Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats.

High levels of airborne manganese can be neurotoxic, yet little is known about absorption of this metal via the lungs. Intestinal manganese uptake is upregulated by iron deficiency and is thought to be mediated by divalent metal transporter 1 (DMT1), an iron-regulated factor known to play a role in dietary iron absorption. To better characterize metal absorption from the lungs to the blood and test whether iron deficiency may modify this process, the pharmacokinetics of pulmonary manganese and iron absorption by control and iron-deficient rats were compared. Levels of DMT1 expression in the lungs were determined to explore potential changes induced by iron deficiency that might alter metal absorption. The pharmacokinetic curves for intratracheally instilled (54)Mn and (59)Fe were significantly different, suggesting that pulmonary uptake of the two metals involves different mechanisms. Intratracheally instilled iron-deficient rats had significantly higher blood (54)Mn levels, whereas blood (59)Fe levels were significantly reduced compared with controls. The same trend was observed when radioisotopes were delivered by intravenous injection, indicating that iron-deficient rats have altered blood clearance of manganese. In situ analysis revealed the presence of DMT1 transcripts in airway epithelium; however, mRNA levels did not change in iron deficiency. Although lung DMT1 levels and metal absorption did not appear to be influenced by iron deficiency, the differences in blood clearance of instilled manganese identified by this study support the idea that iron status can influence the potential toxicity of this metal.