Exposing the link between placental endocrine dysfunction and offspring behavioural outcomes

揭示胎盘内分泌功能障碍与后代行为结果之间的联系

• 批准号: BB/P008623/1
• 负责人: Rosalind John
• 金额: $ 70.31万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP008623%2F1
• 关键词: Exposing; link; between; placental; endocrine

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.

早期生活的逆境（无论是产前还是儿童早期）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不良饮食中，和/或年幼的儿童暴露于次优的母亲护理中会产生终生后果，包括增加多动症、抑郁症和精神分裂症的发生率。然而，怀孕期间和产后不久的母亲情绪障碍也与怀孕期间不良饮食密切相关。在人类队列研究中，剖析这些暴露的相对贡献具有挑战性。我们开发了一种新型动物模型，基于对称为 Phlda2 的印记基因进行基因改造，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，这种变化在报告怀孕期间饮食选择不良的女性的人类胎盘中也观察到。使用我们的动物模型，我们发现胎盘 Phlda2 升高会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。这些激素对于胎儿生长和产妇护理都很重要。我们发现暴露于突变胎盘的雌性小鼠忽视了它们的幼崽。对于人类来说，低出生体重和不良的孕产妇护理都与以后生活中的问题有关，包括心理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及其同窝后代都表现出异常的抑郁迹象。这告诉我们，并不是基因改变导致了异常行为。相反，共享环境中一定有某些因素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产妇护理或潜在的综合逆境。我们能够使用简单的交叉培育技术（本提案中计划进行的实验）来剖析子宫内环境与产后暴露的贡献。然而，我们希望进一步开展这项调查。我们知道，怀孕期间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，次优的母亲饮食与不良的母亲护理和异常的后代行为有关。这提出了一个有趣的可能性，即不良母亲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孩子的异常行为。我们将把我们的遗传模型与饮食模型结合起来，详细研究这种关系。这项工作非常及时，因为我们正在利用该模型领导胎盘内分泌功能障碍的研究。我们处于独特的地位，可以利用我们小组提供的强有力的初步数据来支持计划工作的各个方面，并且我们拥有相关的专业知识来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颖机制之外，我们的工作可能具有转化相关性。我们知道，由于胎儿生长受限而导致低出生体重的人类婴儿中有 25% 的胎盘 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 MRC 资助的“在威尔士长大”研究直接转化为人类怀孕，从而确保我们的动物研究产生最大的影响。因此，由 BBSRC 资助的我们对孕期母亲生活方式的显着发现可以迅速为人类母亲及其孩子带来更好的结果。

项目成果

Placental dysfunction programs abnormal maternal behaviour and adverse outcomes

胎盘功能障碍会导致母亲行为异常和不良后果

• DOI: 10.1016/j.placenta.2017.07.043
• 发表时间: 2017
• 期刊: Placenta
• 影响因子: 3.8
• 作者: John R

In support of the placental programming hypothesis: Placental endocrine insufficiency programs atypical behaviour in mothers and their offspring.

• DOI: 10.1113/ep089916
• 发表时间: 2022-05
• 期刊: EXPERIMENTAL PHYSIOLOGY
• 影响因子: 2.7
• 作者: John, Rosalind M.

Epigenetic Epidemiology

表观遗传流行病学

• DOI: 10.1007/978-3-030-94475-9_8
• 发表时间: 2022
• 作者: John R

Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring.

• DOI: 10.1093/hmg/ddab154
• 发表时间: 2021-09-15
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Harrison DJ;Creeth HDJ;Tyson HR;Boque-Sastre R;Hunter S;Dwyer DM;Isles AR;John RM
• 通讯作者: John RM

The placental programming hypothesis: Placental endocrine insufficiency and the co-occurrence of low birth weight and maternal mood disorders

• DOI: 10.1016/j.placenta.2020.03.011
• 发表时间: 2020-09-01
• 期刊: PLACENTA
• 影响因子: 3.8
• 作者: Creeth, H. D. J.;John, R. M.
• 通讯作者: John, R. M.