Differential toxic effects of methyl tertiary butyl ether and tert-butanol on rat fibroblasts in vitro.
Methyl tertiary butyl ether (MTBE) is the most widely used motor vehicle fuel oxygenate since it reduces harmful emissions due to gasoline combustion. However, the significant increase in its use in recent years has raised new questions related to its potential toxicity. In fact, although available data are somehow conflicting, there is evidence that MTBE is a toxic substance that may have harmful effects on both animals and humans and an unresolved problem is the role played by MTBE metabolites, especially tertiary butyl alcohol (TBA), in determining toxic effects due to MTBE exposure. In this study, the toxic effects of MTBE have been analyzed on a normal diploid rat fibroblast cell line (Rat-1) and compared to the effects of TBA. The results obtained suggest that both MTBE and TBA inhibit cell growth in vitro but with different mechanisms in terms of effects on the cell cycle progression and on the modulation of cell cycle regulatory proteins. In fact, MTBE caused an accumulation of cells in the S-phase of the cell cycle, whereas TBA caused an accumulation in the G0/G1-phase with different effects on the expression of cyclin D1, p27Kip1, and p53. Moreover, both MTBE and TBA were also shown to induce DNA damage, as assessed in terms of oxidative DNA damage and nuclear DNA fragmentation, that appeared to be susceptible of repair by the cell DNA-repair machinery. In conclusion, these findings suggest that both MTBE and TBA can exert, by acting through different molecular mechanisms, important biological effects on fibroblasts in vitro. Further studies are warranted to shed light on the mechanisms responsible for the observed effects and on their potential significance for the in-vivo exposure.
Sgambato
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A
Institute of General Pathology, "Giovanni XXIII" Cancer Research Center, Catholic University of Sacred Heart, Rome, Italy.
Iavicoli
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I
De Paola
B
B
Bianchino
G
G
Boninsegna
A
A
Bergamaschi
A
A
Pietroiusti
A
A
Cittadini
A
A
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects*; D020552:Comet Assay; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage; D053938:DNA Fragmentation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008738:Methyl Ethers / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020002:tert-Butyl Alcohol / Q000633:toxicity*
D000393:Air Pollutants; C530106:Ccnd1 protein, rat; D018797:Cell Cycle Proteins; D008738:Methyl Ethers; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C043243:methyl tert-butyl ether; D020002:tert-Butyl Alcohol