Exposing the link between placental endocrine dysfunction and offspring behavioural outcomes

早期生活中的逆境(无论是在产前还是在童年早期)与儿童的结局明显较差之间存在明确的关联。例如，使发育中的胎儿暴露在不良饮食中，和/或使非常年幼的儿童暴露在不理想的产妇护理之下，会产生终生后果，包括增加ADHD、抑郁症和精神分裂症的发生率。然而，母亲在怀孕期间和产后立即出现的情绪障碍也与怀孕期间不良的饮食密切相关。在人类队列研究中，剖析这些暴露的相对贡献是具有挑战性的。我们开发了一种新的动物模型，基于一种名为Phlda2的印记基因的遗传修改，该模型模拟了雌性小鼠在怀孕期间喂食低蛋白质或高脂肪饮食后胎盘中观察到的变化，在报告怀孕期间饮食选择不佳的妇女的胎盘中也观察到了这种变化。使用我们的动物模型，我们已经证明胎盘Phlda2升高会导致胎盘发育障碍和出生体重降低。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。这些荷尔蒙对胎儿生长和产妇护理都很重要。我们发现，暴露在突变胎盘下的雌性小鼠忽视了它们的幼崽。在人类中，低出生体重和糟糕的产妇护理都与晚年生活中的问题有关，包括精神健康问题的患病率增加。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后代都表现出异常行为，表现出抑郁的迹象。这告诉我们，不是基因变化导致了异常行为。相反，一定是共享环境的某些方面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，胎儿发育不良或出生后低质量的产妇护理，或潜在的综合不利因素。我们能够使用简单的交叉培养技术来分析子宫内环境和出生后暴露的影响，这是本提案中计划的实验。然而，我们希望进一步调查这一事件。我们知道孕期母亲的饮食会改变胎盘中基因的表达。在人类和实验模型中，不理想的母体饮食与糟糕的母体护理和异常的后代行为有关。这提出了一种耐人寻味的可能性，即不良的母亲饮食导致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，因为我们正在使用这一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大初步数据基础上，这些数据支撑着计划工作的每一个方面，我们拥有相关的专业知识来确保我们实现目标。除了研究这种将早期生活逆境与后来的生活结果联系在一起的新机制之外，我们的工作可能具有翻译相关性。我们知道，25%因胎儿生长受限而出生体重较低的人类婴儿胎盘PHLDA2升高。我们最近的数据表明胎盘PHLDA2升高与人类婴儿的行为改变有关。我们可以通过由MRC资助的在威尔士生长的研究直接转化为人类怀孕，确保我们的动物研究产生最大影响。因此，我们关于孕期母亲生活方式的非凡发现，由BBSRC资助，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.