Decreased Dissolution of ZnO by Iron Doping Yields Nanoparticles with Reduced Toxicity in the Rodent Lung and Zebrafish Embryos

Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, California 90095, USA.
ACS Nano (Impact Factor: 12.88). 02/2011; 5(2):1223-35. DOI: 10.1021/nn1028482
Source: PubMed


We have recently shown that the dissolution of ZnO nanoparticles and Zn(2+) shedding leads to a series of sublethal and lethal toxicological responses at the cellular level that can be alleviated by iron doping. Iron doping changes the particle matrix and slows the rate of particle dissolution. To determine whether iron doping of ZnO also leads to lesser toxic effects in vivo, toxicity studies were performed in rodent and zebrafish models. First, we synthesized a fresh batch of ZnO nanoparticles doped with 1-10 wt % of Fe. These particles were extensively characterized to confirm their doping status, reduced rate of dissolution in an exposure medium, and reduced toxicity in a cellular screen. Subsequent studies compared the effects of undoped to doped particles in the rat lung, mouse lung, and the zebrafish embryo. The zebrafish studies looked at embryo hatching and mortality rates as well as the generation of morphological defects, while the endpoints in the rodent lung included an assessment of inflammatory cell infiltrates, LDH release, and cytokine levels in the bronchoalveolar lavage fluid. Iron doping, similar to the effect of the metal chelator, DTPA, interfered in the inhibitory effects of Zn(2+) on zebrafish hatching. In the oropharyngeal aspiration model in the mouse, iron doping was associated with decreased polymorphonuclear cell counts and IL-6 mRNA production. Doped particles also elicited decreased heme oxygenase 1 expression in the murine lung. In the intratracheal instillation studies in the rat, Fe doping was associated with decreased polymorphonuclear cell counts, LDH, and albumin levels. All considered, the above data show that Fe doping is a possible safe design strategy for preventing ZnO toxicity in animals and the environment.

