Differential mechanisms of cell death induced by nitro-polycyclic aromatic hydrocarbons
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AbstractPolycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs are environmental pollutants formed during incomplete combustion of organic material, found attached to particulate matter (PM) in ambient air. PM has been associated with adverse effects on the respiratory and cardiovascular systems and PAHs may contribute to PM effects. Many PAHs possess mutagenic and carcinogenic properties, but their effects on cell death are less known. The work presented in this thesis showed for the first time that two of the most abundant nitro-PAHs, 1-nitropyrene (1-NP) and 3-nitrofluoranthene (3-NF) induced programmed cell death (PCD) with paraptotic and necroptotic features respectively.
Both 1-NP and 3-NF induced chemical-specific changes in cellular morphology. The substrate-specific cell death characteristics fitted well with those of two different types of PCD, termed paraptosis and necroptosis, which are known to be physiologically-relevant processes. 1-NP-exposed cells exhibited a dramatic increase in cellular vacuolization, due to swelling of mitochondria and endoplasmic reticulum, linked with oxidative damage and ionic imbalance typical of paraptotic cells. The typical necroptotic cell induced by 3-NF exhibited partial nuclear chromatin condensation combined with damaged plasma membrane. These cells were characterized by increased size as well as number of lysosomes and myelinosomes/autophagic vesicles, and also in expression of an autophagic marker, LC3B. Autophagy was activated by both 1-NP and 3-NF, but appeared to be a parallel event rather than the cause of cell death. Interestingly, their corresponding amine metabolites elicited only minor apoptotic and necrotic death, and cells with characteristics typical of paraptosis or necroptosis were absent.
Our findings indicate that rather similar PAHs cause death by quite different mechanisms including apoptosis, non-apoptotic PCD and necrosis. Such findings may give information of importance in risk assessment evaluations.
LIST OF PAPERS
Paper I 1-Nitropyrene induces apoptosis and apparently a non-apoptotic programmed cell death (paraptosis) in Hepa1c1c7 cells. N. Asare, N.E. Landvik, D. Lagadic-Gossmann, M. Rissel, X. Tekpli, K. Ask, M. Låg, J. A. Holme. Toxicology and Applied Pharmacology 230 (2008) 175–186
Paper II 3-Nitrofluoranthene but not 3-Aminofluoranthene elicits apoptosis as well as programmed necrosis in Hepa1c1c7 cells. N. Asare, M. Låg, D. Lagadic-Gossmann, M. Rissel, P. Schwarze, J. A. Holme. (under consideration in Toxicology)
Paper III Signalling pathways involved in 1-Nitropyrene- (1-NP) and 3-Nitrofluoranthene (3-NF)-induced cell death in Hepa1c1c7 cells. N. Asare, X. Tekpli M. Rissel, A. Solhaug, N. Landvik, V. Lecureur, G. Brunborg, M. Låg, D. Lagadic-Gossmann, J. A. Holme. (manuscript)