title: A systems toxicology approach on the mechanism of uptake and toxicity of MWCNT in Caenorhabditis elegans.
abstract: The increased volumes of carbon nanotubes (CNTs) being utilized in industrial and biomedical processes carries with it an increased risk of unintentional release into the environment, requiring a thorough hazard and risk assessment. In this study, the toxicity of pristine and hydroxylated (OH-) multiwall CNTs (MWCNTs) was investigated in the nematode Caenorhabditis elegans using an integrated systems toxicology approach. To gain an insight into the toxic mechanism of MWCNTs, microarray and proteomics were conducted for C. elegans followed by pathway analyses. The results of pathway analyses suggested endocytosis, phagocytosis, oxidative stress and endoplasmic reticulum (ER) stress, as potential mechanisms of uptake and toxicity, which were subsequently investigated using loss-of-function mutants of genes of those pathways. The expression of phagocytosis related genes (i.e. ced-10 and rab-7) were significantly increased upon exposure to OH-MWCNT, concomitantly with the rescued toxicity by loss-of-function mutants of those genes, such as ced-10(n3246) and rab-7(ok511). An increased sensitivity of the hsp-4(gk514) mutant by OH-MWCNT, along with a decreased expression of hsp-4 at both gene and protein level suggests that MWCNTs may affect ER stress response in C. elegans. Collectively, the results implied phagocytosis to be a potential mechanism of uptake of MWCNTs, and ER and oxidative stress as potential mechanisms of toxicity. The integrated systems toxicology approach applied in this study provided a comprehensive insight into the toxic mechanism of MWCNTs in C. elegans, which may eventually be used to develop an "Adverse Outcome Pathway (AOP)", a recently introduced concept as a conceptual framework to link molecular level responses to higher level effects.
authors.affiliation: School of Environmental Engineering, Graduate School of Energy and Environmental System Engineering, University of Seoul, Seoul 130-743, Republic of Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Eom
authors.affiliation: Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Tarragona, Catalunya, Spain.
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Roca
authors.affiliation: School of Environmental Engineering, Graduate School of Energy and Environmental System Engineering, University of Seoul, Seoul 130-743, Republic of Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Roh
authors.affiliation: School of Environmental Engineering, Graduate School of Energy and Environmental System Engineering, University of Seoul, Seoul 130-743, Republic of Korea.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: School of Environmental Engineering, Graduate School of Energy and Environmental System Engineering, University of Seoul, Seoul 130-743, Republic of Korea.
authors.forename: Jae-Seong
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Risk Assessment Division, National Institute of Environmental Research, Incheon 404-708, Republic of Korea.
authors.forename: Ilseob
authors.initials: I
authors.lastname: Shim
authors.affiliation: Risk Assessment Division, National Institute of Environmental Research, Incheon 404-708, Republic of Korea.
authors.forename: Hyun-Mi
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Risk Assessment Division, National Institute of Environmental Research, Incheon 404-708, Republic of Korea.
authors.forename: Phil-Je
authors.initials: PJ
authors.lastname: Kim
authors.affiliation: Risk Assessment Division, National Institute of Environmental Research, Incheon 404-708, Republic of Korea.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Choi
authors.affiliation: Departament d'Enginyeria Quimica, Universitat Rovira i Virgili, Tarragona, Catalunya, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Giralt
authors.affiliation: School of Environmental Engineering, Graduate School of Energy and Environmental System Engineering, University of Seoul, Seoul 130-743, Republic of Korea. Electronic address: jinhchoi@uos.ac.kr.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Choi
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D046228:Microarray Analysis; D009154:Mutation; D037742:Nanotubes, Carbon / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D037742:Nanotubes, Carbon
keywords: Adverse outcome pathway; Caenorhabditis elegans; Multiwall carbon nanotubes; Phagocytosis; Systems toxicology