toxicity of nanomaterials. Nanomaterials of nickel oxide and cerium dioxide were classified as having high toxicity, nanomaterials of two types of titanium dioxides and zinc oxide were classified as having low toxicity, and rat biological samples obtained from 3 days to 6 months after intratracheal instillation of those nanomaterials and micron-particles of crystalline silica were used. There were different tendencies of increase between the high- and low-toxicity materials in the concentration of SP-D in bronchoalveolar-lavage fluid (BALF) and serum and in the expression of the SP-D gene in the lung tissue. An analysis of the receiver operating characteristics for the toxicity of the nanomaterials by SP-D in BALF and serum showed a high accuracy of discrimination from 1 week to 3 or 6 months after exposure. These data suggest that the differences in the expression of SP-D in BALF and serum depended on the level of lung inflammation caused by the nanomaterials and that SP-D can be biomarkers for evaluating the pulmonary toxicity of nanomaterials. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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15 pages, 1961 KiB

Open AccessArticle

Oxidative Properties of Polystyrene Nanoparticles with Different Diameters in Human Peripheral Blood Mononuclear Cells (In Vitro Study)

by Kinga Kik, Bożena Bukowska, Anita Krokosz and Paulina Sicińska

Int. J. Mol. Sci. 2021, 22(9), 4406; https://doi.org/10.3390/ijms22094406 - 23 Apr 2021

Cited by 18 | Viewed by 3016

Abstract

With the ongoing commercialization, human exposure to plastic nanoparticles will dramatically increase, and evaluation of their potential toxicity is essential. There is an ongoing discussion on the human health effects induced by plastic particles. For this reason, in our work, we assessed the effect of polystyrene nanoparticles (PS-NPs) of various diameters (29, 44 and 72 nm) on selected parameters of oxidative stress and the viability of human peripheral blood mononuclear cells (PBMCs) in the in vitro system. Cells were incubated with PS-NPs for 24 h in the concentration range of 0.001 to 100 µg/mL and then labeled: formation of reactive oxygen species (ROS) (including hydroxyl radical), protein and lipid oxidation and cell viability. We showed that PS-NPs disturbed the redox balance in PBMCs. They increased ROS levels and induced lipid and protein oxidation, and, finally, the tested nanoparticles induced a decrease in PBMCs viability. The earliest changes in the PBMCs were observed in cells incubated with the smallest PS-NPs, at a concentration of 0.01 μg/mL. A comparison of the action of the studied nanoparticles showed that PS-NPs (29 nm) exhibited a stronger oxidative potential in PBMCs. We concluded that the toxicity and oxidative properties of the PS-NPs examined depended to significant degree on their diameter. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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18 pages, 9635 KiB

Open AccessArticle

Modulation of Innate Immune Toxicity by Silver Nanoparticle Exposure and the Preventive Effects of Pterostilbene

by Rong-Jane Chen, Chiao-Ching Huang, Rosita Pranata, Yu-Hsuan Lee, Yu-Ying Chen, Yuan-Hua Wu and Ying-Jan Wang

Int. J. Mol. Sci. 2021, 22(5), 2536; https://doi.org/10.3390/ijms22052536 - 03 Mar 2021

Cited by 12 | Viewed by 2390

Abstract

Silver nanoparticles pose a potential risk to ecosystems and living organisms due to their widespread use in various fields and subsequent gradual release into the environment. Only a few studies have investigated the effects of silver nanoparticles (AgNPs) toxicity on immunological functions. Furthermore, these toxic effects have not been fully explored. Recent studies have indicated that zebrafish are considered a good alternative model for testing toxicity and for evaluating immunological toxicity. Therefore, the purpose of this study was to investigate the toxicity effects of AgNPs on innate immunity using a zebrafish model and to investigate whether the natural compound pterostilbene (PTE) could provide protection against AgNPs-induced immunotoxicity. Wild type and neutrophil- and macrophage-transgenic zebrafish lines were used in the experiments. The results indicated that the exposure to AgNPs induced toxic effects including death, malformation and the innate immune toxicity of zebrafish. In addition, AgNPs affect the number and function of neutrophils and macrophages. The expression of immune-related cytokines and chemokines was also affected. Notably, the addition of PTE could activate immune cells and promote their accumulation in injured areas in zebrafish, thereby reducing the damage caused by AgNPs. In conclusion, AgNPs may induce innate immune toxicity and PTE could ameliorate this toxicity. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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18 pages, 4058 KiB

