Metals are essential for human health yet potentially toxic in excess. Our understanding of metal homeostasis stems prominently from studies of inherited diseases of metal deficiency and excess. The molecular basis of manganese (Mn) homeostasis is poorly understood relative to other metals, given that inherited Mn-related diseases were only recently identified. In 2012, mutations in a metal export protein SLC30A10 were reported in patients with Mn excess, liver and neurologic disease, increased red blood cell counts, and erythropoietin excess. Mn excess was attributed to impaired biliary Mn excretion, while liver, neurologic, and hematologic defects were ascribed to Mn toxicity. Employing our expertise in mammalian metal homeostasis, we recently demonstrated that murine Slc30a10 is not only essential for systemic and biliary Mn excretion but also for Mn export by the small intestine into the lumen of the gastrointestinal tract (Mercadante et al., J Clin Invest., 2019). This indicates that the role of SLC30A10 in Mn homeostasis is more complicated than anticipated and that extrahepatic organs contribute to Mn excretion. In exploring the mechanistic basis of Mn excess in SLC30A10 deficiency, we also observed that Slc30a10-deficient mice develop paradoxically increased Mn absorption despite severe Mn excess. Our preliminary data suggest a multi-step model underlying this surprising observation. First, excess Mn aberrantly stimulates the liver to express the hormone erythropoietin. Second, erythropoietin excess indirectly suppresses expression of the hormone hepcidin, an inhibitor of dietary iron absorption. Third, hepcidin deficiency leads to increased Mn absorption. As a role for hepcidin in Mn homeostasis is not well-established, this last novel step in our model is based upon our observation that pharmacologic stimulation of hepcidin expression decreases Mn levels in Slc30a10-deficient mice . We propose that SLC30A10 deficiency is a unique pathophysiological context in which hepcidin plays an unexpected but pivotal role in development of Mn excess. The goal of this proposal is to establish the mechanistic link between hepcidin and Mn absorption in SLC30A10 deficiency and to explore pharmacologic stimulation of hepcidin expression as a treatment for Mn excess in SLC30A10 deficiency and other conditions. This will be accomplished using genetic, metabolic, pharmacologic, radioisotopic, dietary, and microscopic techniques. The proposed studies will enable us to not only further establish the molecular basis of mammalian Mn homeostasis but also to design therapeutic strategies for Mn-related diseases based upon our understanding of underlying mechanisms of Mn homeostasis.

Public Health Relevance

Obtained from the diet, the metal manganese is essential for health yet can be toxic in excess. Our research investigates the mechanisms by which manganese levels are regulated in the body. Our studies will enable us to better identify those at risk of manganese-related disease and treat those affected by such diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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Brown University
Schools of Medicine
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Foster, Melanie L; Bartnikas, Thomas B; Maresca-Fichter, Hailey C et al. (2018) Neonatal C57BL/6J and parkin mice respond differently following developmental manganese exposure: Result of a high dose pilot study. Neurotoxicology 64:291-299
Thomason, Rebecca T; Pettiglio, Michael A; Herrera, Carolina et al. (2017) Characterization of trace metal content in the developing zebrafish embryo. PLoS One 12:e0179318
Foster, Melanie L; Bartnikas, Thomas B; Maresca-Fichter, Hailey C et al. (2017) Interactions of manganese with iron, zinc, and copper in neonatal C57BL/6J and parkin mice following developmental oral manganese exposure. Data Brief 15:908-915
Mercadante, Courtney J; Herrera, Carolina; Pettiglio, Michael A et al. (2016) The effect of high dose oral manganese exposure on copper, iron and zinc levels in rats. Biometals 29:417-22
Pettiglio, Michael A; Herrera, Carolina; Foster, Melanie L et al. (2016) Liver metal levels and expression of genes related to iron homeostasis in rhesus monkeys after inhalational manganese exposure. Data Brief 6:989-97