ToxSci Advance Access originally published online on November 6, 2008
Toxicological Sciences 2009 107(2):498-511; doi:10.1093/toxsci/kfn235
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Lung Development in the Holtzman Rat is Adversely Affected by Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
* Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences
Department of Pediatrics, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214
1 To whom correspondence should be addressed at Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Farber Hall 102, 3435 Main Street, Buffalo, NY 14214. Fax: (716) 829-2801. E-mail: jolson{at}buffalo.edu.
Received August 27, 2008; accepted October 27, 2008
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Abstract |
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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that elicits a wide range of toxic effects on the developing organism. In this study, we demonstrate that the fetal and neonatal rat lung contains a responsive Ahr-signaling pathway which upon activation by a gestational exposure to TCDD, leads to altered lung development. Pregnant Holtzman rats received a single oral dose of TCDD (1.5 or 6 µg/kg) on gestation day (GD) 10 or a vehicle control with fetal and neonatal analysis occurring on GD20 or postnatal day (PND) 7. Components of the aryl hydrocarbon receptor (Ahr) signaling pathway (Ahr and Arnt) were identified in the fetal and neonatal lung tissue through the use of real-time PCR and immunohistochemical staining at both time points. Additionally, the Ahr-signaling pathway was found to be responsive to the gestational TCDD exposure as demonstrated by the induction of Cyp1a1, Cyp1b1, and Ahrr in both fetal and neonatal lung tissue. Morphometric analysis of GD20 and PND7 fixed lung tissue sections revealed that treated pups had significant decreases in total airspace area while having significantly wider tissue septa separating the airspaces as well as a decreased dry lung weight to body weight ratio when compared with controls; indicative of lung immaturity and hypoplasia. Finally, the assessment of respiratory mechanics on PND7 pups revealed functionally different pressure-volume curves in TCDD-exposed pups when compared with control animals. Together, these data identify a responsive Ahr-signaling pathway in the developing lung which may be related to the pulmonary immaturity and hypoplasia induced by TCDD and demonstrates that gestational exposure to TCDD alters lung development in such a manner that changes in lung morphology are associated with functional differences in respiratory mechanics.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD; Ahr; Aryl Hydrocarbon receptor; Ahrr; Aryl hydrocarbon receptor repressor; lung development; morphometric analysis; pressure-volume curve; respiratory mechanics.