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Efeitos citotóxicos da interação entre nanopartículas de prata e metais não essenciais em células de hepatocarcinoma humano (HEPG2)

  • Miranda, Renata Rank
Publication Date
Jul 12, 2017
Repositório Digital Institucional da UFPR
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Abstract: Due to the increasing production and applications of AgNP in consumer products, AgNP are expected to be, directly or indirectly, released into natural environments, representing a potential threat to the biota and humans. An increasing number of studies have described the toxic potential of AgNP in cells and organisms. However, co-exposure of AgNP with ubiquitous contaminants, such as metals, may result in non-predictable outcomes. In this thesis, toxicological interactions of AgNP, Cd and Hg were investigated in HepG2 cells. In the first chapter, biochemical endpoints, confocal microscopy and intracellular metal concentration indicated that the co-exposures led to toxicological interactions, with AgNP + Cd being more toxic to HepG2 cells than AgNP + Hg. Early (2-4 h) increases of cytosolic and mitochondrial ROS were observed in the cells co-exposed to AgNP + Cd/Hg, in comparison to the control and individual contaminants, but the effect was partially reverted in AgNP + Hg at the end of 24 h-exposure. In addition, decreases of mitochondrial metabolism, cell viability, cell proliferation and ABC-transporters activity were also more pronounced in the co-exposure groups. Foremost, co-exposure to AgNP and metals potentiated cell death (mainly by necrosis) and Hg (but not Cd) intracellular levels. Therefore, toxicological interactions seem to increase the toxicity of AgNP, Cd and Hg. While an increase of Hg uptake might be related to the increase of toxicity after exposure to AgNP+Hg, this logic is not valid for the high toxicity observed after co-exposure to AgNP+Cd. Therefore, the second chapter was conducted to further explore cellular and molecular effects induced by this co-exposure. Cell viability and ADP/ATP ratio were slightly affected after the 4 h exposure to individual and combined exposures. However, these endpoints were strongly altered after 24 h co-exposure to AgNP+Cd compared to the control and individual exposures. The proteomics data followed the same trend: minor deregulation at 4 h-exposure in all groups and 7% (AgNP), 2% (Cd) and 43% (AgNP+Cd) at 24 h-exposure. Briefly, the toxicity induced by AgNP+Cd seems to be involved the inactivation of Nrf-2, which can result in down-regulation of antioxidant defense and proteasome related proteins, down-regulation of glycolysis related proteins and upregulation of oxidative phosphorylation and lipid metabolism proteins. This may indicate an attempt to reestablish homeostasis. Thus, the adaptation strategy was not able to restore ADP/ATP homeostasis and avoid cell death. Overall, this study provides the first insights into cellular outcomes after the co-exposure to AgNP and non-essential metals. Key words: AgNP, cadmium, mercury, co-exposure, interaction, biochemical endpoints, proteomics.

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