GESTATIONAL ALCOHOL EXPOSURE IMPAIRS MATERNAL‐FETAL IRON HOMEOSTASIS THROUGH HEPCIDIN DYSREGULATION

Abstract

Prenatal alcohol exposure (PAE) causes lifelong neurodevelopmental deficits. Gestational iron deficiency (ID) mimics these disabilities. We reported previously that gestational ID synergizes with alcohol to substantially worsens PAE's growth and learning deficits. The effects of PAE upon fetal-maternal iron homeostasis is unknown. Using a 2nd trimester rat PAE model (5 g/kg ethanol, GD 13.5-19.5), we measured iron content and iron homeostatic biomarkers in fetal brain and liver under maternal iron sufficiency (IS) and ID. We report here that PAE impairs fetal adaptation to maternal IS and ID. Whereas PAE increased fetal liver iron content (IS: 155 vs 182 ppm; ID: 104 vs 166 ppm), it significantly decreased fetal brain iron (IS: 20.6 vs 16.2 ppm) to levels indistinguishable from ID (14.3 vs 14.9 ppm). Fetal liver ferritin expression parallels iron content. PAE also impaired fetal brain adaptation to ID, evidenced by a 50% decrease in brain transferrin (TF) and transferrin receptor (TFRc) expression. PAE did not affect TFRc expression in IS fetal brain, nor TF and TFRc in fetal liver regardless of iron status. Finally, PAE caused a 蠅3-fold induction of hepcidin expression in both fetal and maternal liver, regardless of iron status. We propose that the elevated hepcidin under PAE may drive iron into liver stores at the expense of developing brain. Our results partly explain why maternal ID substantially exacerbates alcohol's neurodevelopmental damage. In summary, alcohol disrupts fetal iron homeostasis and prevents fetal adaptation to maternal ID. ID is common in alcohol-abusing women. Correcting this dysregulation is central for the successful normalization of iron status in women at risk for PAE. Supp: AA21311