Protective action of n-3 fatty acids on benzo[a]pyrene-induced apoptosis through the plasma membrane remodeling-dependent NHE1 pathway.
Plasma membrane is an early target of polycyclic aromatic hydrocarbons (PAH). We previously showed that the PAH prototype, benzo[a]pyrene (B[a]P), triggers apoptosis via DNA damage-induced p53 activation (genotoxic pathway) and via remodeling of the membrane cholesterol-rich microdomains called lipid rafts, leading to changes in pH homeostasis (non-genotoxic pathway). As omega-3 (n-3) fatty acids can affect membrane composition and function or hamper in vivo PAH genotoxicity, we hypothesized that addition of physiologically relevant levels of polyunsaturated n-3 fatty acids (PUFAs) might interfere with B[a]P-induced toxicity. The effects of two major PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were tested on B[a]P cytotoxicity in the liver epithelial cell line F258. Both PUFAs reduced B[a]P-induced apoptosis. Surprisingly, pre-treatment with DHA increased the formation of reactive B[a]P metabolites, resulting in higher levels of B[a]P-DNA adducts. EPA had no apparent effect on B[a]P metabolism or related DNA damage. EPA and DHA prevented B[a]P-induced apoptotic alkalinization by affecting Na(+)/H(+) exchanger 1 activity. Thus, the inhibitory effects of omega-3 fatty acids on B[a]P-induced apoptosis involve a non-genotoxic pathway associated with plasma membrane remodeling. Our results suggest that dietary omega-3 fatty acids may have marked effects on the biological consequences of PAH exposure.
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
Béatrice
B
Dendelé
Université de Rennes 1, SFR Biosit, Rennes, France.
Xavier
X
Tekpli
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
Kévin
K
Hardonnière
Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway.
Jørn A
JA
Holme
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
Laure
L
Debure
Laboratoire de Biochimie, INRA, Agrocampus Rennes, Rennes, France.
Daniel
D
Catheline
Analytical and Environmental Sciences Division, MRC-HPA Centre for Environment & Health, King's College London, London, UK.
Volker M
VM
Arlt
Analytical and Environmental Sciences Division, MRC-HPA Centre for Environment & Health, King's College London, London, UK.
Eszter
E
Nagy
Analytical and Environmental Sciences Division, MRC-HPA Centre for Environment & Health, King's College London, London, UK.
David H
DH
Phillips
Section for Toxicology, Department of Biological and Chemical Working Environment, National Institute of Occupational Health, N-0033 Oslo, Norway.
Steinar
S
Ovrebø
Section for Toxicology, Department of Biological and Chemical Working Environment, National Institute of Occupational Health, N-0033 Oslo, Norway.
Steen
S
Mollerup
Université de Nice Sophia Antipolis, CNRS UMR 6097, Faculté des Sciences, Nice, France.
Mallory
M
Poët
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
Martine
M
Chevanne
Laboratoire de Biochimie, INRA, Agrocampus Rennes, Rennes, France.
Vincent
V
Rioux
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
Marie-Thérèse
MT
Dimanche-Boitrel
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France.
Odile
O
Sergent
Inserm U1085, Institut de Recherche en Santé, Environnement, Travail, Rennes, France; Université de Rennes 1, SFR Biosit, Rennes, France. Electronic address: dominique.lagadic@univ-rennes1.fr.
Dominique
D
Lagadic-Gossmann
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001564:Benzo(a)pyrene; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004249:DNA Damage; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D020011:Protective Agents / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D015525:Fatty Acids, Omega-3; D008055:Lipids; D020011:Protective Agents; C452850:Slc9a1 protein, rat; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D016159:Tumor Suppressor Protein p53; D004281:Docosahexaenoic Acids; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D015118:Eicosapentaenoic Acid
Apoptosis; B[a]P; Benzo[a]pyrene; DHA; DPA; Docosahexaenoic acid; EPA; ER; Eicosapentaenoic acid; HPLC; Lipid rafts; MUFA; Na(+)/H(+) exchanger 1; P450; PAH; PUFA; SFA; benzo[a]pyrene; cytochrome P450; docosahexaenoic acid; docosapentaenoic acid; eicosapentaenoic acid; endoplasmic reticulum; high-performance liquid chromatography; monounsaturated fatty acid; polycylic aromatic hydrocarbon; polyunsaturated fatty acid; saturated fatty acid