Low-dose exposure to graphene oxide significantly increases the metal toxicity to macrophages by altering their cellular priming state

Abstract

Owing to the novel physicochemical properties of graphene, materials such as graphene oxide (GO) are being developed for applications in various fields such as biomedicine. Nonetheless, considerable knowledge gaps still exist regarding the impact of GOs on environmental health and safety (EHS). Thus far, its secondary toxicity, synergistic effects, and mal-adaption have not been focused much upon. Here, we show that at low concentrations (that did not directly result in significant cytotoxicity), GO could greatly enhance metal toxicity in macrophages by altering their cellular priming state. Specifically, GO caused impairments to the cellular morphology and membrane integrity of macrophages, and remarkably enhanced the cellular uptake of Cd and other non-essential metal ions (such as Hg and Gd). Furthermore, upon low-dose GO pre-treatment, the uptake of Cd at a non-toxic concentration brought about a remarkable amount of oxidative stress in macrophages, and ultimately resulted in increased cell death. Mechanistic investigations illustrated that GO pre-treatment triggered cell death through apoptosis because of Cd exposure. Overall, this study’s results reveal a new path for understanding the impact of GOs on EHS through the perspective of its synergistic and secondary effects, previously unidentified mechanisms via which nanomaterials might pose detrimental effects on organisms.