Abstract
BackgroundGiven mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism.MethodsArchived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: HFE [hemochromatosis], TF [transferrin], and ALAD [δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data.ResultsPercentage of participants carrying at least one copy of HFE C282Y, HFE H63D, TF P570S, and ALAD K59N variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either C282Y or H63D allele in HFE gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any HFE variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). TF and ALAD variants were not significant predictors of blood manganese. In animal models, Hfe-/- mice displayed a significant reduction in blood manganese compared with Hfe+/+ mice, replicating the altered manganese metabolism found in our human research.ConclusionsOur study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.
Highlights
Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism
Compared to wildtype HFE carriers, geometric mean manganese was lower among carriers of HFE variants (any HFE variant: 15.4 (1.5) μg/L vs. wildtype: 17.4 (1.5) μg/L, p = 0.04)
The results showed a similar pattern: mean blood manganese was lower among Hfe-/- mice compared with Hfe +/+ mice (6.0 ± 1.8 ng/g vs. 8.7 ± 2.1 ng/g for Hfe-/- and Hfe+/+ mice, respectively; n = 5 per genotype; p = 0.06), suggesting that blood manganese levels are lower in HFE-deficient mice regardless of age and pregnancy history
Summary
Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism. Given the emerging evidence for adverse effects from excess manganese exposure, it is critical to understand host factors that affect manganese metabolism. Such factors may provide mechanistic clues for future interventions or may identify susceptible subpopulations. There is a well-known inverse association between iron stores and manganese absorption. Iron deficiency results in increased absorption and retention of manganese in various organs [17,18,19,20,21]. It is likely that iron and manganese share the same transport and regulatory proteins, and at least one factor, Divalent Metal Transporter-1 (DMT1), is known to mediate uptake of both cations [25]
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