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ATTENUATION OF ADVERSE HEALTH EFFECTS OF METALLIC NANOPARTICLES WITH INNOCUOUS BIOPROTECTORS: MECHANISTIC HYPOTHESES AND EXPERIMENTAL RESULTS. Ilzira A. Minigalieva, PhD (biology ) Head, the Laboratory of the Industrial Toxicology,
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ATTENUATION OF ADVERSE HEALTH EFFECTS OF METALLIC NANOPARTICLES WITH INNOCUOUS BIOPROTECTORS: MECHANISTIC HYPOTHESES AND EXPERIMENTAL RESULTS
Ilzira A. Minigalieva, PhD (biology) Head, the Laboratory of the Industrial Toxicology, The Ekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers Ekaterinburg, Russian Federation In co-authorship with B.A. Katsnelson, L.I. Privalova, M.P. Sutunkova, V.Y. Shur, E.V. Shishkina, O.H. Makeyev, I.E. Valamina, E.V.Grigoryeva, N.V.Loginova
Metallic nanoparticles, both engineered and generated as a by-product of metallurgical and welding technologies, are one of the most dangerous occupational and environmental hazards. Although our studies demonstrated a high efficiency of the organism’s defenses against such nanoparticles’ impact, safe levels of the latter should be very low if possible at all (due to these particles’ especially high toxicity and seemingly obligatory genotoxicity).
Therefore we deemed worthwhile to try and enhance the natural resistance to their toxicity with the help of so called bio-protectors. This idea was based on our long-term experience with a successful bio-protection of the organism against many other toxicants, including some mineral microparticles.
Enhancing the organism’s general defensive reactivity Non-specific action Toxicokinetic effects Bio-protectors Decreasing the sensitivity or increasing the resistance to toxics Specific action Toxicodyna-mic effects
Bioprotectors acting by different toxicokinetic and toxicodynamic mechanisms proved most effective when administered not separately but in combinations (so called “bioprolphylactic complexes” or, abbreviated, BPC). Keeping in mind the further possible usage of bioprotectors for humans, we test in animal experiments only those substances which, on their own, are innocuous when applied for a long time in preventively effective doses.
Specifically, the bio-protectors successfully tested by us during more than 30 years included, separately or in different complexes, the agents listed on the next slide.
some amino acids (glutamate, glycine, methionine, cysteine); phytogenic adaptogens (Araliaceae prepartions); individual vitamins (such as A, E, C) and essential trace elements (selenium, iodine, copper etc); multivitamin-multimineral preparations; fish oils rich in polyunsaturated fatty acids of the omega 3 class; pectin enterosorbents; calcium and iron supplements.
As concerns the bio-protection against adverse effects of metallic nanoparticles, up to now we substantiated theoretically and tested experimentally four BPCs protecting from : nano silver, nano copper oxide, a combination of nano nickel oxide plus nano manganese oxide. a combination of nano copper oxide, nano lead oxide, and nano zinc oxide
As an example, here I present the composition of the BPC tested against CuO nanoparticles Sodium glutamate800–900 mg/kg (as a 1.5% drink instead of water) Apple pectin1 g/kg (added to the fodder) Glycine 12 mg per rat (added to the fodder) N-Acetyl-cysteine30 mg per rat (added to the fodder) A commercial fish oil rich in vitamin A and omega 3 rich PUFA 1 mL per rat (by gavage) Multivitamin-Multimineral Preparations (added to the Fodder) supplying per rat: Vitamin B12 0.15 mcg ; Vitamin C 4.4 mg; Vitamin E 0.84 mg; Iron 0.6 mg ; Selenium 5.8 mcg; Zink 1.25 mg; Molibdenum 3.75 mcg ; Manganese 16.7 mcg
In all the cases we proved that against the background of adequately composed BPCs the toxicity and even genotoxicity of metallic nanoparticles could be markedly attenuated.
This beneficial efficacy of the bioprotection was assessed with a lot of indices, but here we propose only to illustrate it with some examples. Thus all those nanometals are markedly nephrotoxic, that is exerting a significant damage to kidneys – mostly to epithelial cells of proximal convoluted renal tubules. The next slide, taking as an example the combined action of nickel-manganese oxides nanoparticles, demonstrates both such nephrotoxicity and its marked alleviation against the background administration of the tested BPC.
a) b) c) (a) in a control rat; (b) In a rat exposed to nanoparticles (NPs) ; (c) in a rat exposed to the same NPs but against the background BPC administration .
An unrandomness of this effects is confirmed by a statistical analysis of morphometric data: Note:*. statistically significant difference from the control group; + from the group given NiO-NPs+Mn3O4-NPs (without the BPC) (p < 0.05 by Student’s t-test).
Another adverse effect proved specific for the toxicity of copper oxide and of manganese oxide nanoparticles was a marked damage to some specialized structures of the brain (especially, the striatum and the hippocampus). The next slide demonstrates results of the statistical assessment of one of indices for this effect obtained in our experiment with copper oxide particles.
These columns corresond to percentage of markedly damaged Golgi cells in the brain caudate nucleus of rats exposed (A) to water (Control); (B) to water suspension of copper oxide nanoparticles; (C) to the same against the background of bioprotective complex (BPC) administrations, (D) to the BPC only (average values with 95% CI).
This table demonstrates a similar protective efficacy of another BPC against the combined neuronal toxicity of manganese and nickel oxide nanoparticles: *statistically significant difference from the control group; + from the group given nanoparticles without the BPC
Let me illustrate the last Table with a histological picture of the hippocampus in a rat exposed to NPs of manganese and nickel oxides. There are a lot of neurons with marked degenerative changes or pycnosis; in some nuclei the nucleolus is displaced or absent.
This is the same brain area in a rat exposed to the same nanoparticles but against the background BPC administration, and we see a marked alleviation of neuronal damage
As an illustration of the efficacy of bioprotection against less specific (so-called “integral”) toxic effects of metallic nanoparticles we give some numerical results of the same experiment with nickel plus manganese nano-oxides on the next slide.
Note:*. statistically significant difference from the control group; + from the group given NiO-NPs+Mn3O4-NPs (without the BPC) (p < 0.05 by Student’s t-test with Bonferroni correction).
Please note that the BPC which has significantly attenuated the adverse shifts caused by nanoparticles has itself no effect on the respective indices. This is quite typical.
The last but not the least result we’d like to stress is that, while all the nanoparticles were genotoxic, in all the three experiments the tested BPCs significantly attenuated this most worrying effect. The next slide demonstrates it by the example of silver nanoparticles.
CONCLUSIONS The especially high levels of many metallic nanoparticles toxicity make it necessary not only to decrease dangerous exposures as low as possible but also to look for increasing the organism’s resistance to them. We proved that against the background of adequately composed combinations of some bioactive agents used in innocuous doses, the toxicity and even genotoxicity of metallic nanoparticles could be markedly attenuated, and we strongly recommend to further develop this vector of nanotoxicological research . Our previous positive experience in organizing first a selective and then a large-scale “biological prophylaxis” of adverse health effects of other toxicants make us believe that it would be no less practicable in the field of nanotechnologies as well.
A summarizing publication Boris A. Katsnelson, Larisa I. Privalova, Marina P. Sutunkova, Ilzira A. Minigalieva et al. (2015) Is it possible to enhance the organism’s resistance to toxic effects of metallic nanoparticles? Toxicology, 337: 79–82
Patent rights Based on our results we have registered in the Russian Federation Service for Intellectual Property three inventions pertaining to methods for prevention of adverse health effects, first, of silver, second, of copper oxide nanoparticles, third of nickel and manganese oxides nanoparticles in combination.
