title: Hypoxia inducible factor-1 (HIF-1)-flavin containing monooxygenase-2 (FMO-2) signaling acts in silver nanoparticles and silver ion toxicity in the nematode, Caenorhabditis elegans.
abstract: In the present study, nanotoxicity mechanism associated with silver nanoparticles (AgNPs) exposure was investigated on the nematode, Caenorhabditis elegans focusing on the hypoxia response pathway. In order to test whether AgNPs-induced hypoxia inducible factor-1 (HIF-1) activation was due to hypoxia or to oxidative stress, depletion of dissolved oxygen (DO) in the test media and a rescue effect using an antioxidant were investigated, respectively. The results suggested that oxidative stress was involved in activation of the HIF-1 pathway. We then investigated the toxicological implications of HIF-1 activation by examining the HIF-1 mediated transcriptional response. Of the genes tested, increased expression of the flavin containing monooxygenase-2 (FMO-2) gene was found to be the most significant as induced by AgNPs exposure. We found that AgNPs exposure induced FMO-2 activation in a HIF-1 and p38 MAPK PMK-1 dependent manner, and oxidative stress was involved in it. We conducted all experiments to include comparison of AgNPs and AgNO3 in order to evaluate whether any observed toxicity was due to dissolution or particle specific. The AgNPs and AgNO3 did not produce any qualitative differences in terms of exerting toxicity in the pathways observed in this study, however, considering equal amount of silver mass, in every endpoint tested the AgNPs were found to be more toxic than AgNO3. These results suggest that Ag nanotoxicity is dependent not only on dissolution of Ag ion but also on particle specific effects and HIF-1-FMO-2 pathway seems to be involved in it.
authors.affiliation: School of Environmental Engineering and Graduate School of Energy and Environmental System Engineering, University of Seoul, 90 Jeonnong-dong, Dongdaemun-gu, Seoul 130-743, Republic of Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Eom
authors.forename: Jeong-Min
authors.initials: JM
authors.lastname: Ahn
authors.forename: Younghun
authors.initials: Y
authors.lastname: Kim
authors.forename: Jinhee
authors.initials: J
authors.lastname: Choi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D017173:Caenorhabditis elegans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D053768:Metal Nanoparticles / Q000633:toxicity*; D046529:Microscopy, Electron, Transmission; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism*; D010316:Particle Size; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D012834:Silver / Q000378:metabolism / Q000633:toxicity*; D016019:Survival Analysis; D014158:Transcription, Genetic
chemical_list: D051793:Hypoxia-Inducible Factor 1; D012834:Silver; D012313:RNA; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)