Cerium dioxide nanoparticles induce apoptosis and autophagy in human peripheral blood monocytes.
Cerium dioxide nanoparticles (CeO(2) NPs) have diversified industrial uses, and novel therapeutic applications are actively being pursued. There is a lack of mechanistic data concerning the effects of CeO(2) NPs on primary human cells. We aimed at characterizing the cytotoxic effects of CeO(2) NPs in human peripheral blood monocytes. CeO(2) NPs and their suspensions were thoroughly characterized, including using transmission electron microscopy (TEM), dynamic light scattering, and zeta potential analysis. Blood from healthy human volunteers was drawn through phlebotomy, and CD14+ cells were isolated. Cells were exposed to CeO(2) NPs (0.5-10 μg/mL) for 20 or 40 h, and mechanisms of cell injury were studied. TEM revealed that CeO(2) NPs are internalized by monocytes and are found either in vesicles or free in the cytoplasm. CeO(2) NP exposure leads to decrease in cell viability, and treated cells exhibit characteristic hallmarks of apoptosis (activation of Bax, loss of mitochondrial membrane potential, DNA fragmentation). CeO(2) NP toxicity is caused by mitochondrial damage and overexpression of apoptosis inducing factor, but is not due to caspase activation or reactive oxygen species production. Moreover, CeO(2) NP exposure leads to autophagy, which is further increased after pharmacological inhibition of tumor suppressor protein p53. Inhibition of autophagy partially reverses cell death by CeO(2) NPs. It is concluded that CeO(2) NPs are toxic to primary human monocytes at relatively low doses.
Clinical Research Unit, National Institute of Environmental Health Sciences/National Institute of Health, Research Triangle Park 27709, North Carolina, United States. salik.hussain@nih.gov
Salik
S
Hussain
Faris
F
Al-Nsour
Annette B
AB
Rice
Jamie
J
Marshburn
Brenda
B
Yingling
Zhaoxia
Z
Ji
Jeffrey I
JI
Zink
Nigel J
NJ
Walker
Stavros
S
Garantziotis
D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002563:Cerium / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053768:Metal Nanoparticles / Q000633:toxicity* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D036103:Nanotechnology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D002563:Cerium; C030583:ceric oxide