Open AccessArticle

Impact of an Engineered Copper-Titanium Dioxide Nanocomposite and Parent Substrates on the Bacteria Viability, Antioxidant Enzymes and Fatty Acid Profiling

by Oliwia Metryka, Daniel Wasilkowski, Anna Nowak, Małgorzata Adamczyk-Habrajska and Agnieszka Mrozik

Int. J. Mol. Sci. 2020, 21(23), 9089; https://doi.org/10.3390/ijms21239089 - 29 Nov 2020

Cited by 4 | Viewed by 2578

Abstract

Due to the systematic increase in the production of nanomaterials (NMs) and their applications in many areas of life, issues associated with their toxicity are inevitable. In particular, the performance of heterogeneous NMs, such as nanocomposites (NCs), is unpredictable as they may inherit the properties of their individual components. Therefore, the purpose of this work was to assess the biological activity of newly synthesized Cu/TiO₂-NC and the parent nanoparticle substrates Cu-NPs and TiO₂-NPs on the bacterial viability, antioxidant potential and fatty acid composition of the reference Escherichia coli and Bacillus subtilis strains. Based on the toxicological parameters, it was found that B. subtilis was more sensitive to NMs than E. coli. Furthermore, Cu/TiO₂-NC and Cu-NPs had an opposite effect on both strains, while TiO₂-NPs had a comparable mode of action. Simultaneously, the tested strains exhibited varied responses of the antioxidant enzymes after exposure to the NMs, with Cu-NPs having the strongest impact on their activity. The most considerable alternations in the fatty acid profiles were found after the bacteria were exposed to Cu/TiO₂-NC and Cu-NPs. Microscopic images indicated distinct interactions of the NMs with the bacterial outer layers, especially in regard to B. subtilis. Cu/TiO₂-NC generally proved to have less distinctive antimicrobial properties on B. subtilis than E. coli compared to its parent components. Presumably, the biocidal effects of the tested NMs can be attributed to the induction of oxidative stress, the release of metal ions and specific electrochemical interactions with the bacterial cells. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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14 pages, 3948 KiB

Open AccessArticle

Alumina Ceramic Exacerbates the Inflammatory Disease by Activation of Macrophages and T Cells

by Seong-Min Lim, Juyoung Hwang, Hae-Bin Park, Chan Ho Park and Jun-O Jin

Int. J. Mol. Sci. 2020, 21(19), 7114; https://doi.org/10.3390/ijms21197114 - 26 Sep 2020

Cited by 2 | Viewed by 2125

Abstract

(1) Background: Aluminum oxide (Al₂O₃) ceramic is one of the materials used for artificial joints, and it has been known that their fine particles (FPs) are provided by the wear of the ceramic. Al₂O₃ FPs have been shown to induce macrophage activation in vitro; however, the inflammatory effect in vivo has not been studied. (2) Methods: We examined the in vivo effect of Al₂O₃ FPs on the innate and adaptive immune cells in the mice. (3) Results: Al₂O₃ FPs promoted the activation of spleen macrophages; however, conventional dendritic cells (cDCs), plasmacytoid DCs (pDCs), and natural killer (NK) cells were not activated. In addition, increases in the CD4 and CD8 T cells was induced in the spleens of the mice treated with Al₂O₃ FPs, which differentiated into interferon-gamma (IFN-γ)-producing helper T1 (Th1) and cytotoxic T1 (Tc1) cells. Finally, the injection of Al₂O₃ FPs exacerbated dextran sulfate sodium (DSS)-induced inflammation in the colon, mediated by activated and increased number of CD4 and CD8 T cells. (4) Conclusions: These data demonstrate that FPs of Al₂O₃ ceramic may contribute to the exacerbation of inflammatory diseases in the patients. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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21 pages, 2288 KiB

Open AccessArticle

Predicting In Vitro Neurotoxicity Induced by Nanoparticles Using Machine Learning

by Irini Furxhi and Finbarr Murphy

Int. J. Mol. Sci. 2020, 21(15), 5280; https://doi.org/10.3390/ijms21155280 - 25 Jul 2020

