The human placental sexome differs between trophoblast epithelium and villous vessel endothelium - PubMed (original) (raw)

The human placental sexome differs between trophoblast epithelium and villous vessel endothelium

Silvija Cvitic et al. PLoS One. 2013.

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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Placental villi.

Schematic representation (A) and an immunohistochemical staining (B) of a villous cross section showing two main placental compartments. The trophoblast epithelium i.e., syncytiotrophoblast (SCT) and cytotrophoblasts (CT) (syncytial progenitors) is exposed to the maternal circulation (MC) while the fetal circulation (FC) is in direct contact with villous vessel endothelium, composed of arterial (AEC) and venous endothelial cells (AEC).

Figure 2

Figure 2. Study design.

Experimental design applied to identify sex-biased gene expression in four placental cell types: syncytiotrophoblast (SCT), cytotrophoblasts (CT), arterial (AEC) and venous endothelial cells (VEC), two main placental compartments (trophoblast epithelium and villous vessel endothelium), and in the whole placental villi. The cells were isolated from placentas of male and female fetuses and their mRNA subjected to microarray analysis by hybridization to Affymetrix GeneChip Human 1.0 ST arrays. Genes that reached significance (p<0.05) and with a fold-change >1.3 were considered differentially expressed between the two sexes. Placental villi refers to the combined analysis of all expressed transcripts in syncytiotrophoblast, cytotrophoblasts, arterial and venous endothelial cells comparing gene expression in male vs. female cells. Microarray data were validated by RT-qPCR a) using identical samples as used in the microarray analysis and b) in different isolations cultured independently.

Figure 3

Figure 3. Number of genes showing sex-biased expression in four distinct placenta cell types.

Number of differentially expressed genes (p<0.05, fold-change >1.3) between male and female syncytiotrophoblasts, cytotrophoblasts, arterial and venous endothelial cells, trophoblast epithelium, villous vessel endothelium, and for placental villi is shown as number of genes upregulated in males vs. the number of genes upregulated in females. Placental villi refers to combined analysis of all expressed transcripts in syncytiotrophoblasts, cytotrophoblasts, arterial and venous endothelial cells.

Figure 4

Figure 4. Genes whose expression is regulated by fetal sex in common to all cell phenotypes.

Venn diagram depicting the number of sex regulated genes shared between (A) syncytiotrophoblast (SCT), cytotrophoblast (CT), arterial (AEC) and venous endothelial cells (VEC) (B) endothelial and epithelial compartment. Genes found to be in common are shown in boxes on the right (A and B).

Figure 5

Figure 5. Chromosomal distribution of genes showing sex-biased expression in placental endothelium and epithelium.

The number of male- and female-biased genes (p<0.05, fold-change >1.3) is shown for each chromosome separately. The number on top of the bars indicates the number of genes with fold-change >2. The proportion of genes located on autosomal vs. sex chromosomes is given on the top right and left of each graphs, respectively. An ideogram at the right depicts the specific location of upregulated genes in males (blue line) and females (red line) on X and Y chromosomes.

References

    1. Bracero LA, Cassidy S, Byrne DW (1996) Effect of gender on perinatal outcome in pregnancies complicated by diabetes. Gynecol Obstet Invest 41: 10–14. - PubMed
    1. Bekedam DJ, Engelsbel S, Mol BW, Buitendijk SE, van der Pal-de Bruin KM (2002) Male predominance in fetal distress during labor. Am J Obstet Gynecol 187: 1605–1607. - PubMed
    1. Zeitlin J, Ancel PY, Larroque B, Kaminski M, EPIPAGE Study (2004) Fetal sex and indicated very preterm birth: Results of the EPIPAGE study. Am J Obstet Gynecol 190: 1322–1325. - PubMed
    1. Cui W, Ma CX, Tang Y, Chang V, Rao PV, et al. (2005) Sex differences in birth defects: A study of opposite-sex twins. Birth Defects Res A Clin Mol Teratol 73: 876–880. - PubMed
    1. Di Renzo GC, Rosati A, Sarti RD, Cruciani L, Cutuli AM (2007) Does fetal sex affect pregnancy outcome? Gend Med 4: 19–30. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources