Sex-dependent fetal and placental responses to adversity

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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.