Cited by 25 | Viewed by 3629

Abstract

The practice of non-testing approaches in nanoparticles hazard assessment is necessary to identify and classify potential risks in a cost effective and timely manner. Machine learning techniques have been applied in the field of nanotoxicology with encouraging results. A neurotoxicity classification model for diverse nanoparticles is presented in this study. A data set created from multiple literature sources consisting of nanoparticles physicochemical properties, exposure conditions and in vitro characteristics is compiled to predict cell viability. Pre-processing techniques were applied such as normalization methods and two supervised instance methods, a synthetic minority over-sampling technique to address biased predictions and production of subsamples via bootstrapping. The classification model was developed using random forest and goodness-of-fit with additional robustness and predictability metrics were used to evaluate the performance. Information gain analysis identified the exposure dose and duration, toxicological assay, cell type, and zeta potential as the five most important attributes to predict neurotoxicity in vitro. This is the first tissue-specific machine learning tool for neurotoxicity prediction caused by nanoparticles in in vitro systems. The model performs better than non-tissue specific models. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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Review

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22 pages, 1466 KiB

Open AccessReview

Micro- and Nanosized Substances Cause Different Autophagy-Related Responses

by Yung-Li Wang, Cai-Mei Zheng, Yu-Hsuan Lee, Ya-Yun Cheng, Yuh-Feng Lin and Hui-Wen Chiu

Int. J. Mol. Sci. 2021, 22(9), 4787; https://doi.org/10.3390/ijms22094787 - 30 Apr 2021

Cited by 7 | Viewed by 3110

Abstract

With rapid industrialization, humans produce an increasing number of products. The composition of these products is usually decomposed. However, some substances are not easily broken down and gradually become environmental pollutants. In addition, these substances may cause bioaccumulation, since the substances can be fragmented into micro- and nanoparticles. These particles or their interactions with other toxic matter circulate in humans via the food chain or air. Whether these micro- and nanoparticles interfere with extracellular vesicles (EVs) due to their similar sizes is unclear. Micro- and nanoparticles (MSs and NSs) induce several cell responses and are engulfed by cells depending on their size, for example, particulate matter with a diameter ≤2.5 μm (PM2.5). Autophagy is a mechanism by which pathogens are destroyed in cells. Some artificial materials are not easily decomposed in organisms. How do these cells or tissues respond? In addition, autophagy operates through two pathways (increasing cell death or cell survival) in tumorigenesis. Many MSs and NSs have been found that induce autophagy in various cells and tissues. As a result, this review focuses on how these particles interfere with cells and tissues. Here, we review MSs, NSs, and PM2.5, which result in different autophagy-related responses in various tissues or cells. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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14 pages, 1067 KiB

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Current Strategies in Assessment of Nanotoxicity: Alternatives to In Vivo Animal Testing

by Hung-Jin Huang, Yu-Hsuan Lee, Yung-Ho Hsu, Chia-Te Liao, Yuh-Feng Lin and Hui-Wen Chiu

Int. J. Mol. Sci. 2021, 22(8), 4216; https://doi.org/10.3390/ijms22084216 - 19 Apr 2021

Cited by 46 | Viewed by 14494

Abstract

Millions of experimental animals are widely used in the assessment of toxicological or biological effects of manufactured nanomaterials in medical technology. However, the animal consciousness has increased and become an issue for debate in recent years. Currently, the principle of the 3Rs (i.e., reduction, refinement, and replacement) is applied to ensure the more ethical application of humane animal research. In order to avoid unethical procedures, the strategy of alternatives to animal testing has been employed to overcome the drawbacks of animal experiments. This article provides current alternative strategies to replace or reduce the use of experimental animals in the assessment of nanotoxicity. The currently available alternative methods include in vitro and in silico approaches, which can be used as cost-effective approaches to meet the principle of the 3Rs. These methods are regarded as non-animal approaches and have been implemented in many countries for scientific purposes. The in vitro experiments related to nanotoxicity assays involve cell culture testing and tissue engineering, while the in silico methods refer to prediction using molecular docking, molecular dynamics simulations, and quantitative structure–activity relationship (QSAR) modeling. The commonly used novel cell-based methods and computational approaches have the potential to help minimize the use of experimental animals for nanomaterial toxicity assessments. Full article

(This article belongs to the Special Issue Nanotoxicology and Nanosafety 3.0)

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