title: Surface interactions with compartmentalized cellular phosphates explain rare earth oxide nanoparticle hazard and provide opportunities for safer design.
abstract: Growing international exploitation of rare earth oxides (REOs) for commercial and biological use has increased the possibility of human exposure and adverse health effects. Occupational exposure to rare earth materials in miners and polishers leads to a severe form of pneumoconiosis, while gadolinium-containing MRI contrast agents cause nephrogenic systemic fibrosis in patients with renal impairment. The mechanisms for inducing these adverse pro-fibrogenic effects are of considerable importance for the safety assessment of REO particles as well as presenting opportunities for safer design. In this study, using a well-prepared REO library, we obtained a mechanistic understanding of how REOs induce cellular and pulmonary damage by a compartmentalized intracellular biotransformation process in lysosomes that results in pro-fibrogenic growth factor production and lung fibrosis. We demonstrate that rare earth oxide ion shedding in acidifying macrophage lysosomes leads to biotic phosphate complexation that results in organelle damage due to stripping of phosphates from the surrounding lipid bilayer. This results in nanoparticle biotransformation into urchin shaped structures and setting in motion a series of events that trigger NLRP3 inflammasome activation, IL-1β release, TGF-β1 and PDGF-AA production. However, pretreatment of REO nanoparticles with phosphate in a neutral pH environment prevents biological transformation and pro-fibrogenic effects. This can be used as a safer design principle for producing rare earth nanoparticles for biological use.
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , 10833 Le Conte Avenue, Los Angeles, California 90095, United States.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Li
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ji
authors.forename: Chong Hyun
authors.initials: CH
authors.lastname: Chang
authors.forename: Darren R
authors.initials: DR
authors.lastname: Dunphy
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Cai
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Zhang
authors.forename: Bingbing
authors.initials: B
authors.lastname: Sun
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Juyao
authors.initials: J
authors.lastname: Dong
authors.forename: Sijie
authors.initials: S
authors.lastname: Lin
authors.forename: Meiying
authors.initials: M
authors.lastname: Wang
authors.forename: Yu-Pei
authors.initials: YP
authors.lastname: Liao
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.forename: Andre
authors.initials: A
authors.lastname: Nel
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
mesh_terms: D016676:Macrophages, Alveolar / Q000187:drug effects; D008674:Metals, Rare Earth / Q000737:chemistry*; D053758:Nanoparticles / Q000633:toxicity*; D010087:Oxides / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D008674:Metals, Rare Earth; D010087:Oxides; D010710:Phosphates