Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin adversely affects lung development
Kransler, Kevin Michael
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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that elicits a wide range of toxic effect by binding to and activating the aryl hydrocarbon receptor (Ahr), a cytosolic ligand activated transcription factor. In mature laboratory animals, adverse effects on the lung have been observed after chronic exposure to TCDD and include lesions such as alveolar-bronchiolar metaplasia, hyperplasia of the bronchiolar epithelium, adenomatous hyperplasia and keratinizing squamous cell carcinoma. We hypothesized that the developing lung may also be adversely affected by TCDD which may represent a significant factor contributing to the high rate of perinatal mortality observed after gestational exposure. Pregnant Holtzman rats received a single oral dose of TCDD (1.5 or 6μg/kg) on gestation day (GD) 10 or a vehicle control with fetal and neonatal analysis occurring on GD20 or post natal day (PND) 7. High rates of mortality were observed on GD20 and PND7 in the TCDD exposure groups. Pups gestationally exposed to TCDD also exhibited signs of lung hypoplasia indicated by significant decreases in organ weight. 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 septa separating the airspaces when compared to controls. Assessment of respiratory mechanics on PND7 pups revealed functionally different pressure-volume curves in TCDD exposed pups when compared to control animals. Mathematically modeling these pressure-volume curves generated data indicating the TCDD exposed animals had increased elastic properties. Together, the results in this dissertation identify the developing lung as target for the toxicity of TCDD and shed light on the observation that lung hypoplasia is accompanied by significant alterations in morphology and respiratory mechanics. Furthermore, since developing organisms are particularly sensitive to TCDD, these data suggest that the developing human lung could be equally sensitive to TCDD.