Abstract
Molecular mechanisms underlying sexual dimorphism in mammals, fetal sex influences on intrauterine development, and the sex-biased susceptibility for selected diseases in adulthood are novel areas of current research. As importantly, two decades of multifaceted research has established that susceptibility to many adult disorders originates in utero, commonly secondary to the effects of placental dysfunction. We hypothesized that fetal sex influences gene expression and produces functional differences in human placentas. We thus extended previous studies on sexual dimorphism in mammals, which used RNA isolated from whole tissues, to investigate the effects of sex on four cell-phenotypes within a single key tissue, human placental villi. The cells studied included cytotrophoblasts, syncytiotrophoblast, arterial and venous endothelial cells. The cells were isolated from placentas of male or female fetuses and subjected to microarray analysis. We found that fetal sex differentially affected gene expression in a cell-phenotype dependent manner among all four cell-phenotypes. The markedly enriched pathways in males were identified to be signaling pathways for graft-versus-host disease as well as the immune and inflammatory systems that parallel the reported poorer outcome of male fetuses. Our study is the first to compare global gene expression by microarray analysis in purified, characterized, somatic cells from a single human tissue, i.e. placental villi. Importantly, our findings demonstrate that there are cell-phenotype specific, and tissue-specific, sex-biased responses in the human placenta, suggesting fetal sex should be considered as an independent variable in gene expression analysis of human placental villi.
Highlights
Males and females express multiple phenotypic differences, but recent attention has focused on molecular mechanisms underlying sexual dimorphism in mammals and the sex-biased susceptibility for selected diseases in adulthood
1.3% of all annotated transcripts were differentially expressed between the two sexes in arterial, 2.4% in venous endothelial cells, 6.3% in syncytiotrophoblasts, and 1.5% in cytotrophoblasts, respectively
When combining the data sets of all four placental cell phenotypes and removing duplicates, fetal sex influenced the expression of 9% of all genes (p,0.05, fold-change .1.3)
Summary
Males and females express multiple phenotypic differences, but recent attention has focused on molecular mechanisms underlying sexual dimorphism in mammals and the sex-biased susceptibility for selected diseases in adulthood. Fetal sex influences in utero development in both uncomplicated pregnancies and pregnancies with sub-optimal outcomes. Male fetuses in pregnancy maladies have poorer outcomes than female fetuses [5,6] and are more likely to develop hypertension, diabetes mellitus, or metabolic syndrome [7,8]. The placental villous tree provides nutrition, hormones, and growth factors for fetal development. Trophoblasts delimit a villous core through which the umbilical circulation is contiguous with the endothelial lining of the fetal arterial or venous vessels, including capillaries that course throughout the placental villi (Figure 1)
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