title: Use of a pro-fibrogenic mechanism-based predictive toxicological approach for tiered testing and decision analysis of carbonaceous nanomaterials.
abstract: Engineered carbonaceous nanomaterials (ECNs), including single-wall carbon nanotubes (SWCNTs), multiwall carbon nanotubes (MWCNTs), graphene, and graphene oxide (GO), are potentially hazardous to the lung. With incremental experience in the use of predictive toxicological approaches, seeking to relate ECN physicochemical properties to adverse outcome pathways (AOPs), it is logical to explore the existence of a common AOP that allows comparative analysis of broad ECN categories. We established an ECN library comprising three different types of SWCNTs, graphene, and graphene oxide (two sizes) for comparative analysis according to a cell-based AOP that also plays a role in the pathogenesis of pulmonary fibrosis. SWCNTs synthesized by Hipco, arc discharge and Co-Mo catalyst (CoMoCAT) methods were obtained in their as-prepared (AP) state, following which they were further purified (PD) or coated with Pluronic F108 (PF108) or bovine serum albumin (BSA) to improve dispersal and colloidal stability. GO was prepared as two sizes, GO-small (S) and GO-large (L), while the graphene samples were coated with BSA and PF108 to enable dispersion in aqueous solution. In vitro screening showed that AP- and PD-SWCNTs, irrespective of the method of synthesis, as well as graphene (BSA) and GO (S and L) could trigger interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) production in myeloid (THP-1) and epithelial (BEAS-2B) cell lines, respectively. Oropharyngeal aspiration in mice confirmed that AP-Hipco tubes, graphene (BSA-dispersed), GO-S and GO-L could induce IL-1β and TGF-β1 production in the lung in parallel with lung fibrosis. Notably, GO-L was the most pro-fibrogenic material based on rapid kinetics of pulmonary injury. In contrast, PF108-dispersed SWCNTs and -graphene failed to exert fibrogenic effects. Collectively, these data indicate that the dispersal state and surface reactivity of ECNs play key roles in triggering a pro-fibrogenic AOP, which could prove helpful for hazard ranking and a proposed tiered testing approach for large ECN categories.
authors: Xiang
authors: X
authors: Wang
authors: §Departments of Materials Science and Engineering, Chemistry, and Medicine, Northwestern University, Evanston, Illinois 60208, United States.
authors: Matthew C
authors: MC
authors: Duch
authors: §Departments of Materials Science and Engineering, Chemistry, and Medicine, Northwestern University, Evanston, Illinois 60208, United States.
authors: Nikhita
authors: N
authors: Mansukhani
authors: Zhaoxia
authors: Z
authors: Ji
authors: Yu-Pei
authors: YP
authors: Liao
authors: Meiying
authors: M
authors: Wang
authors: Haiyuan
authors: H
authors: Zhang
authors: Bingbing
authors: B
authors: Sun
authors: Chong Hyun
authors: CH
authors: Chang
authors: Ruibin
authors: R
authors: Li
authors: Sijie
authors: S
authors: Lin
authors: Huan
authors: H
authors: Meng
authors: Tian
authors: T
authors: Xia
authors: §Departments of Materials Science and Engineering, Chemistry, and Medicine, Northwestern University, Evanston, Illinois 60208, United States.
authors: Mark C
authors: MC
authors: Hersam
authors: André E
authors: AE
authors: Nel
mesh_terms: D000818:Animals; D002244:Carbon / Q000737:chemistry* / Q000633:toxicity*; D002460:Cell Line; D004738:Engineering; D006108:Graphite / Q000737:chemistry; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D049329:Nanostructures; D010087:Oxides / Q000737:chemistry; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism; D018675:Toxicity Tests; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D053583:Interleukin-1beta; D010087:Oxides; D053773:Transforming Growth Factor beta1; D002244:Carbon; D006108:Graphite
keywords: NLRP3 inflammasome lung fibrosis; SWCNT; engineered carbonaceous nanomaterials; graphene; graphene oxide
references: Pharmacol Ther. 2009 Feb;121(2):192-204
references: 19103221
references: Fibrogenesis Tissue Repair. 2010 Aug 25;3:15
references: 20738867
references: Nanomedicine (Lond). 2011 Jul;6(5):899-920
references: 21793679
references: Angew Chem Int Ed Engl. 2013 May 3;52(19):4986-97
references: 23580235
references: Nanomedicine (Lond). 2011 Feb;6(2):317-24
references: 21385134
references: Nano Lett. 2012 Jun 13;12(6):3050-61
references: 22546002
references: ACS Nano. 2013 Jul 23;7(7):5732-45
references: 23734789
references: Nanotoxicology. 2012 Aug;6(5):526-42
references: 21657814
references: Acc Chem Res. 2013 Mar 19;46(3):702-13
references: 22999420
references: Am J Physiol Lung Cell Mol Physiol. 2008 Oct;295(4):L552-65
references: 18658273
references: Nano Lett. 2010 May 12;10(5):1664-70
references: 20377197
references: Environ Sci Technol. 2013 Jun 18;47(12):6288-96
references: 23668881
references: ACS Nano. 2011 Dec 27;5(12):9772-87
references: 22047207
references: ACS Nano. 2013 Mar 26;7(3):2352-68
references: 23414138
references: Science. 2014 Apr 18;344(6181):261-3
references: 24744363
references: Nanotoxicology. 2010 Dec;4:347-63
references: 20858045
references: ACS Nano. 2014 Oct 28;8(10):10168-77
references: 25226566
references: J Phys Chem C Nanomater Interfaces. 2013 Aug 8;117(31):null
references: 24298299
references: Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L698-708
references: 15951334
references: Nano Lett. 2011 Dec 14;11(12):5201-7
references: 22023654
references: Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12295-300
references: 23840061
references: ACS Nano. 2010 Aug 24;4(8):4725-32
references: 20669897
references: Chem Res Toxicol. 2014 Feb 17;27(2):159-68
references: 24422439
references: Nanomedicine. 2011 Feb;7(1):40-9
references: 20620235
references: ACS Nano. 2010 Dec 28;4(12):7241-52
references: 21067152
references: Environ Health Perspect. 2009 Jul;117(7):1116-23
references: 19654922
references: Nanomedicine (Lond). 2012 Dec;7(12):1801-12
references: 22830500
references: Small. 2013 May 27;9(9-10):1595-607
references: 23180683
references: Part Fibre Toxicol. 2013;10:23
references: 23773277
references: Toxicol Sci. 2004 Jan;77(1):117-25
references: 14514968