Prenatal adversity and the intergenerational transmission of atypical maternal caregiving

产前逆境和非典型孕产妇护理的代际传播

• 批准号: BB/V008684/1
• 负责人: Rosalind John
• 金额: $ 73.06万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV008684%2F1
• 关键词: Prenatal; adversity; intergenerational; transmission; atypical

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.

怀孕期间的不良饮食习惯和产前抑郁症会对母亲及其子女的健康产生重大影响。在子宫内暴露于逆境的儿童出生时体重较轻，在以后的生活中患代谢和心理健康疾病的风险较高。有心理健康障碍病史的妇女在怀孕期间患抑郁症和焦虑症的风险增加，其子女遭受不利后果的风险增加，从而建立代际逆境循环。为了打破这些代际逆境循环，我们需要了解胎儿和胎盘中基因变化的相关性，这些基因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记基因可以对胎儿和胎盘中的产前逆境做出反应。印记基因对胎儿大脑发育很重要，改变它们的表达可能会导致母亲日后行为的改变。印记基因对胎盘发育也很重要，我们已经证明，改变胎盘中的印记基因表达会导致行为改变，但这一次，改变的是母亲的行为。这是因为胎盘是一种激素的来源，需要这种激素来启动母亲的行为，这对养育和照顾年轻人至关重要。这意味着，产前逆境可能会导致母亲和女儿提供非典型的母亲护理，这可能是由于女儿大脑中基因的直接变化，也可能是因为女儿从母亲那里获得了母性的育儿方式。然而，我们已经获得了一个新的模型，它结合了低蛋白饮食的产前逆境后胎儿和胎盘中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的生育行为的影响。我们将使用我们已建立的技术，并结合新技术，包括单细胞测序和蛋白质组学，以充分了解这些组合基因变化对胎盘内分泌谱系发育的影响。我们将研究暴露于胎盘内分泌功能不全的母亲和暴露于质量差的孕产妇护理的女儿的行为。我们将研究遗传野生型的女儿，也转基因的女儿使用交叉寄养，以区分产前和产后暴露的行为。通过这项工作，我们将确定母亲在怀孕期间遭受产前逆境的女儿如何遗传非典型的孕产妇护理。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，近一半的孕妇都面临逆境，有些人经历了多种逆境。英国低出生体重的患病率为7.2%（英国每年约有60，000例出生），产前抑郁症的患病率为14%（112，000例出生）。成年后有心理健康问题的人数正在增加，有心理健康障碍病史的妇女在怀孕期间患抑郁症和焦虑症的风险最高，这就造成了逆境的代际传递。我们所做的工作将突出健康饮食和胎盘功能对母亲及其后代的重要性，并有可能改善健康和福祉。重要的是，我们正在积极地通过我们自己的威尔士妊娠队列将我们的发现从小鼠转化为人类。

项目成果

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