Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice

Abstract

Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1?h after contact with crocidolite. Intraperitoneal injection of 3?mg crocidolite ultimately induced malignant mesothelioma in ～50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p?=?0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.     

Quantitative detection of asbestos fiber in gravelly sand using elastic body-exposure method

Chrysotile or crocidolite colloidal solution containing donor plasmid DNA and Escherichia coli cells was subjected to elastic body friction. These acicular clay minerals mediated E. coli antibiotic resistance plasmid transformation. Other clay minerals had no effect on E. coli transformation. The number of E. coli transformants was counted after elastic body exposure with various crocidolite concentrations. There was a correlation between the number of E. coli transformants and crocidolite concentration (between 40 and 1,000 ng/ml). A mixture consisting of sea sand and crocidolite was utilized as a model for quantitative detection of asbestos in gravelly sand. With sea sand containing 0.15–15 mg of crocidolite, a correlation between crocidolite concentration and the number of colonies derived from E. coli transformants was observed. This indicates that measurement of asbestos is possible even when the asbestos sample includes gravelly sand. Fluorescence microscopic observation of crocidolite colloidal solution indicated that crocidolite was present as spherical aggregates having diameters of 6–9 μm. Thus, the number of transformants correlated with that of 6–9 μm crocidolite aggregates.