PMID- 29672865 OWN - NLM STAT- MEDLINE DCOM- 20191104 LR - 20200306 IS - 1530-0277 (Electronic) IS - 0145-6008 (Print) IS - 0145-6008 (Linking) VI - 42 IP - 6 DP - 2018 Jun TI - Dietary Iron Fortification Normalizes Fetal Hematology, Hepcidin, and Iron Distribution in a Rat Model of Prenatal Alcohol Exposure. PG - 1022-1033 LID - 10.1111/acer.13754 [doi] AB - BACKGROUND: Prenatal alcohol exposure (PAE) causes neurodevelopmental disability. Clinical and animal studies show gestational iron deficiency (ID) exacerbates PAE's behavioral and growth deficits. In rat, PAE manifests an inability to establish iron homeostasis, increasing hepcidin (maternal and fetal), and fetal liver iron while decreasing brain iron and promoting anemia. Here, we hypothesize dietary iron fortification during pregnancy may mitigate alcohol's disruption of fetal iron homeostasis. METHODS: Pregnant Long-Evans rats, fed iron-sufficient (100 ppm iron) or iron-fortified (IF; 500 ppm iron) diets, received either 5 g/kg alcohol (PAE) or isocaloric maltodextrin daily on gestational days (GD) 13.5 through 19.5. Maternal and fetal outcomes were evaluated on GD20.5. RESULTS: PAE reduced mean fetal weight (p < 0.001) regardless of maternal iron status, suggesting iron fortification did not improve fetal growth. Both PAE (p < 0.01) and IF (p = 0.035) increased fetal liver iron. In fetal brain, PAE (p = 0.015) affected total (p < 0.001) and nonheme iron (p < 0.001) such that iron fortification normalized (p = 0.99) the alcohol-mediated reductions in brain iron and nonheme iron. Iron fortification also improved fetal hematologic indices in PAE including hemoglobin, hematocrit, and mean cell volume (ps<0.001). Iron fortification also normalized hepcidin expression in alcohol-exposed maternal and fetal liver. Neither diet nor PAE affected transferrin (Tf) and ferritin (FTN) content in fetal liver, nor Tf or transferrin receptor in fetal brain. However, IF-PAE fetal brains trended to less FTN content (p = 0.074), suggesting greater availability of nonstorage iron. In PAE, hepcidin levels were linearly related to increased liver iron stores and decreased red blood cell count and brain iron. CONCLUSIONS: Maternal oral iron fortification mitigated PAE's disruption of fetal iron homeostasis and improved brain iron content, hematologic indices, and hepcidin production in this rat PAE model. Clinical studies show maternal ID substantially enhances fetal vulnerability to PAE, and our work supports increased maternal dietary iron intake may improve fetal iron status in alcohol-exposed pregnancies. CI - Copyright (c) 2018 by the Research Society on Alcoholism. FAU - Huebner, Shane M AU - Huebner SM AD - Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Helfrich, Kaylee K AU - Helfrich KK AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. FAU - Saini, Nipun AU - Saini N 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 - Cheng, Adrienne A AU - Cheng AA AD - Department of Nutritional Sciences, 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 - Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin. AD - Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. LA - eng GR - F32 AA021311/AA/NIAAA NIH HHS/United States GR - R01 AA011085/AA/NIAAA NIH HHS/United States GR - R01 AA022999/AA/NIAAA NIH HHS/United States GR - R37 AA011085/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180519 PL - England TA - Alcohol Clin Exp Res JT - Alcoholism, clinical and experimental research JID - 7707242 RN - 0 (Hemoglobins) RN - 0 (Hepcidins) RN - 0 (Iron, Dietary) RN - 0 (Receptors, Transferrin) RN - 0 (Transferrin) RN - 9007-73-2 (Ferritins) RN - E1UOL152H7 (Iron) SB - IM MH - Animals MH - Brain/metabolism MH - Dose-Response Relationship, Drug MH - Erythrocyte Indices/drug effects MH - Female MH - Ferritins/metabolism MH - Fetal Development MH - Fetus/*blood supply/drug effects MH - Hematocrit MH - Hemoglobins/drug effects MH - Hepcidins/*biosynthesis MH - Homeostasis MH - Iron/*metabolism MH - Iron, Dietary/*pharmacology MH - Liver/metabolism MH - Male MH - Pregnancy MH - Prenatal Exposure Delayed Effects/*prevention & control MH - Rats MH - Receptors, Transferrin/biosynthesis MH - Transferrin/metabolism PMC - PMC6317737 MID - NIHMS961309 OTO - NOTNLM OT - Anemia OT - Fetal Alcohol Spectrum Disorder OT - Hepcidin OT - Iron Deficiency OT - Iron Homeostasis COIS- The authors have no conflict of interest to declare. EDAT- 2018/04/20 06:00 MHDA- 2019/11/05 06:00 PMCR- 2019/06/01 CRDT- 2018/04/20 06:00 PHST- 2017/11/22 00:00 [received] PHST- 2018/04/04 00:00 [accepted] PHST- 2018/04/20 06:00 [pubmed] PHST- 2019/11/05 06:00 [medline] PHST- 2018/04/20 06:00 [entrez] PHST- 2019/06/01 00:00 [pmc-release] AID - 10.1111/acer.13754 [doi] PST - ppublish SO - Alcohol Clin Exp Res. 2018 Jun;42(6):1022-1033. doi: 10.1111/acer.13754. Epub 2018 May 19.