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Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water

Immunosciences Lab, Inc., Drew University School of Medicine and Science, Department of Medicine, Division of Dermatology

Eli Mordechai

Immunosciences Lab, Inc., Drew University School of Medicine and Science

Nachman Brautbar

Center for Internal, Occupational, and Toxicological Medicine, University of Southern California, School of Medicine, Department of Medicine, Los Angeles, California, USA

1 In this study we hypothesized that in individuals with certain genetic makeup, MTBE, benzene or their metabolites act as adducts and may induce pro grammed cell death.

2 Our study involved a group of 60 male and female subjects who were exposed to MTBE and benzene- 5 contaminated water 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 distribution 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 indivi duals were compared to apoptotic lymphocytes from the control group, statistically-significant 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 ben- a zene-induced apoptosis is attributed to a discrete block within the cell cycle progression. Because cell cycle analysis showed that in PBL from chemically-exposed individuals, between 20-50% of cells were accumu lated at the S-G₂/M boundaries.

One of the signaling molecules which mediates programmed cell death is nuclear factor Kappa-B (NF-kB). NF-kB was examined as one of the many molecular mechanisms for mediating cell death by MTBE and benzene. Indeed, addition of inhibitors of NF-kB activation pyrrolidine dithiocarbamate (PDTC), to the lymphocytes of the chemically-exposed group was capable of inhibiting programmed cell death by 40%. This reversal of apoptosis almost to the control level by inhibitor of NF-kB activation may indicate involvement of this signaling molecule in MTBE and benzene induction of programmed cell death.

Key Words: methyl tertiary-butyl ether • programmed cell death • poptosis • cell cycle progression • nuclear factor Kappa-B

Human & Experimental Toxicology, Vol. 16, No. 9, 485-494 (1997)
DOI: 10.1177/096032719701600902


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