Alcohol's Dysregulation of Maternal-Fetal IL-6 and p-STAT3 Is a Function of Maternal Iron Status.

Abstract

Prenatal alcohol exposure (PAE) causes long-term growth and neurodevelopmental deficits that are worsened by maternal iron deficiency (ID). In our preclinical rat model, PAE causes fetal anemia, brain ID, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron-fortified (IF) diet. Here, we hypothesize that iron status and PAE dysregulate the major upstream pathways that govern hepcidin production-EPO/BMP6/SMAD and IL-6/JAK2/STAT3. Pregnant, Long Evans rat dams consumed ID (2 to 6ppm iron), iron-sufficient (IS, 100ppm iron), or IF (500ppm iron) diets and received alcohol (5g/kg) or isocaloric maltodextrin daily from gestational days (GD) 13.5 to 19.5. Protein and gene expression were quantified in the 6 experimental groups at GD 20.5. PAE did not affect Epo or Bmp6 expression, but reduced p-SMAD1/5/8/SMAD1/5/8 protein ratios in both IS and ID maternal and fetal liver (all p's<0.01). In contrast, PAE stimulated maternal hepatic expression of Il-6 (p=0.03) and elevated p-STAT3/STAT3 protein ratios in both IS and ID maternal and fetal liver (all p's<0.02). PAE modestly elevated maternal Il-1β, Tnf-α, and Ifn-γ. Fetal cytokine responses to PAE were muted compared with dams, and PAE did not affect hepatic Il-6 (p=0.78) in IS and ID fetuses. Dietary iron fortification sharply attenuated Il-6 expression in response to PAE, with IF driving a 150-fold decrease (p<0.001) in maternal liver and a 10-fold decrease (p<0.01) in fetal liver. The IF diet also normalized p-STAT3/STAT3 ratios in both maternal and fetal liver. These findings suggest that alcohol-driven stimulation of the IL-6/JAK2/STAT3 pathway mediates the elevated hepcidin observed in the PAE dam and fetus. Normalization of these signals by IF suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL-6/JAK2/STAT3 pathway. Prenatal dietary IF represents a potential therapeutic approach for PAE that warrants further investigation.