title: Carbon Nanotubes Disrupt Iron Homeostasis and Induce Anemia of Inflammation through Inflammatory Pathway as a Secondary Effect Distant to Their Portal-of-Entry.
abstract: Although numerous toxicological studies have been performed on carbon nanotubes (CNTs), a few studies have investigated their secondary and indirect effects beyond the primary target tissues/organs. Here, a cascade of events are investigated: the initiating event and the subsequent key events necessary for the development of phenotypes, namely CNT-induced pro-inflammatory effects on iron homeostasis and red blood cell formation, which are linked to anemia of inflammation (AI). A panel of CNTs are prepared including pristine multiwall CNTs (P-MWCNTs), aminated MWCNTs (MWCNTs-NH2), polyethylene glycol MWCNTs (MWCNTs-PEG), polyethyleneimine MWCNTs (MWCNTs-PEI), and carboxylated MWCNTs (MWCNTs-COOH). It has been demonstrated that all CNT materials provoke inflammatory cytokine interleukin-6 (IL-6) production and stimulate hepcidin induction, associated with disordered iron homeostasis, irrespective of exposure routes including intratracheal, intravenous, and intraperitoneal administration. Meanwhile, PEG and COOH modifications can ameliorate the activation of IL-6-hepcidin signaling. Long-term exposure of MWCNTs results in AI and extramedullary erythropoiesis. Thus, an adverse outcome pathway is identified: MWCNT exposure leads to inflammation, hepatic hepcidin induction, and disordered iron metabolism. Together, the combined data depict the hazardous secondary toxicity of CNTs in incurring anemia through inflammatory pathway. This study will also open a new avenue for future investigations on CNT-induced indirect and secondary adverse effects.
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: Juan
authors.initials: J
authors.lastname: Ma
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Li
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
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: Guangbo
authors.initials: G
authors.lastname: Qu
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: Jing
authors.initials: J
authors.lastname: Liu
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: Wenli
authors.initials: W
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: Haoyang
authors.initials: H
authors.lastname: Song
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: Xinghong
authors.initials: X
authors.lastname: Li
authors.affiliation: School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Beijing Jishuitan Hospital, Peking University Health Science Center, Beijing, 100035, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.affiliation: School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
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: Sijin
authors.initials: S
authors.lastname: Liu
mesh_terms: D000740:Anemia / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006411:Hematopoiesis, Extramedullary; D064451:Hepcidins / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D019570:Inhalation Exposure; D015850:Interleukin-6 / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D037742:Nanotubes, Carbon / Q000009:adverse effects* / Q000648:ultrastructure; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly / Q000473:pathology
chemical_list: D064451:Hepcidins; D015850:Interleukin-6; D037742:Nanotubes, Carbon; D007501:Iron
keywords: anemia of inflammation; carbon nanotubes; iron homeostasis; pro-inflammatory responses; secondary effects