RESUMO
Abstract Understanding tissue biodistribution and clearance of zinc oxide nanoparticles (ZnO-NPs) is necessary for its risk assessment. Both fed and intraperitoneally injected ZnO-NPs (2.5 g/kg) were absorbed into circulation (within 30 min post-dosing), then biodistributed to the liver, spleen, and kidney. Intraperitoneally injected ZnO-NPs remained in serum for 72 h and could more effectively spread to the heart, lung, and testes, whereas the clearance for fed ZnO-NPs in serum began 6 h after oral administration. Compared with zinc oxide microparticles (ZnO-MPs), ZnO-NPs exhibited much higher absorptivity and tissue biodistribution in fed treatment. A greater fraction of fed ZnO-NPs localised in the liver resulted in transient histopathological lesions. However, superoxide generation and cytotoxicity were showed in vitro treatment with ZnO-NPs (above 20 µg/mL). Considering both in vitro and in vivo data, the ZnO-NPs induced acute liver toxicity which was in compliance with its absorption, biodistribution, and clearance.
Assuntos
Nanopartículas/toxicidade , Óxido de Zinco/farmacocinética , Óxido de Zinco/toxicidade , Absorção , Administração Oral , Análise de Variância , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Injeções Intraperitoneais , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes para Micronúcleos , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , Baço/química , Baço/metabolismo , Superóxidos/metabolismo , Distribuição Tecidual , Testes de Toxicidade Aguda , Óxido de Zinco/administração & dosagemRESUMO
The explosive development of nanotechnology has caused an increase in unintended biohazards in humans and in the ecosystem. Similar to particulate matter, nanoparticles (NPs) are strongly correlated with the increase in incidences of cardiovascular diseases, yet the mechanisms behind this correlation remain unclear. Within the testing concentrations of 0.1-10 µg/ml, which did not cause a marked drop in cell viability, zinc oxide NPs (ZnO-NPs) induced intercellular adhesion molecule-1 (ICAM-1) messenger RNA, and protein expression in both concentration- and time-dependent manner in treated human umbilical vein endothelial cells (HUVECs). ZnO-NPs treatment cause the activation of Ras-related C3 botulinum toxin substrate 1 (Rac1)/cell division control protein 42 homolog (Cdc42) and protein accumulation of mixed lineage kinase 3 (MLK3), followed by c-Jun N-terminal kinase (JNK) and transcription factor c-Jun activation. Induction of ICAM-1 and phosphorylation of JNK and c-Jun could be inhibited by either JNK inhibitor SP600125 or Rac guanosine triphosphatase inhibitor NSC23766 pretreatment. In addition, pretreatment with NSC23766 significantly reduced MLK3 accumulation, suggesting the involvement of Rac1/Cdc42-MLK3-JNK-c-Jun signaling in the regulation of ZnO-NPs-induced ICAM-1 expression, whereas these signaling factors were not activated in zinc oxide microparticles (ZnO-MPs)-treated HUVECs. The increase of ICAM-1 expression on ZnO-NPs-treated HUVECs enables leukocytes to adhere and has been identified as an indicator of vascular inflammation. Our data are essential for safety evaluation of the clinical usage of ZnO-NPs in daily supplements, cosmetics, and biomedicines.