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Extracellular Factor(s) following Exposure to Particles Can Cause Sister Chromatid Exchanges in Normal Human Cells¹

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

The mechanism(s) by which particles like those emitted from inhaled radon and radon progeny cause their mutagenic and carcinogenic effects remains unclear. Although direct nuclear traversals by particles may be involved in mediating these outcomes, increasing evidence indicates that particles can cause alterations in DNA in the absence of direct "hits" to cell nuclei. Using the occurrence of excessive sister chromatid exchanges (SCEs) as an index of DNA damage in human lung fibroblasts, we investigated the hypothesis that particles may induce DNA damage via the generation of extracellular factors. We have found that a relatively low dose of particles indeed results in the generation of extracellular factors, which, upon transfer to unexposed normal human cells, can cause excessive SCEs to an extent equivalent to that observed when the cells are directly irradiated with the same irradiation dose. A short-lived, SCE-inducing factor(s) was generated in -irradiated culture medium containing serum in the absence of cells; it was found that the activity of this factor can be promptly inhibited by superoxide dismutase. A more persistent SCE-inducing factor(s), which can survive freeze-thawing, is heat labile and also can be inhibited by superoxide dismutase, was produced by fibroblasts after exposure to particles. These results indicate that the initiating target for -particle-induced genetic changes can be larger than the nuclear compartment alone and even larger than the cytoplasmic compartment. How transmissible factors like those observed here in vitro may extend to the in vivo condition in the context of -particle-induced carcinogenesis in the respiratory tract and elsewhere remains to be determined.

¹ This investigation was supported by United States Department of Energy-funded projects entitled "Latent Expression of Genetic Damage in Human Lung Cells Caused by Particles and -Rays," "Mechanisms of Pulmonary Damage," and "Chromosome Damage in the One Rad Region," and the work was conducted under the auspices of the Department of Energy.

² To whom requests for reprints should be addressed, at Cell and Molecular Biology Groups, Life Sciences Division, MS M888, Los Alamos National Laboratory, Los Alamos, NM 87545. Phone: (505) 667-2753; Fax: (505) 665-3024; E-mail: lehnert@telomere.lanl.gov.

Received 10/21/96. Accepted 4/ 2/97.

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