Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior
Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior
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DOI：
10.3389/fnins.2019.01335
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发表时间：
2019-12-17
影响因子：
4.3
通讯作者：
Bianchi, Diana W.
中科院分区：
文献类型：
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作者：
Edlow, Andrea G.;Guedj, Faycal;Bianchi, Diana W.
背景 母亲怀孕期间营养过剩和营养不足对胎儿大脑发育和功能起着至关重要的作用。不同母亲饮食成分对胎儿大脑宫内编程的影响是一个较少研究的领域。本研究的目的是在小鼠模型中调查两种母体饮食对胎儿大脑基因表达特征、胎儿/新生儿生长以及新生儿和成人行为的影响。方法 在整个怀孕和哺乳期，雌性 C57Bl/6J 小鼠被喂食两种标准市售饲料之一（颗粒饲料与粉末饲料）。与颗粒饲料相比，粉状饲料的微量营养素相对缺乏，但富含碳水化合物和 n-3 长链多不饱和脂肪酸。从胚胎第 15.5 天的前脑中提取 RNA 并与全基因组表达微阵列杂交（N = 5/母亲饮食组）。使用 Ingenuity Pathways Analysis 和 Gene Set Enrichment Analysis 对显着差异表达的胎儿大脑基因进行功能分析。使用经过验证的量表评估新生儿行为（N = 62 名颗粒暴露者和 31 名粉末暴露者）。使用恐惧调节、旷场测试和旋转测试（N = 16 名颗粒暴露，14 名粉末暴露）对成人子集的海马学习、运动行为和运动协调进行评估。结果 比较粉状饲料和颗粒饲料，怀孕期间母亲的体重轨迹和胚胎大小均没有差异。母亲的粉状食物与 1647 个差异表达的胎儿大脑基因相关。功能分析发现，参与胎儿大脑细胞周期调节、突触可塑性和感觉神经系统发育的经典途径和上游调节因子显着上调，以及与细胞和胚胎死亡相关的途径显着下调。与DNA损伤反应、脑免疫反应、氨基酸和脂肪酸转运以及多巴胺能信号传导相关的通路显着失调。接触粉状食物的新生儿比接触颗粒状食物的新生儿明显更长，但并不重。在新生儿行为测试中，接触粉状食物的新生儿明显更早地达到协调和力量相关的里程碑，但感觉成熟反射明显更晚。在成年行为测试中，接触粉状食物的后代表现出多动症和海马学习缺陷。结论 在野生型后代中，两种主要在微量营养素成分上不同的饮食对胎儿脑转录组、新生儿和成人行为有显着影响。这些影响似乎不是由孕产妇总营养状况或胎儿/新生儿体重的改变介导的。母亲的饮食内容是研究人员评估胎儿大脑发育和后代行为时需要考虑的一个重要变量。
Background Maternal over- and undernutrition in pregnancy plays a critical role in fetal brain development and function. The effects of different maternal diet compositions on intrauterine programing of the fetal brain is a lesser-explored area. The goal of this study was to investigate the impact of two chowmaternal diets on fetal brain gene expression signatures, fetal/neonatal growth, and neonatal and adult behavior in a mouse model. Methods Throughout pregnancy and lactation, female C57Bl/6J mice were fed one of two standard, commercially available chow diets (pellet versus powder). The powdered chow diet was relatively deficient in micronutrients and enriched for carbohydrates and n-3 long-chain polyunsaturated fatty acids compared to the pelleted chow. RNA was extracted from embryonic day 15.5 forebrains and hybridized to whole genome expression microarrays (N = 5/maternal diet group). Functional analyses of significantly differentially expressed fetal brain genes were performed using Ingenuity Pathways Analysis and Gene Set Enrichment Analysis. Neonatal behavior was assessed using a validated scale (N = 62 pellet-exposed and 31 powder-exposed). Hippocampal learning, locomotor behavior, and motor coordination were assessed in a subset of adults using fear conditioning, open field testing, and Rotarod tests (N = 16 pellet-exposed, 14 powder-exposed). Results Comparing powdered to pelleted chow diets, neither maternal weight trajectory in pregnancy nor embryo size differed. Maternal powdered chow diet was associated with 1647 differentially expressed fetal brain genes. Functional analyses identified significant upregulation of canonical pathways and upstream regulators involved in cell cycle regulation, synaptic plasticity, and sensory nervous system development in the fetal brain, and significant downregulation of pathways related to cell and embryo death. Pathways related to DNA damage response, brain immune response, amino acid and fatty acid transport, and dopaminergic signaling were significantly dysregulated. Powdered chow-exposed neonates were significantly longer but not heavier than pelleted chow-exposed counterparts. On neonatal behavioral testing, powdered chow-exposed neonates achieved coordination- and strength-related milestones significantly earlier, but sensory maturation reflexes significantly later. On adult behavioral testing, powdered chow-exposed offspring exhibited hyperactivity and hippocampal learning deficits. Conclusion In wild-type offspring, two diets that differed primarily with respect to micronutrient composition had significant effects on the fetal brain transcriptome, neonatal and adult behavior. These effects did not appear to be mediated by alterations in gross maternal nutritional status nor fetal/neonatal weight. Maternal dietary content is an important variable to consider for investigators evaluating fetal brain development and offspring behavior.