Sex-dependent fetal and placental responses to adversity

胎儿和胎盘对逆境的性别依赖性反应

• 批准号: RGPIN-2021-02853
• 负责人: Christians, Julian
• 金额: $ 2.91万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744713
• 关键词: Sex; dependent; fetal; placental; responses

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.

男性和女性胎儿对子宫内不良条件的反应不同。胎盘在支持胎儿生长方面至关重要，也显示出对逆境的性别依赖性反应（例如，产妇营养不良，产妇压力）。大多数研究只是简单地将性别差异分类，而不是寻找模式和根本原因。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如何不同，以及这些差异的基础。 目标一：性别之间的差异可能源于在整个进化过程中男性和女性所承受的不同压力。我的团队将使用小鼠来研究与进化相关的逆境和结果，例如，母亲/父亲低蛋白饮食、母亲压力和高龄母亲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产后生长和成人代谢的长期影响。目的2：探讨产前逆境的性依赖反应机制我们将探讨性依赖反应如何发生。在哺乳动物中，雄性有一个X和一个Y染色体，而雌性有两个X，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是由于染色体差异和/或胎儿性腺和激素。这种区别很重要，因为胎儿激素预计对环境挑战更具反应性。为了区分胎盘功能的性别差异是胎盘固有的还是由胎儿信号塑造的，我们将产生嵌合体以获得与男性胎盘相关的女性胎儿，反之亦然。目标三：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开启某些基因的程度不同，这些差异对于应对子宫内环境很重要。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。影响了解男性和女性之间的生物学差异与健康公平，进化研究和畜牧业生产有关。我们将使用新的方法来解决有关差异如何发生的基本问题：是由于染色体或性腺性别的差异？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的生命科学研究人员的兴趣，并将提高我们对产前环境如何塑造动物生命的理解。