Carcinogenesis, Vol 18, 423-430, Copyright © 1997 by Oxford University Press
KE Driscoll, LC Deyo, JM Carter, BW Howard, DG Hassenbein and TA Bertram
To investigate mechanisms underlying development of lung adenomas and
carcinomas in rats exposed to poorly soluble particles the relationships
between particle exposure, inflammation and mutagenesis in rat alveolar
type II cells were characterized. Rats were exposed to saline or saline
suspensions of 10 and 100 mg/kg of alpha-quartz, carbon black or titanium
dioxide by intratracheal instillation. Fifteen months after exposure,
bronchoalveolar lavage (BAL) cells were characterized as to number and type
and lung histopathology performed. The alveolar type II cells were isolated
and cultured in 6 thioguanine (6TG) containing media to select for mutation
in the hprt gene. The potential contribution of lung inflammatory cells to
in vivo mutagenic responses, were evaluated by co-culturing BAL cells with
the rat alveolar epithelial cell line, RLE-6TN for 24 h and the RLE-6TN
cells selected for 6TG resistance. Neutrophilic inflammation was detected
in all rats exposed to 10 and 100 mg/kg of alpha-quartz and carbon black
and 100 mg/kg titanium dioxide; epithelial hyperplasia was observed in rats
exposed to 10 and 100 mg/kg of alpha-quartz and 100 mg/kg carbon black.
Hprt mutation frequency was increased in alveolar type II cells from rats
exposed to 10 and 100 mg/kg of alpha-quartz, 100 mg/kg carbon black and 100
mg/kg titanium dioxide. In vitro exposure of RLE-6TN cells to BAL cells
from rats treated with 10 and 100 mg/kg of alpha- quartz or 100 mg/kg
carbon black increased hprt mutant frequency. Both macrophage and
neutrophil enriched BAL cell populations were mutagenic to RLE-6TN cells,
however, the mutagenic activity appeared greatest for neutrophils. Addition
of catalase to BAL cell:RLE-6TN co-cultures inhibited the increase in hprt
mutation frequency. These studies demonstrate exposure of rats to doses of
particles producing significant neutrophilic inflammation is associated
with increased mutation in rat alveolar type II cells. The ability of
particle- elicited macrophages and neutrophils to exert a mutagenic effect
on epithelial cells in vitro supports a role for these inflammatory cells
in the in vivo mutagenic effects of particle exposure. The inhibition of
BAL cell-induced mutations by catalase implies a role for cell- derived
oxidants in this response.
ARTICLES
Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar epithelial cells
The Procter and Gamble Company, Miami Valley Laboratories, Cincinnati, OH 45253, USA.
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