Role of excretion in manganese homeostasis and neurotoxicity: a historical perspective

Abstract

The essential metal manganese (Mn) induces incurable neurotoxicity at elevated levels that manifests as parkinsonism in adults and fine motor and executive function deficits in children. Studies on Mn neurotoxicity have largely focused on the role and mechanisms of disease induced by elevated Mn exposure from occupational or environmental sources. In contrast, the critical role of excretion in regulating Mn homeostasis and neurotoxicity has received less attention although (1) studies on Mn excretion date back to 1920s; (2) elegant radiotracer Mn excretion assays in the 1940s-60s established the routes of Mn excretion; and; (3) studies in patients with liver cirrhosis in the 1990s-2000s identified an association between decreased Mn excretion and the risk of developing Mn-induced parkinsonism in the absence of elevated Mn exposure. Notably, the last few years have seen renewed interest in Mn excretion largely driven by the discovery that hereditary Mn neurotoxicity due to mutations in SLC30A10 or SLC39A14 are caused, at least in part, by deficits in Mn excretion. Quite remarkably, some of the recent results on SLC30A10 and SLC39A14 provide explanations for observations made ~40-50 years ago. The goal of the current review is to integrate the historic studies on Mn excretion with more contemporary recent work, and provide a comprehensive state-of-the-art overview of Mn excretion and its role in regulating Mn homeostasis and neurotoxicity. A related goal is to discuss the significance of some of the foundational studies on Mn excretion so that these highly consequential earlier studies remain influential in the field.

Short- and long-term exposure to trace metal(loid)s from the production of ferromanganese alloys by personal sampling and biomarkers

“…3 ), being unable to differentiate between highly and moderately exposed groups (medians 9.16 µg/L vs. 9.18 µg/L, p = 0.865), even after adjusting for potential confounders. This is in agreement with previous studies reporting that Mn levels are tightly regulated in this matrix, with excess being quickly eliminated by the liver and excreted in bile and urine (Gurol et al, 2022 ). The correlation analysis also confirmed that whole blood cannot be used as biomarker of environmental exposure to Mn with epidemiological purposes, as it did not show significant correlations with any of the Mn fractions analysed in PM, nor with other biomarkers, nor with distance to the source.…”

The Mitochondrial RNA Granule Modulates Manganese-Dependent Cell Toxicity

“…However, we found that the expression of influx manganese transporters was each decreased to ~60% in these mutant cells (Fig. 6C, SLC11A2, SLC39A8 and SCL39A14) (46, 47). These transporter phenotypes were different from the phenotypes in SLC30A10 Δ cells (Fig.…”

Activity of the manganese efflux transporter SLC30A10 in dopaminergic but not GABAergic neurons protects against neurotoxicity

“…Note that, in addition to the basal ganglia regions, we included the thalamus in these assays because it expresses SLC30A10 30 and receives the basal ganglia output 23,24 , and we conducted the experiment at PND 21 because previous studies show that the effect of oral Mn exposure on brain Mn levels is highest in early postnatal life (i.e. around PND 21) before Mn excretory capacity of rodents is fully developed 22,39-41 . Importantly, Mn treatment also increased blood Mn levels at PND 21, but there was no difference between pan-neuronal/glial knockouts and littermate controls ( Fig.1C ), implying that Mn level increases observed in the basal ganglia and thalamus of the pan-neuronal/glial knockouts were independent of the excretory function of SLC30A10.…”

“…Mn-induced parkinsonism is also recognized in individuals with compromised hepatic excretory function (e.g. due to cirrhosis), even in the absence of elevated Mn exposure, because Mn is primarily excreted by the liver 22 . More recently, epidemiological studies have suggested that environmental Mn exposure (e.g.…”