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. 2019;82(2):99-112.
doi: 10.1080/15287394.2019.1566105. Epub 2019 Jan 17.

Metal bashing: iron deficiency and manganese overexposure impact on peripheral nerves

Robyn M Amos-Kroohs  1 , Vanina Usach  2 , Gonzalo Piñero  2 , Charles V Vorhees  3   4 , Rocío Martinez Vivot  2 , Paula A Soto  2 , Michael T Williams  3   4 , Patricia Setton-Avruj  2
Affiliations

Metal bashing: iron deficiency and manganese overexposure impact on peripheral nerves

Robyn M Amos-Kroohs et al. J Toxicol Environ Health A. 2019.

Abstract

Iron (Fe) deficiency (FeD) and manganese (Mn) overexposure (MnOE) may result in several neurological alterations in the nervous system. Iron deficiency produces unique neurological deficits due to its elemental role in central nervous system (CNS) development and myelination, which might persist after normalization of Fe in the diet. Conversely, MnOE is associated with diverse neurocognitive deficits. Despite these well-known neurotoxic effects on the CNS, the influence of FeD and MnOE on the peripheral nervous system (PNS) remains poorly understood. The aim of the present investigation was to examine the effects of developmental FeD and MnOE or their combination on the sciatic nerve of young and adult rats. The parameters measured included divalent metal transporter 1 (DMT1), transferrin receptor (TfR), myelin basic protein (MBP) and peripheral myelin protein 22 (PMP22) expression, as well as Fe levels in the nerve. Our results showed that FeD produced a significant reduction in MBP and PMP22 content at P29, which persisted at P60 after Fe-sufficient diet replenishment regardless of Mn exposure levels. At P60 MnOE significantly increased sciatic nerve Fe content and DMT1 expression. However, the combination of FeD and MnOE produced no marked motor skill impairment. Evidence indicates that FeD appears to hinder developmental peripheral myelination, while MnOE may directly alter Fe homeostasis. Further studies are required to elucidate the interplay between these pathological conditions.

Keywords: Iron; manganese; myelination; peripheral nervous system.

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Conflict of interest statement

Conflict of interest: Authors declare no conflict of interest.

Figures

Figure 1:
Figure 1:. Study design.
At E15, dams were removed from the NIH-07 diet and placed on a purified FeS or a purified FeD diet, which differed only in Fe content (350 ppm vs 35 ppm). Male offspring were exposed via gavage to either 100 mg/kg MnCl2 or isotonic VEH every other day from P4 to P28. MnOE and FeD diet were continued until P28, when offspring were placed back on an NIH-07 diet for the remainder of the experiment. Two or three male pups per litter were included in each experimental group, with a total of 3 litters included.
Figure 2:
Figure 2:. Iron content in the sciatic nerve.
A, Perls’ staining of sciatic nerve from P29 in the FeS (n=8) and FeD (n=6) groups. C, Perls’ staining of sciatic nerve from P60 rats (n=4) in both groups in each experimental condition. B, D: Relative Fe quantification. E: Negative control image of a Perls’ staining. Values are expressed as the mean ± SEM in arbitrary units. Statistical analysis was performed through two-way ANOVA followed by Bonferroni post-test (*p< 0.05).
Figure 3:
Figure 3:. MBP levels and distribution in the sciatic nerve.
A, MBP immunofluorescence in sciatic nerve slices from P29 in the FeS (n=8) and FeD (n=6) groups. C, MBP immunofluorescence in sciatic nerve slices from P60 rats in the FeS (n=6) and FeD (n=5) groups in each experimental condition. B, D: IOD quantification for MBP. Values are expressed as the mean ± SEM in arbitrary units. Statistical analysis was performed through two-way ANOVA followed by Bonferroni post-test (*p<0.05,). E: Negative control staining for MBP.
Figure 4:
Figure 4:. PMP22 levels and distribution in the sciatic nerve.
A, PMP22 immunofluorescence in sciatic nerve slices from P29 in the FeS (n=8) and FeD (n=6) groups. C, PMP22 immunofluorescence in sciatic nerve slices from P60 rats in the FeS (n=6) and FeD (n=5) groups in each experimental condition. B, D: IOD quantification for PMP22. Values are expressed as the mean ± SEM in arbitrary units. Statistical analysis was performed through two-way ANOVA followed by Bonferroni post-test (*p<0.05). E: Negative control staining for PMP22.
Figure 5:
Figure 5:. DMT1 levels and distribution in the sciatic nerve.
A, DMT1 immunofluorescence in sciatic nerve slices from P29 in the FeS (n=8) and FeD (n=6) groups. C, DMT1 immunofluorescence in sciatic nerve slices from P60 rats in the FeS (n=6) and FeD (n=5) groups in each experimental condition. B, D: IOD quantification for DMT1. Values are expressed as the mean ± SEM in arbitrary units. Statistical analysis was performed through two-way ANOVA followed by Bonferroni post-test (*p < 0.05). E: Negative control staining for DMT1.
Figure 6:
Figure 6:. TfR levels and distribution in the sciatic nerve.
A, TfR immunofluorescence in sciatic nerve slices from P29 in the FeS (n=8) and FeD (n=6) groups. C, TfR immunofluorescence in sciatic nerve slices from P60 rats (n=5) in both groups in each experimental condition. B, D: IOD quantification for TfR. Values are expressed as the mean ± SEM in arbitrary units. Statistical analysis was performed through two-way ANOVA followed by Bonferroni post-test (*p < 0.05). E: Negative control staining for TfR.
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