Figure 9.

Possible mechanisms involved in ZnO NP-induced changes in HaCaT cells at epigenetic and molecular levels.

Notes: ZnO NPs release ROS extra- and intracellularly. The transient ROS explosion and the ZnO NPs accumulated in perinucleus might result in G2/M cell cycle arrest associated with the nuclear stress (DNA damage and chromatin structure remodeling) before the viability of HaCaT cells was reduced. When the nucleus is subjected to stress, histone lysine residue modifications (H4K5ac and H3K9me2) near the DNA break regions might provide signals for recruitment of DNA repair proteins, resulting in the chromatin structure remodeling such as chromatin condensation and nucleus shrinking. The G2/M checkpoint prevented DNA-damaged cells from entering mitosis to allow for the repair of DNA prior to mitosis; the checkpoint signaling might activate pathways that lead to apoptosis if the damage is irreparable. The upregulation of the proapoptotic Bcl-2 family relevant genes Bax, Noxa, and Puma that are related to mitochondrial apoptotic pathway indicates that the apoptosis induced by ZnO NPs may be involved in mitochondrion damage. The mitochondrion squeezed by ZnO NPs directly may also result in mitochondrion dysfunction and subsequent cell apoptosis.

Abbreviations: ZnO NPs, zinc oxide nanoparticles; ROS, reactive oxygen species.