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Induction of Lung Lesions in Female Rats Following Chronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin
Angelika M. Tritscher
Nestle Research Center, PO Box 44, CH-1000 Lausanne 26, Switzerland, tritscher{at}rdls.nestle.com
Joel Mahler
Laboratory of Experimental Pathology
Christopher J. Portier
Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
George W. Lucier
Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
Nigel J. Walker
Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA
2,3,7,8,-Tetrachlorodibenzo- p-dioxin (TCDD) has been classified as a known human carcinogen, and epidemiologic studies identify the lung as one of the target organs. Few experimental studies have attempted to characterize pulmonary effects of TCDD exposure. In this study, we characterize the induction of lesions in the lung by chronic oral TCDD exposure in diethylnitrosamine (DEN)-initiated or noninitiated female Sprague-Dawley rats. Two or 18 weeks after initiation, rats were treated with TCDD continuously for 14, 30, or 60 weeks by biweekly oral gavage (1,750 ng TCDD/kg) at a dose equivalent to 125 ng/kg body weight per day (controls received corn oil). To assess the time dependence and reversibility of potential changes, some groups included withdrawal periods of 16 or 30 weeks after 30 weeks of TCDD treatment. TCDD treatment alone for 60 weeks caused significant increases in alveolar-bronchiolar (AB) metaplasia. TCDD treatment of DEN-initiated animals for 60 weeks resulted in a significant increase in bronchiolar epithelial hyperplasia. These increases were not observed in animals treated with TCDD for 30 weeks followed by corn oil for 30 weeks, indicating that the development of these lesions required continuous exposure to TCDD. AB hyperplasia increased in an age-dependent manner after DEN initiation but was unaffected by TCDD treatment. Expression of the aromatic hydrocarbon receptor (AHR) and induction of CYP1A1 was observed only in bronchiolar Clara and ciliated cells, indicating that the mechanism of induction of AB metaplasia may be mediated by the AHR. TCDD elimination half-life was monophasic in the lung, and serum and was estimated to be 39.7 days and 44.6 days, respectively, independent of age, tissue TCDD concentration, or body weight. This is the first report to identify the AB region as a target for TCDD-induced metaplastic and proliferative changes after chronic oral exposure.
Key Words: TCDD • hyperplasia • metaplasia • tissue concentration • CYP1A1 • half-life
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Toxicologic Pathology, Vol. 28, No. 6,
761-769 (2000)
DOI: 10.1177/019262330002800601
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