ABNORMAL APOPTOSIS AND CELL-CYCLE PROGRESSION IN HUMANS EXPOSED TO METHYL TERTIARY-BUTYL ETHER AND BENZENE CONTAMINATING WATER

1 In this study we hypothesized that in individuals with certain genet ic makeup, MTBE, benzene or their metabolites act as adducts and may i nduce programmed cell death. 2 Our study involved a group of 60 male a nd female subjects who were exposed to MTBE and benzene-contaminated w ater concentrations up to 76 PPB for MTBE and 14 PPB for benzene, for a period of 5 to 8 years. For comparison, we recruited a control group consisting of 32 healthy males and females with similar age distribut ion and without a history of exposure to MTBE or benzene. 3 Peripheral blood lymphocytes (PBL) of both groups were tested for the percentage of apoptotic cells and cell cycle progression using flow cytometry. 4 When apoptotic lymphocytes from exposed individuals were compared to apoptotic lymphocytes from the control group, statistically-significan t differences between each mean group were detected (26.4 +/- 1.8 and 12.1 +/- 1.3, respectively), indicating an increased rate of apoptosis in 80.5% of exposed individuals (P<0.0001, Mann-Whitney U-Test), MTBE and benzene-induced apoptosis is attributed to a discrete block withi n the cell cycle progression. Because cell cycle analysis showed that in PBL from chemically-exposed individuals, between 20-50% of cells we re accumulated at the S-G(2)/M boundaries. 5 One of the signaling mole cules which mediates programmed cell death is nuclear factor Kappa-B ( NF-LE). NF-kB was examined as one of the many molecular mechanisms for mediating cell death by MTBE and benzene, Indeed, addition of inhibit ors of NF-kB activation pyrrolidine dithiocarbamate (PDTC), to the lym phocytes of the chemically-exposed group was capable of inhibiting pro grammed cell death by 40%. This reversal of apoptosis almost to the co ntrol level by inhibitor of NF-kB activation may indicate involvement of this signaling molecule in MTBE and benzene induction of programmed cell death.