Sub-acute oral exposure of zinc oxide nanoparticles causes alteration in iron homeostasis through acute phase response: A protective effect by surface modification.

Graphical abstract ZnO NPs interact with cell systems and cellular organelles as intact particles as well as ions. Resultant induces inflammation mediated acute phase response that altered the iron homeostasis and promotes anemic condition. ZnO NPs – Zinc oxide nanoparticles, ROS-reactive oxygen species, APR- Acute phase response, Hep- hepcidin, Hp- haptoglobin, Heph- Hephaestin, FPN- ferroportin, TF- Transferrin receptor, TFR-1- Transferrin receptor-1, LDH- lactate dehydrogenase, Hb-hemoglobin, RBC- red blood cells. Highlights • Surface engineered ZnO nanoparticles (c-ZnO NPs) were synthesized & characterized. • Sub-acute oral toxicity of non functionalized b-ZnO and c-ZnO NPs were performed. • b-ZnO NPs induced higher inflammation that led to the acute phase response (APR). • APR leads to progression of anemia by altering interlinked iron signaling pathway. • Further, the surface modified c-ZnO NPs reduced the toxicity. Abstract Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials. Following oral exposure, these NPs can accumulate in various organs and induce the toxicity due to their physiochemical characteristics. In present study to reduce the toxicity, surface engineered ZnO NPs (c-ZnO NPs) were in-situ synthesized by using polyacrylamide grafted guar gum (PAm-g-GG) polymer in alkaline media. Further, the comparative effect of bared ZnO NPs (b-ZnO NPs) and c-ZnO NPs were assessed on secondary target organ liver and kidneys of Swiss mice at doses of 10, 50 and 300 mg/kg following 28 days repeated oral treatment. The b-ZnO NPs were incited severe damages in liver and kidney tissue than c-ZnO NPs as seen by transmission electron microscopy and histopathology. The increased levels of serum biomarkers (AST, ALT, ALP, creatinine, uric acid, and urea) were also observed, that remarking a disturbance in the function of liver and kidney. After sub-acute oral treatment of b-ZnO NPs, the hepatic pro-inflammatory cytokines (IL-6, TNF-α, and MMP-9) were up-regulated that causes the activation of acute phase response (APR). We also observed significantly increased in expression of hepatic acute phase proteins (hepcidin and haptoglobin) and altered interlinked iron (Fe) signaling biomarkers (hephaestin, TF, TFR-1, LDH, and ferroportin). This study emphasizes that exposure to ZnO NPs may cause inflammation mediated APR through ultra-structural damage of tissue that could escort the progression of anemia. Nevertheless, the capping with PAm-g-GG in c- ZnO NPs has reduced the toxicity by altering the surface reactive property of ZnO NPs. [ABSTRACT FROM AUTHOR]