Prenatal adversity and the intergenerational transmission of atypical maternal caregiving

怀孕期间的逆境，如不良饮食和产前抑郁，会对母亲和孩子的健康产生重大影响。在子宫内遭遇逆境的儿童出生时体重过低，并在以后的生活中出现代谢和精神健康障碍的风险更高。有精神健康障碍史的妇女在怀孕期间出现抑郁和焦虑的风险增加，她们的孩子面临不利后果的风险增加，形成了代际逆境循环。为了打破这些逆境的代际循环，我们需要了解胎儿和胎盘中基因变化的相关性，这些变化是对产前逆境的反应。我们知道，受表观遗传标记调控的印迹基因可以对胎儿和胎盘中的产前逆境做出反应。印迹基因对胎儿大脑发育很重要，改变它们的表达会导致母亲在以后的生活中行为发生变化。印记基因对胎盘发育也很重要，我们已经证明改变胎盘中印记基因的表达会导致行为的改变，但这次，改变的是母亲的行为。这是因为胎盘是激素的来源，而激素是母性行为的基础，而母性行为是养育和照顾孩子所必需的。这意味着暴露在产前逆境中可能导致暴露的母亲和她的女儿提供非典型的母性护理，这要么是由于女儿大脑基因的直接变化，要么是因为女儿从母亲那里获得了母亲的养育方式。拆解这些复杂的关系真的很有挑战性。然而，我们已经获得了一个新的模型，结合了胎儿和胎盘在产前低蛋白饮食逆境后发生的关键基因变化。这个模型提供了一个很好的系统来探索产前逆境对母亲和女儿照顾行为的影响。我们将利用现有的技术，并结合包括单细胞测序和蛋白质组学在内的新技术，全面了解这些组合基因变化对胎盘内分泌谱系发育的影响。我们将检查暴露于胎盘内分泌不全的母亲和暴露于质量差的产妇护理的女儿的行为。我们将检查基因野生型和基因改良型的后代的行为，使用交叉培养来区分产前和产后暴露。通过这项工作，我们将确定非典型的产妇护理是如何遗传给那些母亲在怀孕期间暴露于产前逆境的女儿的。利用小鼠了解哺乳动物生物学的基本原理对人类健康具有重要意义。在英国，近一半的怀孕经历了逆境，其中一些经历了多重逆境。在英国，低出生体重的患病率为7.2%（英国每年约有6万新生儿），产前抑郁症的患病率为14%（11.2万新生儿）。成年后有精神健康问题的人数正在增加，有精神健康障碍史的妇女在怀孕期间患抑郁症和焦虑症的风险最高，形成了逆境的跨代传递。我们所做的工作将强调健康饮食和胎盘功能对母亲和她的后代的重要性，并有可能改善健康和福祉。重要的是，我们正在积极地将我们的发现从小鼠转化为人类，通过我们自己的威尔士怀孕队列。

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.