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      Hormesis Effects of Silver Nanoparticles at Non-Cytotoxic Doses to Human Hepatoma Cells

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          Abstract

          Silver nanoparticles (AgNPs) have attracted considerable attentions due to their unique properties and diverse applications. Although it has been reported that AgNPs have acute toxic effects on a variety of cultured mammalian cells and animal models, few studies have been conducted to evaluate the associated risk of AgNPs to human health at non-cytotoxic doses. In this paper, HepG2 cells were exposed to 10 nm and 100 nm AgNPs under non-cytotoxic conditions, and cell viability was assessed. At low doses, AgNPs displayed “hormesis” effects by accelerating cell proliferation. Further studies indicated that the activation states of MAPKs were differentially regulated in this process. Specifically, by increasing the expression of downstream genes, p38 MAPK played a central role in non-cytotoxic AgNP-induced hormesis. Moreover, the treatment of HepG2 cells with silver ions (Ag +) at the same dose levels induced distinct biological effects, suggesting that different intrinsic properties exist for AgNPs and Ag +.

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          Negligible particle-specific antibacterial activity of silver nanoparticles.

          Zong-ming Xiu, Qing-bo Zhang, Hema L Puppala … (2012)
          For nearly a decade, researchers have debated the mechanisms by which AgNPs exert toxicity to bacteria and other organisms. The most elusive question has been whether the AgNPs exert direct "particle-specific" effects beyond the known antimicrobial activity of released silver ions (Ag(+)). Here, we infer that Ag(+) is the definitive molecular toxicant. We rule out direct particle-specific biological effects by showing the lack of toxicity of AgNPs when synthesized and tested under strictly anaerobic conditions that preclude Ag(0) oxidation and Ag(+) release. Furthermore, we demonstrate that the toxicity of various AgNPs (PEG- or PVP- coated, of three different sizes each) accurately follows the dose-response pattern of E. coli exposed to Ag(+) (added as AgNO(3)). Surprisingly, E. coli survival was stimulated by relatively low (sublethal) concentration of all tested AgNPs and AgNO(3) (at 3-8 μg/L Ag(+), or 12-31% of the minimum lethal concentration (MLC)), suggesting a hormetic response that would be counterproductive to antimicrobial applications. Overall, this work suggests that AgNP morphological properties known to affect antimicrobial activity are indirect effectors that primarily influence Ag(+) release. Accordingly, antibacterial activity could be controlled (and environmental impacts could be mitigated) by modulating Ag(+) release, possibly through manipulation of oxygen availability, particle size, shape, and/or type of coating.
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            Unique cellular interaction of silver nanoparticles: size-dependent generation of reactive oxygen species.

            C. Carlson, S. Hussain, A M Schrand … (2008)
            The rapid advancement of nanotechnology has created a vast array of engineered nanomaterials (ENMs) which have unique physical (size, shape, crystallinity, surface charge) and chemical (surface coating, elemental composition and solubility) attributes. These physicochemical properties of ENMs can produce chemical conditions to induce a pro-oxidant environment in the cells, causing an imbalanced cellular energy system dependent on redox potential and thereby leading to adverse biological consequences, ranging from the initiation of inflammatory pathways through to cell death. The present study was designed to evaluate size-dependent cellular interactions of known biologically active silver nanoparticles (NPs, Ag-15 nm, Ag-30 nm, and Ag-55 nm). Alveolar macrophages provide the first defense and were studied for their potential role in initiating oxidative stress. Cell exposure produced morphologically abnormal sizes and adherence characteristics with significant NP uptake at high doses after 24 h. Toxicity evaluations using mitochondrial and cell membrane viability along with reactive oxygen species (ROS) were performed. After 24 h of exposure, viability metrics significantly decreased with increasing dose (10-75 microg/mL) of Ag-15 nm and Ag-30 nm NPs. A more than 10-fold increase of ROS levels in cells exposed to 50 microg/mL Ag-15 nm suggests that the cytotoxicity of Ag-15 nm is likely to be mediated through oxidative stress. In addition, activation of the release of traditional inflammatory mediators were examined by measuring levels of cytokines/chemokines, including tumor necrosis factor (TNF-alpha), macrophage inhibitory protein (MIP-2), and interleukin-6 (IL-6), released into the culture media. After 24 h of exposure to Ag-15 nm nanoparticles, a significant inflammatory response was observed by the release of TNF-alpha, MIP-2, and IL-1beta. However, there was no detectable level of IL-6 upon exposure to silver nanoparticles. In summary, a size-dependent toxicity was produced by silver nanoparticles, and one predominant mechanism of toxicity was found to be largely mediated through oxidative stress.
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              Nanosilver: a nanoproduct in medical application.

              X. Chen, H J Schluesener (2008)
              Nanotechnology is a most promising field for generating new applications in medicine. However, only few nanoproducts are currently in use for medical purposes. A most prominent nanoproduct is nanosilver. Nanosilver particles are generally smaller than 100nm and contain 20-15,000 silver atoms. At nanoscale, silver exhibits remarkably unusual physical, chemical and biological properties. Due to its strong antibacterial activity, nanosilver coatings are used on various textiles but as well as coatings on certain implants. Further, nanosilver is used for treatment of wounds and burns or as a contraceptive and marketed as a water disinfectant and room spray. Thus, use of nanosilver is becoming more and more widespread in medicine and related applications and due to increasing exposure toxicological and environmental issues need to be raised. In sharp contrast to the attention paid to new applications of nanosilver, few studies provide only scant insights into the interaction of nanosilver particle with the human body after entering via different portals. Biodistribution, organ accumulation, degradation, possible adverse effects and toxicity are only slowly recognized and this review is focusing on major questions associated with the increased medical use of nanosilver and related nanomaterials.
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                Author and article information

                Contributors
                Tobias Stoeger: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 17 July 2014
                Volume: 9
                Issue: 7
                Electronic Location Identifier: e102564
                Affiliations
                [1]Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Control and Prevention, Beijing, China
                Helmholtz Zentrum München, Germany
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ZHJ BS. Performed the experiments: ZHJ ML YXF JCS. Analyzed the data: ZHJ JZ BS. Wrote the paper: ZHJ BS.

                Article
                Publisher ID: PONE-D-14-10845
                DOI: 10.1371/journal.pone.0102564
                PMC ID: 4102499
                PubMed ID: 25033410
                SO-VID: 62154e8b-0ebc-4a11-aaa0-4810570f6518
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 10 March 2014
                Date accepted : 20 June 2014
                Page count
                Pages: 12
                Funding
                This work was supported by the Capital Health Research and Development of Special (2011-1014-01, http://www.bjhb.gov.cn/) and the Beijing Municipal Senior Technical Training Plan in Health System (2011-2-29, http://www.bjhb.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Biophysics
                Subject: Bionanotechnology
                Subject: Cell biology
                Subject: Cell Processes
                Subject: Cell Proliferation
                Subject: Signal transduction
                Subject: Cell signaling
                Subject: Signaling cascades
                Subject: MAPK signaling cascades
                Subject: Toxicology
                Subject: Toxic Agents
                Subject: Toxins
                Subject: Heavy Metals
                Subject: Cytotoxicity
                Subject: Cytotoxicity Assay
                Custom metadata
                Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All data are included within the manuscript.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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