Objective In recent years, accumulating evidence indicated that epigenetic alterations may be used as the potential biomarkers to detect toxicity caused by metal nanoparticles (MNPs). Thus, the effects of MNPs exposure on the phosphorylation of histone H3 at serine 10 (p-H3S10) were clarified, and the changes of whole gene expression in cells exposed to typical MNPs were explored in this study to provide a theoretical basis for screening the biomarkers of early toxicity of MNPs.Methods The effects of ten kinds of MNPs exposure on the p-H3S10 were evaluated using Western blotting and flow cytometry. In addition, the effects of copper oxide (CuO) NPs, which is a typical MNPs, on the whole gene expression of cells were explored at the transcriptional level by RNA sequencing technology.Results All the tested MNPs except nickel oxide NPs induced p-H3S10 to different degrees. Among, upregulation of p-H3S10 was observed at immediately after CuO-NPs and zinc oxide NPs treatment, and continued for 10 h. Moreover, p-H3S10 increased slightly after aluminium oxide NPs and antimony (III) oxide NPs treatment, and reached the highest point at 0.5 h. After that, p-H3S10 began to decrease and obtained the lowest value at 2 h. However, p-H3S10 began to rise again after treatment over 2 h until the final observation time point. In addition, p-H3S10 was temporarily induced after treatment with iron (II,III) oxide NPs, silica NPs, cobalt (II,III) oxide NPs, chromium (III) oxide NPs or titanium dioxide NPs, but rapidly ceased. Further analysis indicated that MNP-induced p-H3S10 was highly related to the cellular uptake of MNPs, and the sustained release of ions from MNPs inside cells might generate p-H3S10 for an extended period after the initial uptake of MNPs. In addition, RNA sequencing analysis revealed that CuO-NPs treatment caused significant differential expression of 275 genes (P<0.05), 185 of which were upregulated and 90 of which were downregulated. Gene Ontology (GO) analysis showed that the majority of differentially expressed genes (DEGs) were involved in regulation of signaling, transcription factor activity and kinase activity. Through analyzing enriched GO pathways related to stress, two prominent membrane-activated cascades emerged: the mitogen-activated protein kinase (MAPK) cascade, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) cascade. Genetic markers specific to extracellular signal-regulated kinases ERK1/ERK2 regulation, stress-activated MAPK cascades, and JAK/STAT cascade were also significantly altered after CuO-NPs treatment. It was observed that a large number of genes related to MAPK tyrosine/serine/threonine phosphatase activity were differentially expressed due to CuO-NPs treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed strong associations between the DEGs and signal transduction, signaling molecules and interactions, immune and endocrine systems. Moreover, several DEGs were also correlated with transport, catabolism, cell growth and cell death. MAPK cascades were also significantly upregulated after CuO-NPs exposure.Conclusion These results indicated that early induction of p-H3S10 by MNPs is highly related to the cellular uptake of MNPs, and the persistent release of ions from MNPs inside cells might generate p-H3S10 for a long time after the initial uptake of MNPs. Taken together, the p-H3S10 has potential as a suitable candidate biomarker for evaluating the toxicity of MNPs.