Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin.
Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina.
Alcohol Clin Exp Res. 2018 Jun;42(6):1022-1033. doi: 10.1111/acer.13754. Epub 2018 May 19.
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.
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.
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.
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.
产前酒精暴露（PAE）会导致神经发育障碍。临床和动物研究表明，妊娠期铁缺乏（ID）会加重 PAE 的行为和生长缺陷。在大鼠中，PAE 表现为无法建立铁稳态，增加了（母体和胎儿的）hepcidin 和胎肝铁，同时减少了脑铁并促进了贫血。在这里，我们假设在怀孕期间进行饮食铁强化可能会减轻酒精对胎儿铁稳态的破坏。
给怀孕的长耳大仓鼠喂食铁充足（100ppm 铁）或铁强化（IF；500ppm 铁）饮食，在妊娠第 13.5 天至 19.5 天期间，每天接受 5g/kg 酒精（PAE）或等热量麦芽糊精。在妊娠第 20.5 天评估母婴结局。
PAE 无论母体铁状况如何，均降低了平均胎儿体重（p<0.001），表明铁强化并未改善胎儿生长。PAE（p<0.01）和 IF（p=0.035）均增加了胎肝铁。在胎脑中，PAE（p=0.015）影响了总铁（p<0.001）和非血红素铁（p<0.001），铁强化使酒精介导的脑铁和非血红素铁减少正常化（p=0.99）。铁强化还改善了 PAE 中的胎儿血液学指标，包括血红蛋白、血细胞比容和平均红细胞体积（p<0.001）。铁强化还使酒精暴露的母体和胎肝中的 hepcidin 表达正常化。饮食和 PAE 均不影响胎肝中的转铁蛋白（Tf）和铁蛋白（FTN）含量，也不影响胎脑中的 Tf 或转铁蛋白受体。然而，IF-PAE 胎脑的 FTN 含量有下降趋势（p=0.074），提示非储存铁的可用性增加。在 PAE 中，hepcidin 水平与肝铁储存增加和红细胞计数减少以及脑铁减少呈线性相关。
母体口服铁强化减轻了 PAE 对胎儿铁稳态的破坏，并改善了这种大鼠 PAE 模型中的脑铁含量、血液学指标和 hepcidin 产生。临床研究表明，母体 ID 大大增加了胎儿对 PAE 的易感性，我们的工作支持增加母体膳食铁摄入可能会改善暴露于酒精的妊娠中的胎儿铁状况。