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Available from: Xiang Wang, Oct 03, 2015
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    • "The authors attributed the reduced toxicity of Fe@ZnO NPs to lesser dissolution in the growth media [25]. The extent of dissolution decreases (>30% in case of 10% Fe doping) with increase in the amount of Fe compared to that of ZnO NPs [25]. Conversely, Li et al. reported no correlation between the IC 50 (half maximal inhibitory concentration) values and percentage of iron doping of Fe@ZnO in Bacillus subtilis, Escherichia coli, and Pseudomonas putida in aquatic media. "
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    ABSTRACT: Iron doping has shown to reduce toxicity of zinc oxide nanoparticles (ZnO NPs) in several organisms. To the best of authors' knowledge, this is the first report on toxicological studies of Fe@ZnO NPs on terrestrial plants. In this study, green pea plants (Pisum sativum L) were grown for 25 days in soil treated with 10% Fe@ZnO NPs at 0-500 mg/kg. Effects were compared with our previous study where phytotoxicity of bare-ZnO NPs had been investigated on green pea plants grown under similar environmental conditions. Different physiological and biochemical growth parameters were measured. Results showed increased Zn bioaccumulation in roots (200%) and stems (31-48%) as the exposed NP concentration increased (p <= 0.05) but Fe absorption was not affected. At 500 mg/kg Fe@ZnO NPs treatment, chlorophyll content (27%) and H2O2 production (similar to 50%) decreased significantly (p <= 0.05) compared to control. Toxicity of doped ZnO NPs is less than that of bare ZnO NPs as per zinc uptake, chlorophyll content, and ROS (H2O2) production are considered. Therefore, iron doping can be considered as a safer approach to reduce toxicity of ZnO NPs in terrestrial plants.
    Chemical Engineering Journal 12/2014; 258:394–401. DOI:10.1016/j.cej.2014.06.112 · 4.32 Impact Factor
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    • "Our previous toxicity studies of copper, iron or silver NPs [28,29,44] are in agreement with “the higher solubility - the higher toxicity effect” [11,45]; however ZnO NPs despite very high solubility in acidic milieu that contain coordinating ligands demonstrated minimal toxicity in our inhalation studies. Of the many pulmonary biomarkers measured, we observed biologically significant increase only in total number of cells in BAL fluid mainly due to an increase in macrophages and a moderate increase in IL-12(p40) and MIP-1α in BAL fluid. "
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    ABSTRACT: Although ZnO nanoparticles (NPs) are used in many commercial products and the potential for human exposure is increasing, few in vivo studies have addressed their possible toxic effects after inhalation. We sought to determine whether ZnO NPs induce pulmonary toxicity in mice following sub-acute or sub-chronic inhalation exposure to realistic exposure doses. Mice (C57Bl/6) were exposed to well-characterized ZnO NPs (3.5 mg/m3, 4 hr/day) for 2 (sub-acute) or 13 (sub-chronic) weeks and necropsied immediately (0 wk) or 3 weeks (3 wks) post exposure. Toxicity was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid as well as measurements of pulmonary mechanics. Generation of reactive oxygen species was assessed in the lungs. Lungs were evaluated for histopathologic changes and Zn content. Zn concentration in blood, liver, kidney, spleen, heart, brain and BAL fluid was measured. An elevated concentration of Zn2+ was detected in BAL fluid immediately after exposures, but returned to baseline levels 3 wks post exposure. Dissolution studies showed that ZnO NPs readily dissolved in artificial lysosomal fluid (pH 4.5), but formed aggregates and precipitates in artificial interstitial fluid (pH 7.4). Sub-acute exposure to ZnO NPs caused an increase of macrophages in BAL fluid and a moderate increase in IL-12(p40) and MIP-1alpha, but no other inflammatory or toxic responses were observed. Following both sub-acute and sub-chronic exposures, pulmonary mechanics were no different than sham-exposed animals. Our ZnO NP inhalation studies showed minimal pulmonary inflammation, cytotoxicity or lung histopathologic changes. An elevated concentration of Zn in the lung and BAL fluid indicates dissolution of ZnO NPs in the respiratory system after inhalation. Exposure concentration, exposure mode and time post exposure played an important role in the toxicity of ZnO NPs. Exposure for 13 wks with a cumulative dose of 10.9 mg/kg yielded increased lung cellularity, but other markers of toxicity did not differ from sham-exposed animals, leading to the conclusion that ZnO NPs have low sub-chronic toxicity by the inhalation route.
    Particle and Fibre Toxicology 04/2014; 11(1):15. DOI:10.1186/1743-8977-11-15 · 7.11 Impact Factor
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    • "For example, 0.405 mg/L Zn 2+ was initially released from 1 mg/L nZnO (Bai et al. 2010), over 25% of Zn 2+ dissolved from 50 mg/L nZnO (Xia et al. 2011) and 1 mg/L dissolution from 10 mg/L ZnO (Zhu et al. 2009). Limiting NP dissolution via capping or doping methods are being explored to abrogate the effects caused by free metal toxicity (Xia et al. 2011). It is not clear whether delayed hatch can be attributed to the NPs or to the free metal dissolved from the NPs, therefore identifying the active species is of paramount importance. "
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    ABSTRACT: Aquatic organisms are susceptible to waterborne nanoparticles (NP) and there is only limited understanding of the mechanisms by which these emerging contaminants may affect biological processes. This study used silicon (nSi), cadmium selenide (nCdSe), silver (nAg) and zinc NPs (nZnO) as well as single-walled carbon nanotubes (SWCNT) to assess NP effects on zebrafish (Danio rerio) hatch. Exposure of 10 mg/L nAg and nCdSe delayed zebrafish hatch and 100 mg/L of nCdSe as well as 10 and 100 mg/L of uncoated nZnO completely inhibited hatch and the embryos died within the chorion. Both the morphology and the movement of the embryos were not affected, and it was determined that the main mechanism of hatch inhibition by NPs is likely through the interaction of NPs with the zebrafish hatching enzyme. Furthermore, it was concluded that the observed effects arose from the NPs themselves and not their dissolved metal components.
    Nanotoxicology 02/2014; 8(3):295-304. DOI:10.3109/17435390.2013.778345 · 6.41 Impact Factor
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