Exposing the link between placental endocrine dysfunction and offspring behavioural outcomes

早期生活逆境（产前或幼儿期）与儿童的不良结局之间存在明确的关联。发育中的胎儿暴露于例如不良饮食和/或非常年幼的儿童暴露于次优的母亲护理具有终身后果，包括ADHD、抑郁症和精神分裂症的发生率增加。然而，母亲在怀孕期间和产后期间的情绪障碍也与怀孕期间的不良饮食密切相关。在人类队列研究中，分离这些暴露的相对贡献是一项挑战。我们已经开发了一种新的动物模型，基于对一种名为Phlda 2的印迹基因的遗传修饰，该模型模拟了雌性小鼠在怀孕期间喂食低蛋白或高脂肪饮食后在胎盘中观察到的变化，也可以在人类胎盘中观察到，这些胎盘来自报告怀孕期间饮食选择不佳的女性。使用我们的动物模型，我们已经表明胎盘Phlda 2升高导致胎盘发育功能障碍和低出生体重。我们在胎盘中观察到的一个关键变化是制造胎盘激素的细胞数量减少。这些激素对胎儿生长和产妇护理都很重要。我们发现，暴露在突变胎盘中的雌性小鼠会忽视它们的幼崽。在人类中，出生体重低和产妇护理不良都与以后的生活问题有关，包括心理健康问题的发病率增加。我们最近进行了试点工作，以检查我们的模型中的后代行为。值得注意的是，我们发现携带转基因的后代和他们的同窝出生的孩子都表现出异常的抑郁症状。这告诉我们，并不是基因的变化导致了异常行为。相反，一定有一些关于共享环境的东西导致了这些行为的变化。这可能是在子宫内暴露于低胎盘激素水平，胎儿生长不良或出生后质量差的孕产妇护理或潜在的组合逆境。我们能够使用一种简单的交叉培养技术来剖析子宫内环境与出生后暴露的贡献，这是本提案中计划的实验。不过，我们希望进一步调查。我们知道母亲在怀孕期间的饮食会改变我们在胎盘中的基因表达。在人类和实验模型中，不理想的母亲饮食与母亲护理不良和后代行为异常有关。这提出了一个有趣的可能性，即由不良的母体饮食引起的胎盘内分泌功能障碍通过胎盘功能障碍导致母亲和她的孩子的异常行为。我们将联合收割机结合我们的遗传模型和饮食模型来详细研究这种关系。这项工作非常及时，因为我们正在使用该模型领导胎盘内分泌功能障碍的研究。我们处于一个独特的位置，可以建立在我们团队的强有力的初步数据基础上，支持计划工作的每个方面，我们拥有相关的专业知识，以确保我们实现我们的目标。除了研究这种将早期生活逆境与晚年生活结果联系起来的新机制外，我们的工作可能具有转化意义。我们知道，由于胎儿生长受限而出生体重低的人类婴儿中有25%的胎盘PHLDA 2升高。我们最近的数据将胎盘PHLDA 2升高与人类婴儿的行为改变联系起来。我们可以通过由MRC资助的威尔士生长研究直接转化为人类妊娠，确保我们的动物研究产生最大影响。因此，我们在BBSRC资助的怀孕期间对母亲生活方式的显着发现可以迅速为人类母亲及其子女带来更好的结果。

There is a well-defined association between early life adversity (either prenatally or in early childhood) and significantly poorer outcomes for children. Exposure of the developing fetus, for example to poor diet, and/or exposure of very young children to suboptimal maternal care has life long consequences including the increased occurrence of ADHD, depression and schizophrenia. However, maternal mood disorders during pregnancy and in the immediate postnatal period are also intimately linked to poor diet in pregnancy. Dissecting apart the relative contributions of these exposures is challenging in human cohort studies. We have developed a novel animal model, based on genetic modification of an imprinted gene called Phlda2, which models an alteration observed in the placenta after female mice are fed a low protein or a high fat diet during pregnancy also seen in human placenta from women reporting poor diet choices in pregnancy. Using our animal model, we have shown that elevated placental Phlda2 results in dysfunctional placental development and low birth weight. A key change we observe in the placenta is a reduction in the number of cells manufacturing placental hormones. These hormones are important for both fetal growth and maternal care. We have found that the female mice exposed to the mutant placenta neglect their pups. In humans, both low birth weight and poor maternal care have been linked to problems later in life including the increased prevalence of mental health issues. We have recently performed pilot work to examine offspring behaviour in our model. Remarkably, we found that both the offspring carrying the transgene and their littermates behaved abnormally showing signs of depression. This tells us that it is not the gene change that causes the abnormal behaviour. Instead there must be something about the shared environment which causes these changes in behaviour. This could be the exposure in utero to low placental hormone levels, poor fetal growth or poor quality maternal care after birth or potentially the combined adversities. We are able to dissect apart the contribution of the in utero environment versus postnatal exposures using a simple cross fostering techniques, experiments that are planned in this proposal. However, we wish to take this investigation even further. We know that maternal diet during pregnancy alters the expression of our gene in the placenta. Suboptimal maternal diets have been linked in humans and experimental models to both poor maternal care and abnormal offspring behaviour. This raises the intriguing possibility that placental endocrine dysfunction induced by a poor maternal diet contributes to both the abnormal behaviour of the mother and her child via placental dysfunction. We will combine our genetic model with a dietary model to examine this relationship in detail. This work is exceptionally timely as we are leading the studies on placental endocrine dysfunction using this model. We are in a unique position to build on strong preliminary data from our groups underpinning each aspect of the planned work, and we have the relevant expertise to ensure we achieve our aims.In addition to examining this novel mechanism linking early life adversity to later life outcomes, our work may have translational relevance. We know that 25% of human babies who are low birth weight due to fetal growth restriction have elevated placental PHLDA2. We have recent data linking elevated placental PHLDA2 to altered behaviour in human infants. We can ensure the maximum impact of our animal studies by translating directly to human pregnancy via our Grown in Wales study funded by the MRC. Consequently, our remarkable findings on maternal lifestyles during pregnancy funded by the BBSRC could rapidly lead to better outcomes for human mothers and their children.