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.
Lee et al. (Sat,) studied this question.