Short- and Long-Term Effects of Commercially Available Gold Nanoparticles in Rodents

Abstract

Gold nanoparticles (GNPs) are currently being intensely investigated for their potential use in biomedical applications. Nanotoxicity studies are urgently needed to validate their safety in clinical practice. The objective of this research was to assess the acute, subacute, and chronic effects of a single intravenous exposure to commercially available GNPs in two in vivo models, mice and rats. Gold nanoparticles were purchased and independently characterized. Animals were exposed to either 1000 mg GNPs/kg body weight (GNP group) or an equivalent volume of phosphate buffered saline (PBS group) intravenously via the tail vein. Subsets of animals were euthanized 1, 7, 14, 21, 28 days (female BALB/c mice and female F344 rats) or 20 weeks (female and male C57BL/6 mice) post-exposure and samples were collected for biochemistry, histopathology, electron microscopy, and atomic absorption spectrometry analysis. Independent characterization demonstrated that the physicochemical properties of the purchased GNPs were in good agreement with the information provided by the supplier. Important differences in GNP-induced immune responses were identified when comparing mice and rats 1 to 28 days post-exposure. Gold nanoparticles stimulated the formation of liver microgranulomas in mice, along with transiently increased serum levels of the proinflammatory cytokine interleukin-18. No such alterations were found in rats. Species differences in GNP biodistribution and excretion were also detected, with higher relative accumulation of GNPs in spleen and longer fecal excretion in rats. In the long-term (20 weeks after dosing), exposure to GNPs incited chronic inflammation in mice, characterized by the persistence of microgranulomas in liver, spleen, and lymph nodes, as well as further increased serum levels of interleukin-18. Impairment of body weight gain was also observed in the GNP-exposed group. No sex differences were detected. In conclusion, GNPs are not innocuous and have the ability to incite a robust macrophage response in mice. However, considering the mildness of the toxic effects identified despite the high dose selected for the study, GNPs continue to have great potential for biomedical uses. Further studies are needed in order to determine specific mechanisms of toxicity and the role of chronic inflammation in the development of adverse effects after co- or post-exposures.