Exposing the link between placental endocrine dysfunction and offspring behavioural outcomes

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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.