Protective action of n-3 fatty acids on benzo[a]pyrene-induced apoptosis through the plasma membrane remodeling-dependent NHE1 pathway

Béatrice Dendelé (1) , Xavier Tekpli (1) , Kévin Hardonnière (2) , Jørn A Holme (3) , Laure Debure (4) , Daniel D. Catheline (5) , Volker M Arlt (6) , Eszter Nagy (6) , David H Phillips (6) , Steinar Ovrebø (3) , Steen Mollerup (3) , Mallory Poët (7) , Martine Chevanne (2) , Vincent V. Rioux (5) , Marie-Thérèse Dimanche-Boitrel (2) , Odile Sergent (2) , Dominique Lagadic-Gossmann (2)

1 Irset - Institut de recherche en santé, environnement et travail
2 SMS - Stress, membrane et signalisation
3 NIPH - Norwegian Institute of Public Health [Oslo]
4 Récepteur de mort et échappement tumoral
5 Laboratoire de Biochimie et Nutrition Humaine
6 King‘s College London
7 IPMC - Institut de pharmacologie moléculaire et cellulaire

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.

Mots clés: lipid rafts; apoptosis; benzo[a]pyrene; eicosapentaenoic acid; docosahexaenoic acid; Na+/H+ exchanger 1

Domaines: Médecine humaine et pathologie; Biochimie [q-bio.BM]

Béatrice Dendelé, Xavier Tekpli, Kévin Hardonnière, Jørn A Holme, Laure Debure, et al.. Protective action of n-3 fatty acids on benzo[a]pyrene-induced apoptosis through the plasma membrane remodeling-dependent NHE1 pathway. Chemico-Biological Interactions, 2014, 207, pp.41-51. ⟨10.1016/j.cbi.2013.11.002⟩. ⟨hal-00950341⟩