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

Abstract

of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats. Am J Physiol Lung Cell Mol Physiol 288: L887-L893, 2005. First published December 23, 2004; doi:10.1152/ajplung.00382.2004.-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. divalent metal transporter 1; iron metabolism; manganese toxicity; lung metal absorption NEUROTOXIC EFFECTS OF MANGANESE due to occupational airborne exposures are well documented. Workers exposed to high concentrations often display a Parkinson's-like disorder called manganism (24,25,31,35). More recently, concern has been raised over the potential consequences of chronic low-level airborne exposures due to the introduction of methylcyclopentadienyl manganese tricarbonyl (MMT), a gasoline additive (3). Despite the importance of understanding the molecular basis for intoxication by airborne manganese, however, absorption of this metal from the lungs to the blood has yet to be fully explored.Divalent metal transporter 1 (DMT1), a transporter that interacts with both iron and manganese (12,21,22), is expressed by airway epithelial cells (36) and could be involved in active uptake of both metals by the lungs. Two of the known DMT1 mRNA isoforms contain iron-responsive elements (IREs) and are therefore subject to potential regulation by iron response proteins (23). Iron deficiency is known to be an important modifier of manganese absorption in the gut (8,9,20,26,37), an...

HFE Genotype, Particulate Air Pollution, and Heart Rate Variability

“…The HFE variant may reduce immediate absorption of toxic divalent metals in particulate matter, because subjects with this variant have higher iron stores and downregulated iron absorption. Recently, Heilig et al 35 demonstrated that iron-deficient rats will absorb increased levels of manganese instilled in the lungs. The present findings are consistent with those results and support the hypothesis that genes that regulate intestinal absorption of divalent metals also regulate pulmonary metal absorption.…”

Manganese neurotoxicity: A focus on the neonate

“…Kidney studies remain to show the importance of DMT1 as well as different isoforms (Abouhamed et al, 2006;Canonne-Hergaux & Gros, 2002;Wareing et al, 2003;. Pharmacokinetic studies show that iron status can alter lung Mn transport to circulation Heilig et al, 2005;Thompson et al, 2006) DMT1 is not the transporter involved . Recently is has been verified that the b/b Belgrade rat lacks transport mechanisms for divalent metals in its small intestine (Knopfel et al, 2005).…”

Manganese Transport Across the Pulmonary Epithelium

“…79 Surprisingly, 54 Mn also failed to associate with Tf present in BAL from control rats. 64 This combined evidence completely rules out a role for DMT1, suggesting the existence of additional transport pathways for manganese in the lungs. …”

“…[61][62][63] These channels, and others, are thought to maintain fluid balance in lungs, but potential roles in the transport of manganese and other metals are possible as well. 64 …”

“…Interestingly, iron-deficient rats had increased 54 Mn in the brain suggesting that iron status can modify the potential toxicity of metal taken up by pulmonary absorption, potentially through plasma transport pathways. 64 …”