Poster Topical Area: Experimental Animal Nutrition

Location: Hall D

Poster Board Number: 611

E09-03 - Dietary Iron Fortification Mitigates Hepcidin Dysregulation and Inflammation Created by Gestational Iron Deficiency and Prenatal Alcohol Exposure

Monday, Jun 11
8:00 AM – 3:00 PM

Objectives: Prenatal alcohol exposure (PAE) causes long-term growth and neurodevelopmental deficits, collectively termed fetal alcohol spectrum disorders (FASD). Infants born to iron-deficient (ID) mothers have poorer growth outcomes in response to gestational PAE than infants born to iron sufficient (IS) mothers. Studies in our rat PAE model affirm that maternal ID worsens FASD outcomes such as associative learning deficits and cellular losses in fetal brain. A recent finding suggests a potential mechanism for this association; PAE upregulates the iron regulatory peptide hepcidin, even during ID states when hepcidin is normally repressed. Multiple factors regulate hepcidin expression including the JAK2/STAT3 inflammatory pathway and the BMP/hemojuvelin/SMAD pathway. Here, we investigate mechanisms by which PAE dysregulates hepcidin production.

Methods: Pregnant, Long-Evans rat dams were fed an ID (2-6 ppm), IS (100 ppm) or iron-fortified (IF, 500 ppm) diet and were gavaged with alcohol (5 g ethanol/kg) or isocaloric maltodextrin from gestational days (GD) 13.5-19.5. Protein and gene expression were quantified at GD20.5.

Results: Neither iron status nor PAE altered BMP6 expression in maternal liver. ID significantly reduced phospho-SMAD1/5/8 irrespective of alcohol treatment, suggesting that this pathway did not mediate the hepcidin upregulation under PAE. In contrast, IL-6 mRNA and phospho-STAT3 protein were significantly up-regulated in both ID and PAE mother and fetus, suggesting the involvement of inflammation-driven hepcidin regulation. Indeed, PAE upregulated IL-1β, TNFα, and IFNγ expression in maternal and fetal liver. ID itself was mildly pro-inflammatory. PAE and ID also induced IL-1β, TNFα, and the brain inflammation markers IBA-1 and GFAP in fetal brain. Importantly, dietary iron fortification normalized hepatic hepcidin production in PAE dams and fetuses, and attenuated brain inflammation (IBA-1) in PAE fetuses. Dietary IF also reversed the fetal anemia caused by PAE in both IS and ID fetuses.

Conclusions: These findings suggest PAE elevates hepcidin through the inflammatory pathway. Dietary iron fortification may attenuate the dysregulated iron metabolism, inflammatory response, and anemia observed in alcohol-exposed mothers and fetuses.




Funding Source: Supported by R01 AA22999

CoAuthors: Nipun Saini – University of North Carolina, Chapel Hill; Shane Huebner – University of Wisconsin-Madison; George Flentke – University of North Carolina, Chapel Hill; Susan Smith – University of North Carolina, Chapel Hill

Kaylee Helfrich

Graduate Research Assistant
University of North Carolina, Chapel Hill
Kannapolis, North Carolina