Features of the response to subchronic low-dose exposure to copper oxide nanoparticles in rats.

Copper is an essential trace element for human health and, at the same time, a major industrial metal widely used both in its elemental form and in compounds. We conducted a dose-dependent assessment of the response of outbred albino male rats to subchronic low-dose exposure to copper oxide nanoparticles administered intraperitoneally at cumulative doses of 18 and 36 mg/kg during 6 weeks to exposure groups 1 and 2, respectively. We observed disorders at different levels of organization of the body in the exposed animals, from molecular to organismal. The observed decrease in the activity of succinate dehydrogenase in nucleated blood cells gave evidence of impaired bioenergetics processes. In view of the results of the metabolomics analysis, we assume mitochondrial damage and contribution of apoptotic processes to the pathology induced by copper poisoning. We also assume neurodegenerative effects based on the assessed morphological parameters of the nervous system, results of behavioral tests, and a decreased level of expression of genes encoding NMDA receptor subunits in the hippocampus. The hepatotoxic effect noted by a number of metabolomics-based, biochemical, and cytological indicators was manifested by the impaired protein-synthesizing function of the liver and enhanced degenerative processes in its cells. We also observed a nephrotoxic effect of nanosized copper oxide with a predominant lesion of proximal kidney tubules. At the same time, both doses tested demonstrated such positive health effects as a statistically significant decrease in the activity of alkaline phosphatase and the nucleated blood cell DNA fragmentation factor. Judging by the changes observed, the cumulative dose of copper oxide nanoparticles of 18 mg/kg body weight administered intraperitoneally approximates the threshold one for rats. The established markers of health impairments may serve as a starting point in the development of techniques of early diagnosis of copper poisoning.

Some data on the comparative and combined toxic activity of nanoparticles containing lead and cadmium with special attention to their vasotoxicity.

Moderate subchronic intoxication was induced in rats by repeated intraperitoneal injections of PbO (49.6 ± 16.0 nm) and/or CdO (57.0 ± 13.0 nm) nanoparticles (NP) three times a week during 6 weeks. In particular, there was a reduction in arterial blood pressure and in blood concentrations of a number of factors controlling vasoconstriction and vasodilation, particularly of endothelin 1 (ET-1). This toxic effect was attenuated with a bioprotective complex administered in the background. The study confirmed as well that the combined binary action typology varies depending on which effect it is estimated by.

Some outcomes and a hypothetical mechanism of combined lead and benzo(a)pyrene intoxication, and its alleviation with a complex of bioprotectors.

Rats were exposed 3 times a week during 6 weeks to repeated intraperitoneal injections of lead acetate solution in water (Pb) and/or benzo(а)pyrene solution in petrolatum oil (B(а)P) in various dose ratios. Towards the end of the period, the animals developed a moderate subchronic intoxication having some features characteristic of lead effects. The type of combined toxicity estimated with the help of isoboles constructed by the Response Surface Methodology was found to be varied depending on a particular effect, its level, and dose ratio. However, Pb and B(a)P in combination often displayed an additive or even superadditive action. In the group exposed to this combination compared with the group of rats exposed to B(a)P alone, its concentration in the organism was increased while the concentration of some B(a)P oxidative metabolism products was reduced. Such inhibition of B(a)P biotransformation, assumingly associated with impaired heme and, thus, cytochrome P450 synthesis induced by lead intoxication, can serve as an explanation for certain enhancement of the genotoxic effect of B(a)P. This effect was not present in the same combined intoxication if a complex of antitoxic bioprotectors was being administered in the background.

Combined Subchronic Toxicity of Aluminum (III), Titanium (IV) and Silicon (IV) Oxide Nanoparticles and Its Alleviation with a Complex of Bioprotectors.

Stable suspensions of metal/metalloid oxide nanoparticles (MeO-NPs) obtained by laser ablation of 99.99% pure elemental aluminum, titanium or silicon under a layer of deionized water were used separately, or in three binary combinations, or in a ternary combination to induce subchronic intoxications in rats. To this end, the MeO-NPs were repeatedly injected intraperitoneally (i.p.) 18 times during 6 weeks before measuring a large number of functional, biochemical, morphological and cytological indices for the organism's status. In many respects, the Al2O3-NP was found to be the most toxic species alone and the most dangerous component of the combinations studied. Mathematical modeling with the help of the Response Surface Methodology showed that, as well as in the case of any other binary toxic combinations previously investigated by us, the organism's response to a simultaneous exposure to any two of the MeO-NP species under study was characterized by a complex interaction between all possible types of combined toxicity (additivity, subadditivity or superadditivity of unidirectional action and different variants of opposite effects) depending on which outcome this type was estimated for and on effect and dose levels. With any third MeO-NP species acting in the background, the type of combined toxicity displayed by the other two remained virtually the same or changed significantly, becoming either more or less unfavorable. Various harmful effects produced by the (Al2O3-NP + TiO2-NP + SiO2-NP)-combination, including its genotoxicity, were substantially attenuated by giving the rats per os during the entire exposure period a complex of innocuous bioactive substances expected to increase the organism's antitoxic resistance.