ToxSci Advance Access originally published online on July 25, 2003
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Toxicological Sciences 75, 423-431 (2003)
Copyright © 2003 by the Society of Toxicology
RESPIRATORY TOXICOLOGY |
Vinyl Acetate Decreases Intracellular pH in Rat Nasal Epithelial Cells
* Department of Cell Biology and Anatomy, Southwest Environmental Health Science Center, The University of Arizona, P.O. Box 245044, Tucson, Arizona 85724, and
DuPont Haskell Laboratory for Health and Environmental Sciences, E. I. DuPont de Nemours and Co., Inc., P.O. Box 50, Newark, Delaware 19714
Vinyl acetate is a synthetic organic ester that has been shown to produce nasal tumors in rats following exposure to 600 ppm in air. The proposed mechanism of action involves the metabolism of vinyl acetate by carboxylesterases and the production of protons leading to cellular acidification. While vinyl acetate–induced decreases in intracellular pH (pHi) have been demonstrated in rat hepatocytes, comparable data from nasal epithelial cells do not exist. Using an in vitro assay system, we have determined the effects of vinyl acetate exposure on pHi in respiratory and olfactory nasal epithelial cells from rats. The respiratory and olfactory epithelial cells were isolated from dissected maxillo- and ethmoturbinates by enzyme digestion. The cells were plated; loaded with the pH-sensitive dye, carboxyseminaphthorhodafluor-1 (SNARF-1); and observed using confocal microscopy. Individual cellular analysis demonstrated that both respiratory and olfactory epithelial cells responded to vinyl acetate exposures with a dose-dependent decrease in pHi. Changes occurred at 100 µM but reached a plateau above 250 µM. Maximal decreases in pHi were 0.3 pH unit in respiratory epithelial cells. While pHi values were normally distributed for the respiratory epithelial cells, the olfactory epithelial cells demonstrated a bimodal distribution, indicating at least two populations of cells, with only one population of cells responding to vinyl acetate. Acidification in these cells did not plateau but continued to increase at 1000 µM. Bis(p-nitrophenyl)phosphate (BNPP), a carboxylesterase inhibitor, was able to attenuate the vinyl acetate–induced decrease in pHi. Data obtained from the isolated cells were validated using tissue explants. These results are consistent with the proposed mode of action for vinyl acetate and supply further data for developing appropriate risk assessments for vinyl acetate exposure.
Key Words: vinyl acetate; nasal epithelial cells; acidification; dose-response; confocal microscopy.
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