title: Insight into the Mechanisms of Combined Toxicity of Single-Walled Carbon Nanotubes and Nickel Ions in Macrophages: Role of P2X7Receptor.
abstract: Coexistence of nanomaterials and environmental pollutants requires in-depth understanding of combined toxicity and underlying mechanism. In this work, we found that coexposure to the mixture of noncytotoxic level of single-walled carbon nanotubes (SWCNTs) (10 μg/mL) and Ni2+(20 μM) induced significant cytotoxicity in macrophages. However, almost equal amount of intracellular Ni2+was detected after Ni2+/SWCNT coexposure or Ni2+single exposure, indicating no enhanced cellular uptake of Ni2+occurred. SDS-PAGE analysis revealed 50% more SWCNTs retained in Ni2+/SWCNT exposed cells than that with SWCNT exposure alone, regardless of the exposure sequence (coexposure, Ni2+pre- or post-treatment), suggesting inhibited SWCNT exocytosis by Ni2+. The increased cellular dose of SWCNTs could quantitatively account for the elevated toxicity of Ni2+/SWCNT mixture to cells. It was then found that agonist (ATP) and antagonist (o-ATP) of P2X7R could regulate intracellular SWCNT amount and the cytotoxicity accordingly. In addition, inhibition of P2X7R by P2X7-targeting siRNA diminished the inhibitory effect of Ni2+. It was therefore concluded that Ni2+impeded SWCNT exocytosis by inhibiting P2X7R, leading to higher intracellular retention of SWCNTs and elevated cytotoxicity. Our work identified exocytosis inhibition as an important mechanism for SWCNT/Ni2+toxicity, and revealed the crucial role of P2X7R in mediating such inhibitory effect.
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.|University of Chinese Academy of Sciences , Beijing 100049, China.|Institute of Environment and Health, Jianghan University , Wuhan, Hubei 430056, China.
authors.forename: Liang-Hong
authors.initials: LH
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Ren
mesh_terms: D007477:Ions; D008264:Macrophages / Q000187:drug effects*; D037742:Nanotubes, Carbon / Q000633:toxicity*; D009532:Nickel; D058486:Receptors, Purinergic P2X7
chemical_list: D007477:Ions; D037742:Nanotubes, Carbon; D058486:Receptors, Purinergic P2X7; D009532:Nickel