Postnatal Iron Supplementation Fails to Fully Rescue Brain Metal and Transcriptional Defects Caused by Nutrition-Based Gestational Iron Deficiency.

BACKGROUND

Gestational iron deficiency (GID) is associated with long-term cognitive and behavioral impairments in offspring, but the effectiveness of postnatal iron supplementation in restoring brain metal homeostasis and developmental programming remains unclear.

OBJECTIVES

This study aimed to determine how the timing of postnatal iron supplementation influences brain metal homeostasis and long-term gene expression after GID.

METHODS

A nutrition-based mouse model included 3 groups: nutritional iron-normal controls (NIN; 240 mg iron (Fe)/kg diet), GID offspring repleted with iron at birth (P0GID), and at postnatal day 7 (P7GID). Dams received an iron-deficient diet (2.2 mg Fe/kg) before and during gestation. Fe, copper (Cu), zinc (Zn), calcium (Ca), manganese (Mn), and magnesium (Mg) concentrations were measured in blood, cerebral cortex, and hippocampus at postnatal days (P) 7, P14, and P40 using inductively coupled plasma mass spectrometry. Cohorts contained 7 to 19 offspring mice from ≥3 litters. Metal concentrations were analyzed using linear models controlling for age, sex, litter size, treatment, and treatment-by-age interactions. Spatial transcriptomics, cell-type deconvolution, differential expression, and gene set enrichment analyses were performed in P40 male P7GID and NIN brains (n = 3/group).

RESULTS

GID caused persistent, region-specific disruptions in brain metal homeostasis that were not fully corrected by postnatal iron supplementation. At P40, cortical Mg was significantly reduced, whereas hippocampal Fe, Cu, Mn, and Ca were significantly elevated relative to NIN controls (all P < 0.05). Developmental trajectories of Fe, Zn, Mn, and Ca differed significantly between treatment groups. Blood metal concentrations poorly reflected brain metal status in GID, with significant correlations for Fe observed only at P7 and P14 in the P7GID cortex (P < 0.03). Transcriptomic analyses revealed persistent dysregulation of iron-responsive, myelination-related, and neurodevelopmental pathways.

CONCLUSIONS

GID induces lasting alterations in brain metal balance and developmental gene expression programs that are not fully rescued by postnatal iron supplementation, highlighting gestation as a critical window for iron-dependent neurodevelopment.