title: Accumulation of lipids and oxidatively damaged DNA in hepatocytes exposed to particles.
abstract: Exposure to particles has been suggested to generate hepatosteatosis by oxidative stress mechanisms. We investigated lipid accumulation in cultured human hepatocytes (HepG2) and rat liver after exposure to four different carbon-based particles. HepG2 cells were exposed to particles for 3h and subsequently incubated for another 18h to manifest lipid accumulation. In an animal model of metabolic syndrome we investigated the association between intake of carbon black (CB, 14nm) particles and hepatic lipid accumulation, inflammation and gene expression of Srebp-1, Fasn and Scd-1 involved in lipid synthesis. There was a concentration-dependent increase in intracellular lipid content after exposure to CB in HepG2 cells, which was only observed after co-exposure to oleic/palmitic acid. Similar results were observed in HepG2 cells after exposure to diesel exhaust particles, fullerenes C60 or pristine single-walled carbon nanotubes. All four types of particles also generated oxidatively damaged DNA, assessed as formamidopyrimidine DNA glycosylase (FPG) sensitive sites, in HepG2 cells after 3h exposure. The animal model of metabolic syndrome showed increased lipid load in the liver after one oral exposure to 6.4mg/kg of CB in lean Zucker rats. This was not associated with increased iNOS staining in the liver, indicating that the oral CB exposure was associated with hepatic steatosis rather than steatohepatitis. The lipid accumulation did not seem to be related to increased lipogenesis because there were unaltered gene expression levels in both the HepG2 cells and rat livers. Collectively, exposure to particles is associated with oxidative stress and steatosis in hepatocytes.
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark.
authors.forename: Lise K
authors.initials: LK
authors.lastname: Vesterdal
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark.
authors.forename: Pernille H
authors.initials: PH
authors.lastname: Danielsen
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark.
authors.forename: Janne K
authors.initials: JK
authors.lastname: Folkmann
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark.
authors.forename: Line F
authors.initials: LF
authors.lastname: Jespersen
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Aguilar-Pelaez
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Roursgaard
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Loft
authors.affiliation: Department of Public Health, Section of Environmental Health, University of Copenhagen, Øster Farimagsgade 5A, DK-1014 Copenhagen K, Denmark. Electronic address: pemo@sund.ku.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Møller
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000187:drug effects*; D043382:DNA-Formamidopyrimidine Glycosylase / Q000378:metabolism; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D037741:Fullerenes / Q000633:toxicity; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019308:Palmitic Acid / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D053260:Soot / Q000633:toxicity; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity
chemical_list: D037741:Fullerenes; D017382:Reactive Oxygen Species; C497387:SREBF1 protein, human; D053260:Soot; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D001335:Vehicle Emissions; C530172:pristine (C60); D019301:Oleic Acid; D019308:Palmitic Acid; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D043382:DNA-Formamidopyrimidine Glycosylase; C069837:fullerene C60
keywords: 8-oxo-7,8-dihydro-2′deoxyguanine; 8-oxodG; ABCG5; ABCG8; ATP-binding cassette, sub-family G (WHITE), member 5; ATP-binding cassette, sub-family G (WHITE), member 8; CB; Comet assay; DEP; DNA damage; FASN; FFA; FPG; Inflammation; NAFLD; Nanoparticles; Oxidative stress; ROS; SCD-1; SREBP-1; SREBP-2; SRM2975; SWCNT; Steatosis; carbon black; diesel exhaust particles; fatty acid synthase; formamidopyrimidine DNA glycosylase; free fatty acids; iNOS; inducible nitric oxidase synthase; non-alcoholic fatty liver disease (NAFLD); reactive oxygen species; single-walled carbon nanotube; standard reference material 2975; sterol regulating element-binding protein 1; sterol regulating element-binding protein 2; steroyl-coenzyme A desaturase 1