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In our preclinical rat model, PAE<\/jats:styled-content> causes fetal anemia, brain ID<\/jats:styled-content>, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron\u2010fortified (IF<\/jats:styled-content>) diet. Here, we hypothesize that iron status and PAE<\/jats:styled-content> dysregulate the major upstream pathways that govern hepcidin production\u2014EPO<\/jats:styled-content>\/BMP<\/jats:styled-content>6\/SMAD<\/jats:styled-content> and IL<\/jats:styled-content>\u20106\/JAK<\/jats:styled-content>2\/STAT<\/jats:styled-content>3.<\/jats:p><\/jats:sec>Methods<\/jats:title>Pregnant, Long Evans rat dams consumed ID<\/jats:styled-content> (2 to 6\u00a0ppm iron), iron\u2010sufficient (IS<\/jats:styled-content>, 100\u00a0ppm iron), or IF<\/jats:styled-content> (500\u00a0ppm iron) diets and received alcohol (5\u00a0g\/kg) or isocaloric maltodextrin daily from gestational days (GD<\/jats:styled-content>) 13.5 to 19.5. Protein and gene expression were quantified in the 6 experimental groups at GD<\/jats:styled-content> 20.5.<\/jats:p><\/jats:sec>Results<\/jats:title>PAE<\/jats:styled-content> did not affect Epo<\/jats:italic> or Bmp6<\/jats:italic> expression, but reduced p\u2010SMAD<\/jats:styled-content>1\/5\/8\/SMAD<\/jats:styled-content>1\/5\/8 protein ratios in both IS<\/jats:styled-content> and ID<\/jats:styled-content> maternal and fetal liver (all p<\/jats:italic>'s\u00a0<\u00a00.01). In contrast, PAE<\/jats:styled-content> stimulated maternal hepatic expression of Il\u20106<\/jats:italic> (p\u00a0<\/jats:italic>=\u00a0<\/jats:italic>0.03) and elevated p\u2010STAT<\/jats:styled-content>3\/STAT<\/jats:styled-content>3 protein ratios in both IS<\/jats:styled-content> and ID<\/jats:styled-content> maternal and fetal liver (all p<\/jats:italic>'s\u00a0<\u00a00.02). PAE<\/jats:styled-content> modestly elevated maternal Il\u20101\u03b2<\/jats:italic>, Tnf\u2010\u03b1<\/jats:italic>, and Ifn\u2010\u03b3<\/jats:italic>. Fetal cytokine responses to PAE<\/jats:styled-content> were muted compared with dams, and PAE<\/jats:styled-content> did not affect hepatic Il\u20106<\/jats:italic> (p\u00a0<\/jats:italic>=\u00a0<\/jats:italic>0.78) in IS<\/jats:styled-content> and ID<\/jats:styled-content> fetuses. Dietary iron fortification sharply attenuated Il\u20106<\/jats:italic> expression in response to PAE<\/jats:styled-content>, with IF<\/jats:styled-content> driving a 150\u2010fold decrease (p\u00a0<\/jats:italic><\u00a0<\/jats:italic>0.001) in maternal liver and a 10\u2010fold decrease (p\u00a0<\/jats:italic><\u00a0<\/jats:italic>0.01) in fetal liver. The IF<\/jats:styled-content> diet also normalized p\u2010STAT<\/jats:styled-content>3\/STAT<\/jats:styled-content>3 ratios in both maternal and fetal liver.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>These findings suggest that alcohol\u2010driven stimulation of the IL<\/jats:styled-content>\u20106\/JAK<\/jats:styled-content>2\/STAT<\/jats:styled-content>3 pathway mediates the elevated hepcidin observed in the PAE<\/jats:styled-content> dam and fetus. Normalization of these signals by IF<\/jats:styled-content> suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL<\/jats:styled-content>\u20106\/JAK<\/jats:styled-content>2\/STAT<\/jats:styled-content>3 pathway. Prenatal dietary IF<\/jats:styled-content> represents a potential therapeutic approach for PAE<\/jats:styled-content> that warrants further investigation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14200","type":"journal-article","created":{"date-parts":[[2019,9,16]],"date-time":"2019-09-16T14:20:10Z","timestamp":1568643610000},"page":"2332-2343","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Alcohol's Dysregulation of Maternal\u2013Fetal IL\u20106 and p\u2010STAT3 Is a Function of Maternal Iron Status"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6775-3486","authenticated-orcid":false,"given":"Nipun","family":"Saini","sequence":"first","affiliation":[{"name":"Nutrition Research Institute, University of North Carolina at Chapel Hill Kannapolis North 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