Maternal antioxidant treatment prevents the adverse effects of prenatal stress on the offspring's brain and behavior [NanoString nCounter rat miRNA]

Maternal exposure to stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. The mechanisms through which the effects of maternal stress are transmitted to the fetus are unclear, however the placenta, as the interface between mother and fetus, is likely to play a key role. Using a rat model, we investigated a role for placental oxidative stress in conveying the effects of maternal social stress to the fetus and the potential for treatment using a nanoparticle-bound antioxidant to prevent adverse outcomes in the offspring. Maternal psychosocial stress increased circulating corticosterone in the mother, but not in the fetuses. Maternal stress also induced oxidative stress in the placenta, but not in the fetal brain. Blocking oxidative stress using an antioxidant prevented the prenatal stress-induced anxiety phenotype in the male offspring, and prevented sex-specific neurobiological changes, specifically a reduction in dendrite lengths in the hippocampus, as well as reductions in the number of parvalbumin-positive neurons and GABA receptor subunits in the hippocampus and basolateral amygdala of the male offspring. Importantly, many of these effects were mimicked in neuronal cultures by application of placental-conditioned medium or fetal plasma from stressed pregnancies, indicating molecules released from the placenta may mediate the effects of prenatal stress on the fetal brain. Indeed, both placenta-conditioned medium and fetal plasma contained differentially abundant microRNAs following maternal stress, and their predicted targets were enriched for genes relevant to nervous system development and psychiatric disorders. The results highlight placental oxidative stress as a key mediator in transmitting the maternal social stress effects on the offspring's brain and behaviour, and offer a potential intervention to prevent stress-induced fetal programming of affective disorders. Samples that underwent microRNA analysis were foetal plasma, pooled per litter, collected from pregnant rats (gestational day 20) or culture medium conditioned by placentae collected from the pregnant rats. Pregnant rats had been exposed to chronic social stress while control rats were left undisturbed. Both stressed rats and control rats had been injected with nanoparticle bound MitoQ (MitoQ-NP) or saline prior to the stress episode. n = 3 pregnant rats in each of 4 experimental groups.

孕期母体暴露于应激环境，与子代成年后精神疾病患病风险升高密切相关。目前母体应激信号传递至胎儿的具体机制尚不明确，但作为母体与胎儿之间界面的胎盘，极有可能发挥关键调控作用。
本研究以大鼠为模型，探究了胎盘氧化应激（placental oxidative stress）在传递母体社会应激至胎儿过程中的作用，以及使用纳米颗粒结合抗氧化剂（nanoparticle-bound antioxidant）预防子代不良结局的潜在可行性。
母体心理社会应激可升高母体循环皮质酮水平，但不会影响胎儿循环皮质酮含量。同时，母体应激会诱导胎盘出现氧化应激，但对胎儿大脑无此效应。
使用抗氧化剂阻断氧化应激，可逆转产前应激诱导的雄性子代焦虑表型，并阻断性别特异性神经生物学改变：具体表现为逆转雄性子代海马体（hippocampus）树突长度缩短，以及海马体与基底外侧杏仁核（basolateral amygdala）中小白蛋白阳性神经元（parvalbumin-positive neurons）数量、γ-氨基丁酸（GABA）受体亚基（GABA receptor subunits）水平的降低。
值得注意的是，将应激妊娠来源的胎盘条件培养基（placental-conditioned medium）或胎儿血浆应用于神经元培养后，可复制上述多数效应，提示胎盘释放的分子可能介导了产前应激对胎儿大脑的影响。
进一步检测发现，母体应激后，胎盘条件培养基与胎儿血浆中的微小RNA（microRNAs）表达存在显著差异，其预测靶基因显著富集于神经系统发育与精神疾病相关的基因通路中。
本研究结果表明，胎盘氧化应激是传递母体社会应激对子代大脑与行为产生影响的关键中介因子，并为预防应激诱导的情感障碍胎儿编程（fetal programming）提供了潜在干预靶点。
本研究中用于微小RNA分析的样本包括：妊娠第20天的孕鼠胎血浆（按每窝混合），以及从孕鼠胎盘中制备的条件培养基。孕鼠曾暴露于慢性社会应激，对照组孕鼠则保持无干扰状态。应激组与对照组孕鼠均在应激处理前，分别注射了纳米颗粒结合型MitoQ（MitoQ-NP）或生理盐水。4个实验组每组均包含3只孕鼠。