Evidence for a role of calcium and vitamin D in the regulation of manganese homeostasis and in the prevention or management of manganese-induced disease.

SLC30A10 mediates manganese (Mn) efflux in both the 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)2D3 in mouse intestine and human enteroids. In addition, in Slc30a10 knockout 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-wk-old male and female mice fed diets either low, adequate, or high in calcium for 4 wk. 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)2D3 and 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 wk, there was a decrease in serum 1,25(OH)2D3, in renal Cyp27b1 and 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)2D3 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.NEW & NOTEWORTHY This study demonstrates that low calcium levels in growing mice markedly elevate Mn in blood and other tissues thus contributing to the pathogenesis of Mn-induced toxicity, that interaction between Mn and calcium are mediated in part by 1,25(OH)2D3 and that there is a protective mechanism of control of Mn homeostasis by vitamin D and calcium with potential therapeutic relevance for prevention or management of Mn induced diseases.