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ToxSci Advance Access published online on October 13, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi006
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received August 25, 2004
Accepted October 6, 2004

Respiratory Toxicology

Propylene Oxide in Blood and Soluble Non-Protein Thiols in Nasal Mucosa and Other Tissues of Male Fischer 344/N Rats Exposed to Propylene Oxide Vapors - Relevance of Glutathione Depletion for Propylene Oxide Induced Rat Nasal Tumors

Moung S. Lee 1, Thomas H. Faller 2, Paul E. Kreuzer 2, Winfried Kessler 2, György A. Csanády 1, Christian Pütz 2, Melva N. Ríos-Blanco 3, Lynn H. Pottenger 4, Dan Segerbäck 5, Siv Osterman-Golkar 6, James A. Swenberg 3, and Johannes G. Filser 1*

1 Institute of Toxicology, GSF National Research Center for Environment and Health, D-85764 Neuherberg, Germany; Institut für Toxikologie und Umwelthygiene, Technische Universität München, München, Germany
2 Institute of Toxicology, GSF National Research Center for Environment and Health, D-85764 Neuherberg, Germany
3 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
4 Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674, USA
5 Department of Biosciences, Karolinska Institute, Novum, S-14157 Huddinge, Sweden
6 Department of Molecular Biology and Functional Genomics, Stockholm University, S-10691 Stockholm, Sweden

* To whom correspondence should be addressed. E-mail: johannes.filser{at}gsf.de.


  Abstract

High concentrations of propylene oxide (PO) induced inflammation in the respiratory nasal mucosa (RNM) of rodents. Concentrations ≥300 ppm caused nasal tumors. In order to investigate if glutathione depletion could be relevant for these effects, we determined in PO exposed male Fischer 344/N rats PO in blood and soluble non-protein SH-groups (NPSH) in RNM and other tissues. Rats were exposed once (6h) to PO concentrations between 0 and 750 ppm, and repeatedly for up to 20 days (6h, 5d/w) to concentrations between 0 and 500 ppm. At the end of the exposures, PO in blood and NPSH in tissues were determined. PO in blood was dependent on concentration and duration of exposure. After the one-day exposures, NPSH depletion was most distinctive (RNM > liver > lung). Compared to controls, NPSH levels were 43% at 50 ppm PO in RNM and 16% at ≥300 ppm in both RNM and liver. Lung-NPSH fell linearly to 20% at 750 ppm. After repeated exposures over 3 and 20 days to 5, 25, 50, 300 and 500 ppm, NPSH losses were less pronounced. At both time-points, NPSH were 90%, 70%, 50%, 30% and 30% of the control values in RNM. Liver-NPSH decreased to 80% and 50% at 300 and 500 ppm, respectively. After 20 days, lung-NPSH declined to 70% (300 ppm) and 50% (500 ppm). We conclude that continuous, severe perturbation of GSH in RNM following repeated high PO exposures may lead to inflammatory lesions and cell proliferation, critical steps on the path towards tumorigenicity.

Keywords: Propylene oxide; Glutathione; Lung; Liver; Blood; Inhalation; Respiratory nasal mucosa; Rat.
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