Sex-dependent fetal and placental responses to adversity

男性和女性胎儿对子宫内恶劣环境的反应是不同的。胎盘在支持胎儿生长方面起着至关重要的作用，它对逆境（如母体营养不良、母体压力）也表现出性别依赖性反应。大多数研究只是简单地列出性别差异，而不是寻找模式和潜在的原因。我研究的长期目标是更好地了解胎儿和胎盘对逆境的反应，以及产前环境如何影响成年后的特征。拟议的短期目标将侧重于两性之间的反应和长期影响的差异，以及这些差异的基础。目的1：确定对产前逆境的反应和影响的性别差异。性别差异可能源于进化过程中雄性和雌性所承受的不同压力。我的团队将使用小鼠来检查进化相关的逆境和结果，例如，母亲/父亲低蛋白饮食，母亲压力和母亲高龄对胎儿生长和胎盘功能的影响。我们将研究这些产前挑战对出生后生长和成人代谢的长期影响。目的2：研究产前逆境性别依赖反应的机制我们将探讨性别依赖反应是如何发生的。在哺乳动物中，雄性有一条X染色体和一条Y染色体，而雌性有两条X染色体，但使用转基因小鼠，我们可以产生具有雄性性腺的XX小鼠和具有雌性性腺的XY小鼠。我们将把这些与正常的XX女性和XY男性进行比较，以确定性别差异是否由于染色体差异和/或胎儿性腺和激素。这种区别很重要，因为胎儿激素对环境挑战的反应更灵敏。为了区分胎盘功能的性别差异是胎盘固有的还是由胎儿的信号形成的，我们将制造嵌合体，以获得与男性胎盘相关的女性胎儿，反之亦然。目的3：确定染色体和性腺性别对胎盘基因表达的影响男性和女性胎盘在某些基因的开启程度上存在差异，这些差异对于子宫内环境的反应是重要的。我们将使用下一代测序方法和转基因小鼠来研究导致胎盘基因表达性别差异的原因。影响了解男女之间的生物学差异与健康、进化研究和畜牧生产方面的公平有关。我们将使用新的方法来解决关于差异如何发生的基本问题：差异是由于染色体还是性腺性别？胎儿性别还是胎盘性别？这项工作将强调考虑性别依赖效应的必要性。我们的发现将引起从健康到进化等生命科学领域的研究人员的兴趣，并将提高我们对产前环境如何塑造动物生命的理解。

Male and female fetuses differ in how they respond to poor conditions in the womb. The placenta, crucial in supporting fetal growth, also shows sex-dependent responses to adversity (e.g., poor maternal nutrition, maternal stress). Most studies simply catalogue sex differences rather than seeking patterns and underlying causes. The long-term goal of my research is to better understand fetal and placental responses to adversity and how prenatal environment affects traits in adulthood. The proposed short-term objectives will focus on how responses and long-term effects differ between the sexes, and the basis of these differences. Objective 1: Identify sex differences in responses to and effects of prenatal adversity Differences between the sexes may stem from different pressures on males and females throughout evolution. My team will use mice to examine evolutionarily relevant adversities and outcomes, e.g., effects of maternal/ paternal low-protein diet, maternal stress, and advanced maternal age on fetal growth and placental function. We will examine the long-term consequences of these prenatal challenges on postnatal growth and adult metabolism. Objective 2: Examine mechanisms underlying sex-dependent responses to prenatal adversity We will probe how sex-dependent responses occur. In mammals, males have an X and a Y chromosome, whereas females have two Xs, but using genetically modified mice, we can generate XX mice with male gonads and XY mice with female gonads. We will compare these with normal XX females and XY males to determine whether sex differences are due to chromosomal differences and/ or fetal gonads and hormones. This distinction is important because fetal hormones are expected to be more responsive to environmental challenges. To distinguish if sex differences in placental function are inherent to the placenta or shaped by signals from the fetus, we will produce chimeras to obtain female fetuses associated with male placentas and vice-versa. Objective 3: Identify effects of chromosomal and gonadal sex on placental gene expression Male and female placentas differ in the extent to which they turn on certain genes, and these differences are important for responding to the in utero environment. We will use next generation sequencing approaches and genetically modified mice to investigate what causes sex differences in placental gene expression. Impact Understanding biological differences between males and females is relevant to equity in health, the study of evolution, and livestock production. We will use novel approaches to address fundamental questions regarding how differences occur: Are differences due to chromosomal or gonadal sex? Fetal or placental sex? This work will underscore the need to consider sex-dependent effects. Our findings will be of interest to researchers across the life sciences from health to evolution, and will improve our understanding of how prenatal environment shapes the lives of animals.