Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of these defects in the offspring. Because the placenta is central in supporting fetal development, we investigated whether maternal iron status similarly modulates alcohol's effects in the placenta. We hypothesized that PAE causes placental insufficiency by decreasing placental weight and efficiency, and we hypothesized that these are worsened by maternal iron deficiency (ID) and alleviated by dietary iron fortification (IF). We also determined whether altered placental iron flux and inflammatory balance contribute to placental insufficiency. Pregnant Long-Evans rats consumed an iron-deficient (ID; 2-6 ppm), iron-sufficient (IS; 100 ppm), or iron-fortified (IF; 500 ppm) diet. Alcohol (5 g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE reduced fetal weight (p < 0.0001), placental weight (p = 0.0324), and placental efficiency (p = 0.0043). PAE downregulated placental transferrin receptor (p = 0.0032); it also altered placental Il1b and Tnf expression and the Il6:Il10 ratio (p = 0.0337, 0.0300, and 0.0034, respectively) to generate a response favoring inflammation. ID-PAE further reduced fetal growth and placental efficiency and induced a heightened pro-inflammatory placental profile. IF did not rescue the alcohol-reduced fetal weight, but it normalized placental efficiency and decreased placental inflammation. These placental cytokines correlated with fetal and placental growth, and explained 45% of the variability in fetal weight and 20% of the variability in placental efficiency. In summary, alcohol induces placental insufficiency and is associated with a pro-inflammatory cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because the placenta is closely linked to intrauterine growth, the placental insufficiency reported here may correlate with the lower birth weights in a subgroup of individuals who experienced PAE.

中文翻译：

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母体铁营养调节胎儿酒精谱系障碍的大鼠模型中的胎盘发育。

产前酒精暴露（PAE）会导致发育异常，称为胎儿酒精光谱异常（FASD）。母体铁的状态调节后代中这些缺陷的严重程度。由于胎盘在支持胎儿发育中起着中心作用，因此我们调查了母体铁的状态是否同样可调节酒精在胎盘中的作用。我们假设PAE会通过降低胎盘重量和效率而导致胎盘功能不全，并且我们假设这些会因母体铁缺乏症（ID）而恶化，而饮食铁强化（IF）会减轻。我们还确定胎盘铁通量和炎症平衡的改变是否会导致胎盘功能不全。怀孕的Long-Evans大鼠进食了铁缺乏（ID; 2-6 ppm），铁充足（IS; 100 ppm）或铁强化（IF; 500 ppm）的饮食。从妊娠日（GD）13.5-19.5开始每天饮酒（5 g / kg体重）或异麦芽糖糊精（MD）。胎盘预后在GD20.5上评估。PAE可降低胎儿体重（p <0.0001），胎盘重量（p = 0.0324）和胎盘效率（p = 0.0043）。PAE下调胎盘转铁蛋白受体（p = 0.0032）；它也会改变胎盘的Il1b和Tnf表达以及Il6：Il10的比例（分别为p = 0.0337、0.0300和0.0034），从而产生有利于炎症的反应。ID-PAE进一步降低了胎儿的生长和胎盘效率，并诱发了促炎性胎盘结构。IF不能挽救酒精减少的胎儿体重，但可以使胎盘效率正常化，并减少胎盘炎症。这些胎盘细胞因子与胎儿和胎盘的生长有关，并解释了45％的胎儿体重变异性和20％的胎盘效率变异性。总之，酒精会诱发胎盘功能不全，并与母体ID加剧而母体IF减轻的促炎性细胞因子有关。由于胎盘与子宫内生长密切相关，因此此处报道的胎盘功能不全可能与经历PAE的亚组个体的较低出生体重有关。