Abstract
SLC30A10 mediates Mn efflux in both intestine and liver, protecting against Mn toxicity. In previous studies we found that Slc30a10 is one of the genes most induced by 1,25(OH)(2)D(3) in mouse intestine and human enteroids. In addition, in Slc30a10 knock out mice we noted a significant decrease in Trpv6, a vitamin D target gene involved in intestinal calcium transport indicating a link between Mn efflux transport in the intestine, calcium and the vitamin D endocrine system. In this study we examined the effect of varying levels of Mn in 3-week-old male and female mice fed diets either low, adequate or high in calcium for 4 weeks. Mn levels were markedly elevated in the mice fed the low calcium diets (0.02%, 0.1%) in tissues and blood. Under low calcium conditions serum 1,25(OH)(2)D(3) as well as intestinal Slc30a10 were induced as possible compensatory mechanisms to manage Mn toxicity. However, when older mice were similarly fed a high Mn low calcium diet for 4 weeks, there was a decrease in serum 1,25(OH)(2)D(3), in renal Cyp27b1 as well as either no effect or a decreased Mn response to low calcium in tissues and blood. Our findings indicate that low dietary calcium may contribute to the pathogenesis of Mn-induced toxicity, that the interactions between Mn and calcium are mediated in part by 1,25(OH)(2)D(3) and that there is a protective mechanism of control of Mn homeostasis by vitamin D and calcium with potential therapeutic relevance for the prevention or management of Mn induced disease.