Individuals exposed to gestational stressors such as alcohol exhibit a spectrum of growth patterns, suggesting individualized responses to the stressors. We hypothesized that intrauterine growth responses to gestational alcohol are modified not only by the stressor’s severity but by fetal sex and the placenta’s adaptive capacity. Pregnant C57BL/6J mice were assigned to one of three groups. Group 1 consumed a normal protein diet (18% protein by weight) and received 4.5 g alcohol/kg body weight (NP-Alc-8) or isocaloric maltodextrin (NP-MD-8) daily from embryonic day (E) 8.5–E17.5. Group 2 consumed the same diet but received alcohol (NP-Alc-13) or maltodextrin (NP-MD-13) daily from E13.5–E17.5. Group 3 consumed the same diet but containing a lower protein content (12% protein by weight) from E0.5 and also received alcohol (LP-Alc-8) or maltodextrin (LP-MD-8) daily from E8.5–E17.5. Maternal, placental, and fetal outcomes were assessed on E17.5 using 2-way ANOVA or mixed linear model. We found that intrauterine growth differed in the alcohol-exposed fetuses depending on sex and insult severity. Both NP-Alc-8 (vs. NP-MD-8) males and females had lower body weight and asymmetrical growth, but only NP-Alc-8 females had lower placental weight (P < 0.05). NP-Alc-13 (vs. NP-MD-13) females, but not their male littermates, had lower body weight (P = 0.019). Alcohol exposure beginning from E8.5 (vs. E13.5) decreased the ratio of fetal liver-to-body weight and increased the ratio of fetal brain-to-liver weight in both sexes (P < 0.05). LP-Alc-8 (vs. NP-MD-8) group had smaller litter size (P = 0.048), but the survivors had normal placental and body weight at E17.5. Nevertheless, LP-Alc-8 fetuses still showed asymmetrical growth. Correlation analyses reveal a relationship between litter size and placental outcomes, which were related to fetal outcomes in a sex-dependent manner, suggesting that the placenta may mediate the consequence of LP-Alc-altered litter size on fetal development. Our data indicate that the placenta is strongly involved in the fetal stress response and adapts in a sex-dependent fashion to support fetal development under the alcohol stressor. These variables may further influence the spectrum of intrauterine growth outcomes observed in those diagnosed with fetal alcohol spectrum disorder.

中文翻译：

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在 FASD 小鼠模型中，胎儿性别与胎盘重量和效率之间的相互作用可预测子宫内生长对母体蛋白质不足和妊娠暴露窗口的反应。

暴露于妊娠应激源（如酒精）的个体表现出一系列的生长模式，表明对应激源的个体化反应。我们假设子宫内对妊娠酒精的生长反应不仅会受到压力源的严重程度的影响，还会受到胎儿性别和胎盘的适应能力的影响。怀孕的 C57BL/6J 小鼠被分配到三组之一。第 1 组消耗正常蛋白质饮食（按重量计 18% 蛋白质）并从胚胎日 (E) 8.5–E17 每天接受 4.5 克酒精/公斤体重 (NP-Alc-8) 或等热量麦芽糊精 (NP-MD-8) .5. 第 2 组食用相同的饮食，但从 E13.5-E17.5 每天接受酒精 (NP-Alc-13) 或麦芽糖糊精 (NP-MD-13)。第 3 组食用相同的饮食，但从 E0 开始，蛋白质含量较低（12% 蛋白质重量）。5 并且每天从 E8.5-E17.5 接受酒精 (LP-Alc-8) 或麦芽糖糊精 (LP-MD-8)。母体、胎盘和胎儿结局在 E17.5 上使用 2 向方差分析或混合线性模型进行评估。我们发现暴露于酒精的胎儿的宫内生长因性别和侮辱的严重程度而异。NP-Alc-8 (vs. NP-MD-8) 雄性和雌性体重较低且生长不对称，但只有 NP-Alc-8 雌性的胎盘重量较低 (P < 0.05)。NP-Alc-13 (vs. NP-MD-13) 雌性，但不是它们的雄性同窝仔，体重较低 (P = 0.019)。从 E8.5 开始的酒精暴露（与 E13.5 相比）降低了胎儿肝脏与体重的比率，并增加了胎儿大脑与肝脏重量的比率（P < 0.05）。LP-Alc-8（与 NP-MD-8 相比）组的产仔数较小（P = 0.048），但幸存者的胎盘和体重在 E17.5 时正常。尽管如此，LP-Alc-8 胎儿仍表现出不对称生长。相关性分析揭示了窝产仔数与胎盘结局之间的关系，胎盘结局以性别依赖的方式与胎儿结局相关，这表明胎盘可能介导 LP-Alc 改变胎仔数量对胎儿发育的影响。我们的数据表明，胎盘强烈参与胎儿应激反应，并以性别依赖的方式适应酒精应激下的胎儿发育。这些变量可能会进一步影响在诊断为胎儿酒精谱系障碍的人中观察到的宫内生长结果的范围。相关性分析揭示了窝产仔数与胎盘结局之间的关系，胎盘结局以性别依赖的方式与胎儿结局相关，这表明胎盘可能介导 LP-Alc 改变胎仔数量对胎儿发育的影响。我们的数据表明，胎盘强烈参与胎儿应激反应，并以性别依赖的方式适应酒精应激下的胎儿发育。这些变量可能会进一步影响在诊断为胎儿酒精谱系障碍的人中观察到的宫内生长结果的范围。相关性分析揭示了窝产仔数与胎盘结局之间的关系，胎盘结局以性别依赖的方式与胎儿结局相关，这表明胎盘可能介导 LP-Alc 改变胎仔数量对胎儿发育的影响。我们的数据表明，胎盘强烈参与胎儿应激反应，并以性别依赖的方式适应酒精应激下的胎儿发育。这些变量可能会进一步影响在诊断为胎儿酒精谱系障碍的人中观察到的宫内生长结果的范围。我们的数据表明，胎盘强烈参与胎儿应激反应，并以性别依赖的方式适应酒精应激下的胎儿发育。这些变量可能会进一步影响在诊断为胎儿酒精谱系障碍的人中观察到的宫内生长结果的范围。我们的数据表明，胎盘强烈参与胎儿应激反应，并以性别依赖的方式适应酒精应激下的胎儿发育。这些变量可能会进一步影响在诊断为胎儿酒精谱系障碍的人中观察到的宫内生长结果的范围。