Superfund Research Program
Toxicological Impact of Mine Tailings Dust on Lung Epithelial Barrier Function
Project Leader: Robert Clark Lantz
Co-Investigators: Scott Boitano, Donna D. Zhang
Grant Number: P42ES004940
Funding Period: 2005-2020
Final Progress Reports
In utero and early postnatal exposure to arsenic in drinking water at environmentally relevant doses alters future lung development and function. The research program previously has shown that exposure of pregnant mice to arsenic at 10, 50 and 100 ppb in drinking water during lung development leads to increased airway reactivity and alterations in pulmonary resistance. These changes are specific for exposure during lung development and are not reversible. This result suggested that at least part of the functional changes may be due to anatomical alterations. The researchers have found that arsenic exposure during development resulted in a dose-dependent increase in the levels of smooth muscle around airways. These alterations were seen mostly in smaller airways. Changes in smooth muscle were accompanied by decreases in collagen levels, suggesting that at least part of the increased airway smooth muscle could be due to decreased collagen expression. Because arsenic may affect methylation status, the team tested the effect of dietary folate supplementation. Folate supplementation reduced the arsenic-induced airway reactivity (50 ppb arsenic) and eliminated the arsenic-induced increases in airway smooth muscle (50 and 100 ppb arsenic). Alterations in airway connective tissue and smooth muscle and increases in airway reactivity suggest that arsenic may be affecting expression of mediators such as TGFβ-1, MMP-9, or IL-13. The researchers measured the levels of these mediators in whole lung and have found that arsenic exposure leads to increased protein expression of all of these mediators on day 12 after birth. Taken together, these data indicate that exposure to environmentally relevant levels of arsenic in drinking water during sensitive developmental times can lead to adverse, irreversible alterations in lung function and structure. Dietary intervention with folate was effective at reducing arsenic-induced functional and structural alterations but only at exposure levels of 50 ppb and lower.