Abstract:
:Dioxins are a class of extremely toxic environmentally persistent pollutant, comprised of halogenated dibenzo-p-dioxins, dibenzofurans and biphenyls. Despite significant human exposure via multiple routes, very little is known about toxicity induced by dibenzofuran (DF). Current study shed lights on the potential toxicity mechanism of DF using human hepatoma cell line (HepG2). It was observed that the exposure to DF potentiate oxidative stress, apoptosis and necrosis at 10μM within 8h in HepG2 cells. Interestingly, when we pre-incubated the cells with α-NF (1nM) for 12h, an aromatic hydrocarbon receptor antagonist, the IC(50) of DF increased by 14 folds indicating the cytoprotective ability of α-NF from DF induced toxicity. Furthermore, three additional metabolites were observed while studying the metabolic profile of DF in HepG2 cells with and without pre-incubation with α-NF using chromatography-mass spectroscopy (GC-MS). Of these, two metabolites were characterized as dihydroxylated derivative of DF and third metabolite was characterized as quinone derivative of DF. By flow cytometry and confocal laser microscopy analysis we followed the ROS formation after DF (10μM) exposure for 3h. Significantly low ROS was generated in cells which were pre-incubated with α-NF than cells which were not pre-incubated with α-NF underlining the importance of metabolism in DF toxicity. The same pattern of protection was consistent while measuring mitochondrial membrane potential (MMP), i.e., less MMP dip was observed in 'with α-NF pre-incubated and DF (10μM) exposed cells' than 'without α-NF pre-incubated but DF exposed cells'. In cell cycle studies, it was confirmed that cell population of HepG2 at G1 stage progressively increased in number (∼74%) within 24h. Thus, DF and its metabolites induce significantly higher cytotoxicity after metabolism in HepG2 cells than its parent compound (DF) by ROS formation, MMP dip and impaired cell cycle.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Jaiswal PK,Srivastava S,Gupta J,Thakur ISdoi
10.1016/j.toxlet.2012.08.014subject
Has Abstractpub_date
2012-10-17 00:00:00pages
137-44issue
2eissn
0378-4274issn
1879-3169pii
S0378-4274(12)01259-3journal_volume
214pub_type
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