Prenatal adversity and the intergenerational transmission of atypical maternal caregiving

Adversities in pregnancy, such as poor diet and prenatal depression, can have a major impact on both the health of the mother and her children. Children exposed to adversity in utero are at higher risk of being born low birth weight and developing both metabolic and mental health disorders later in life. Women with a history mental health disorders are at increased of developing depression and anxiety in pregnancy and their children are at increased risk of adverse outcomes establishing intergenerational cycles of adversity. In order to break these intergenerational cycles of adversity, we need to understand the relevance of genes changes in both the fetus and the placenta that occur in response to prenatal adversity.

We know that imprinted genes, which are regulated by epigenetic marks, can respond to prenatal adversity both in the fetus and in the placenta. Imprinted genes are important for fetal brain development and altering their expression can cause changes in maternal behaviour later in life. Imprinted genes are also important for placental development, and we have shown that altering imprinted gene expression in the placenta can cause changes in behaviour but this time, it is the mother's behaviour that is altered. This occurs because the placenta is a source of hormones which are required to prime maternal behaviour essential for nurturing and caring for young. This means that exposure to prenatal adversity can result in atypical maternal care provided both by the exposed mother and by her daughters, either due to direct changes in genes in the daughter's brain or because daughters acquire maternal parenting styles from their mothers.

Teasing apart these complex relationships is really challenging. However, we have acquired a new model which combines the key gene changes that occur in the fetus and placenta after the prenatal adversity of a low protein diet. This model provides an excellent system to explore the impact of prenatal adversity on the mother's and daughter's caregiving behaviour. We will use our established techniques and incorporate new techniques including single cell sequencing and proteomics to fully understand the consequences of these combined gene changes for placental endocrine lineage development. We will examine the behaviour of mothers exposed to placental endocrine insufficiency and the daughters exposed to poor quality maternal care. We will examine the behaviour of both the genetically wild type daughters and also the genetically modified daughters using cross fostering to distinguish between prenatal and postnatal exposures. Through this work, we will establish how atypical maternal care is inherited by daughters whose mothers were exposed to prenatal adversity in their pregnancy.

Understanding basic principles of mammalian biology using mice has important implications for human health. Nearly half of all pregnancies in the UK are exposed to adversity with some experiencing multiple adversities. The prevalence of low birth weight in the UK is 7.2% (approximately 60,000 births per annum in UK) and of prenatal depression is 14% (112,000 births). The number of individuals with mental health problems in adulthood is increasing and women with a history mental health disorders are at highest risk of developing depression and anxiety in pregnancy, establishing transgenerational transmission of adversity. The work that we do will highlight the importance of healthy diet and placental function for both the mother and her offspring with potential to improve health and wellbeing. Importantly, we are actively translating our findings from mouse to human via our own Grown in Wales pregnancy cohort.

Prenatal low protein diet results in changes in the expression of IC2 domain imprinted genes in the mouse fetus and placenta. Genetic disruption of IC2 domain imprinted genes in the placenta can result in atypical maternal behaviour provided by wild-type mothers as a consequence of placental endocrine insufficiency. Daughters are known to copy their mother's parenting style acquiring atypical maternal behaviour. Changes to imprinted genes in the fetus can also directly cause atypical maternal behaviour in daughters by disrupting the neuronal circuitry regulating parental care. Consequently, whether due to intrinsic gene changes or through exposure to atypical maternal care, daughters can perpetuate adversities into subsequent generations.

To extend our current data on individual genes from the IC2 imprinted domain and tease apart the complex relationships between mothers and daughters, we will use a mouse model combining the IC2 domain changes (2xCdkn1c/2xPhlda2/2xAscl2). We will apply histology, RNAscope, single cell RNAseq and proteomic analysis to characterise the consequence of IC2 domain-wide loss-of-imprinting on placental endocrine lineage development. We will use well established protocols to ask whether the maternal brain and behaviour is altered in wild-type mothers who carry and care for mutant pups, as we have shown for isolated loss-of-imprinting of Phlda2. We will examine the maternal behaviour of both genetically modified and wild-type daughters exposed to suboptimal maternal care, and use cross fostering to distinguish between the direct effect of loss-of-imprinting and the indirect effect of exposure to suboptimal maternal care. This work will test our hypothesis that prenatal adversity-driven changes in IC2 domain imprinted gene expression in the fetus and placenta program atypical maternal behaviour in both mothers and their daughters uncovering a new a mechanism contributing to the intergenerational inheritance of adversity.