Potiris Anastasios, Manousopoulou Antigoni, Zouridis Andreas, Sarli Polyxeni-Maria, Pervanidou Panagiota, Eliades George, Perrea Despina N, Deligeoroglou Efthymios, Garbis Spiros D, Eleftheriades Makarios
Second Department of Obstetrics and Gynaecology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
Front Neurosci. 2021 Apr 14;15:665354. doi: 10.3389/fnins.2021.665354. eCollection 2021.
Fetal growth restriction (FGR) has been associated with a higher risk of developing adverse perinatal outcomes and distinct neurodevelopmental and neurobehavioral disorders. The aim of the present study was to investigate the impact of prenatal food restriction on the brain proteome in both FGR and appropriately grown rats and to identify potential pathways connecting maternal malnutrition with altered brain development.
Ten time-dated pregnant Wistar rats were housed individually at their 12th day of gestation. On the 15th day of gestation, the rats were randomly divided into two groups, namely the food restricted one ( = 6) and the control group ( = 4). From days 15 to 21 the control group had unlimited access to food and the food restricted group was given half the amount of food that was on average consumed by the control group, based on measurements taken place the day before. On the 21st day of gestation, all rats delivered spontaneously and after birth all newborn pups of the food restricted group were weighed and matched as appropriately grown (non-FGR) or growth restricted (FGR) and brain tissues were immediately collected. A multiplex experiment was performed analyzing brain tissues from 4 FGR, 4 non-FGR, and 3 control male offspring. Differentially expressed proteins (DEPs) were subjected to bioinformatics analysis in order to identify over-represented processes.
Proteomic analysis resulted in the profiling of 3,964 proteins. Gene ontology analysis of the common DEPs using DAVID (https://david.ncifcrf.gov/) showed significant enrichment for terms related to cellular morphology, learning, memory and positive regulation of NF-kappaB signaling. Ingenuity Pathway Analysis showed significant induction of inflammation in FGR pups, whereas significant induction of cell migration and cell spreading were observed in non-FGR pups.
This study demonstrated that in both FGR and non-FGR neonates, a range of adaptive neurodevelopmental processes takes place, which may result in altered cellular morphology, chronic stress, poor memory and learning outcomes. Furthermore, this study highlighted that not only FGR, but also appropriately grown pups, which have been exposed to prenatal food deprivation may be at increased risk for impaired cognitive and developmental outcomes.
胎儿生长受限（FGR）与围产期不良结局以及明显的神经发育和神经行为障碍的发生风险较高有关。本研究的目的是调查产前食物限制对FGR大鼠和生长正常大鼠大脑蛋白质组的影响，并确定将母体营养不良与大脑发育改变联系起来的潜在途径。
10只按受孕时间记录的怀孕Wistar大鼠在妊娠第12天单独饲养。在妊娠第15天，将大鼠随机分为两组，即食物限制组（n = 6）和对照组（n = 4）。从第15天到第21天，对照组可无限制获取食物，食物限制组根据前一天的测量结果，给予对照组平均消耗量一半的食物量。在妊娠第21天，所有大鼠自然分娩，出生后对食物限制组的所有新生幼崽称重，并分为生长正常（非FGR）或生长受限（FGR），并立即收集脑组织。进行了一项多重实验，分析了4只FGR、4只非FGR和3只对照雄性后代的脑组织。对差异表达蛋白（DEP）进行生物信息学分析，以确定过度富集的过程。
蛋白质组学分析鉴定出3964种蛋白质。使用DAVID（https://david.ncifcrf.gov/）对常见DEP进行基因本体分析，结果显示与细胞形态、学习、记忆和NF-κB信号正调控相关的术语显著富集。Ingenuity通路分析显示FGR幼崽中炎症显著诱导，而非FGR幼崽中观察到细胞迁移和细胞铺展显著诱导。
本研究表明，在FGR和非FGR新生儿中，都发生了一系列适应性神经发育过程，这可能导致细胞形态改变、慢性应激、记忆力和学习能力下降。此外，本研究强调，不仅FGR，而且暴露于产前食物剥夺的生长正常的幼崽，认知和发育受损的风险可能会增加。
