PMID- 31524964 OWN - NLM STAT- MEDLINE DCOM- 20200928 LR - 20201101 IS - 1530-0277 (Electronic) IS - 0145-6008 (Print) IS - 0145-6008 (Linking) VI - 43 IP - 11 DP - 2019 Nov TI - Alcohol's Dysregulation of Maternal-Fetal IL-6 and p-STAT3 Is a Function of Maternal Iron Status. PG - 2332-2343 LID - 10.1111/acer.14200 [doi] AB - BACKGROUND: 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. METHODS: Pregnant, Long Evans rat dams consumed ID (2 to 6 ppm iron), iron-sufficient (IS, 100 ppm iron), or IF (500 ppm iron) diets and received alcohol (5 g/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. RESULTS: 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-1beta, Tnf-alpha, and Ifn-gamma. 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. CONCLUSIONS: 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. CI - (c) 2019 by the Research Society on Alcoholism. FAU - Saini, Nipun AU - Saini N AUID- ORCID: 0000-0001-6775-3486 AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. FAU - Helfrich, Kaylee K AU - Helfrich KK AUID- ORCID: 0000-0002-9811-1029 AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. FAU - Kwan, Sze Ting Cecilia AU - Kwan STC AUID- ORCID: 0000-0002-5280-9253 AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. FAU - Huebner, Shane M AU - Huebner SM AD - Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Abazi, Juna AU - Abazi J AD - Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Flentke, George R AU - Flentke GR AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. FAU - Blohowiak, Sharon E AU - Blohowiak SE AD - Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Kling, Pamela J AU - Kling PJ AD - Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Smith, Susan M AU - Smith SM AUID- ORCID: 0000-0003-4782-6857 AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. LA - eng SI - GENBANK/NM_013107.1 SI - GENBANK/NM_017001.1 SI - GENBANK/NM_017008.4 SI - GENBANK/NM_138880.2 SI - GENBANK/NM_031512.2 SI - GENBANK/NM26744.1 SI - GENBANK/NM_012854.2 SI - GENBANK/NM_012675.3 GR - R01 AA011085/AA/NIAAA NIH HHS/United States GR - F32 AA021311/AA/NIAAA NIH HHS/United States GR - F32 AA027121/AA/NIAAA NIH HHS/United States GR - T32 DK007686/DK/NIDDK NIH HHS/United States GR - P30 DK056350/DK/NIDDK NIH HHS/United States GR - R01 AA022999/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20191008 PL - England TA - Alcohol Clin Exp Res JT - Alcoholism, clinical and experimental research JID - 7707242 RN - 0 (Il6 protein, rat) RN - 0 (Interleukin-6) RN - 0 (Iron, Dietary) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, rat) RN - 3K9958V90M (Ethanol) SB - IM MH - Anemia, Iron-Deficiency/*complications MH - Animals MH - Disease Models, Animal MH - Ethanol/*adverse effects MH - Female MH - Fetus/*drug effects/metabolism MH - Interleukin-6/*blood/metabolism MH - Iron, Dietary MH - Pregnancy MH - Prenatal Exposure Delayed Effects/*blood MH - Rats MH - Rats, Long-Evans MH - Real-Time Polymerase Chain Reaction MH - STAT3 Transcription Factor/*blood/metabolism MH - Signal Transduction/drug effects PMC - PMC7001854 MID - NIHMS1050658 OTO - NOTNLM OT - Fetal Alcohol Spectrum Disorder OT - Hepcidin OT - IL-6 OT - Iron Deficiency OT - Iron Fortification EDAT- 2019/09/17 06:00 MHDA- 2020/09/29 06:00 PMCR- 2020/11/01 CRDT- 2019/09/17 06:00 PHST- 2019/07/09 00:00 [received] PHST- 2019/09/06 00:00 [accepted] PHST- 2019/09/17 06:00 [pubmed] PHST- 2020/09/29 06:00 [medline] PHST- 2019/09/17 06:00 [entrez] PHST- 2020/11/01 00:00 [pmc-release] AID - 10.1111/acer.14200 [doi] PST - ppublish SO - Alcohol Clin Exp Res. 2019 Nov;43(11):2332-2343. doi: 10.1111/acer.14200. Epub 2019 Oct 8.