The toxicity of perfluorooctane sulfonate (PFOS) to the developing lung in rats.

摘要

Prenatal exposure to perfluorooctane sulfonate (PFOS) in rodents leads to mortality in newborns within hours to days after birth; the underlying pathophysiology remains unknown. We have shown that a critical period for this insult exists late in gestation, with exposure on gestation days (GD) 19-20 sufficient to induce neonatal death. Pups exposed to high levels of PFOS were born alive but presented with labored breathing that worsened until death, and lungs from these pups were pale and unable to expand fully upon perfusion. Therefore, we hypothesized that PFOS exposure interrupted terminal airway maturation and differentiation, resulting in deficient pulmonary surfactant production and leading to respiratory distress in the neonate.; Results from histological and morphometric analyses indicated that lungs from PFOS-exposed pups had thicker alveolar septal walls, suggestive of immaturity, compared to those of controls. However, treatment with dexamethasone or retinyl palmitate did not significantly ameliorate the PFOS-induced mortality, suggesting that lung immaturity was likely not the primary cause of death. Phospholipid analysis showed that lungs of PFOS-exposed pups were capable of synthesizing normal pulmonary surfactant. Additionally, ultrastructural analysis of newborn lung tissue confirmed that surfactant was being properly stored in the AEC-II cells of neonates in all treatment groups. A moderate increase in lamellar bodies was noted in samples from the 50 mg/kg group, leading us to suspect surfactant secretion was being inhibited. However, analysis of F-actin and beta-tubulin localized expression in newborn lung tissue using ICC revealed no differences between control and 50 mg/kg neonates, suggesting that intracellular transport of the lamellar bodies was likely unaffected by PFOS exposure. Additionally, we detected SP-B in newborn bronchoalveolar lavage fluid from all groups, indicating that pulmonary surfactant was present in the airways and suggesting that secretion was not inhibited by late gestational exposure to PFOS. These findings were supported by microarray analysis and proteomic studies, in which no changes in markers of ABC maturation and differentiation or the surfactant biosynthetic pathway were detected. Alternative reasons for the PFOS-induced effects we observed in the alveolar interstitium as well as other potential mechanisms leading to pulmonary toxicity and neonatal mortality must be considered.