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Factors Underlying the Cell Growth-related Bystander Responses to Particles¹

Cell and Molecular Biology Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545

Increases in cell proliferation are widely viewed as being of importance in carcinogenesis. We report that exposure of normal human lung fibroblasts to a low dose of particles like those emitted by radon/radon progeny stimulates their proliferation in vitro, and this response also occurs when unirradiated cells are treated with supernatants from -irradiated cells. We attribute the promitogenic response to superoxide dismutase- and catalase-inhibitable particle-induced increases in the concentrations of transforming growth factor ß1 (TGF-ß1) in cell supernatants. TGF-ß1 at concentrations commensurate with those in the supernatants capably induces increases in intracellular reactive oxygen species (ROS) in unirradiated cells. Furthermore, the addition of supernatants from -irradiated cells to unirradiated cells decreases cellular levels of TP53 and CDKN1A and increases CDC2 and proliferating cell nuclear antigen in the latter. Like the increased intracellular ROS bystander effect, this "decreased TP53/CDKN1A response" can be mimicked in otherwise untreated cells by the addition of low concentrations of TGF-ß1. Our results indicate that particle-associated increases in cell growth correlate with intracellular increases in ROS along with decreases in TP53 and CDKN1A, and that these cellular responses are mechanistically coupled. As well, the proliferating cell nuclear antigen and CDC2 increases that occur along with the decreased TP53/CDKN1A bystander effect also would expectedly favor enhanced cell growth. Such processes may account for cell hyperplastic responses in the conducting airways of the lower respiratory track that occur after inhalation exposure to radon/radon progeny, as well as, perhaps, other ROS-associated environmental stresses.

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