ZnO nanoparticles (NPs) have been assessed to show adverse effects on the liver, but the molecular mechanisms and the role of nanoparticle properties in these adverse reactions have not been sufficiently studied. In this study, the toxicity of various sizes of ZnO particles (bulk, 90 nm, and 30 nm) that were ingested orally over a period of 3 days were evaluated in mice. The blood biochemistry, hematological analyses, and histopathological evaluation showed that there was apparent toxicity caused by smaller ZnO NPs (30 nm) in liver. The smallest ZnO NPs showed highest accumulation in the mice liver. The RT-qPCR data indicated that 30 nm ZnO NPs can induce significant endoplasmic reticulum (ER) stress responses. The ER stress marker of PERK, eIF2 alpha, ATF4, Chop, JNK, caspase-12, caspase-9, GRP94, and Box at the mRNA levels were higher expression in 30 nm ZnO NP than that in bulk or 90 nm ZnO. These findings implied that the smaller ZnO NPs (30 nm) activated ER stress responses that signified severe apoptosis in murine liver. (C) 2016 Elsevier B.V. All rights reserved.