Biotransformation of Graphene Oxide in Lung Fluids Enhances its Synergistic Cytotoxic Effect with Cadmium

Graphene oxide (GO) has been widely studied and applied in numerous industrial fields and biomedical fields for its excellent physical and chemical properties. Along with the production and applications of GO persist increasing, the environmental health and safety risk (EHS) of GO has been widely studied. However, previous studies almost focused on biotoxicity of pristine GO under a relatively high exposure dose, without considering its transformation process within environmental and biological mediums. Meanwhile, its secondary toxicity or synergistic effects have not been taken seriously. Here, two different kinds of artificial lung fluid were adopted to incubate pristine GO to mimic the biotransformation process of GO in the lung fluids. And, we explored that biotransformation within the artificial lung fluids could significantly change the physicochemical properties of GO and could enhance its cytotoxicity. To reveal the synergistic effects of GO and toxic metal ions, we uncovered that GO could enhance the cellular uptake of metal ions by inhibiting the efflux function of ATP binding cassette (ABC) transporters which distributed on the cellular membrane, and artificial lung fluids incubation of GO could enhance this synergistic effect. Finally, toxic metal ions induced a series of cytotoxic reactions through oxidative stress response and promoted cell death. In summary, this study explored the impact and mechanism of biotransformation of GO in the lung fluids on the synergistic and secondary effects between GO and metal ions