Sex differences in early and term placenta are conserved in adult tissues

Abstract

Background Pregnancy complications vary based on the fetus’s genetic sex, which may, in part, be modulated by the placenta. Furthermore, developmental differences early in life can have lifelong health outcomes. Yet, sex differences in gene expression within the placenta at different timepoints throughout pregnancy and comparisons to adult tissues remains poorly characterized. Methods Here, we collect and characterize sex differences in gene expression in term placentas (≥ 36.6 weeks; 23 male XY and 27 female XX). These are compared with sex differences in previously collected first trimester placenta samples and 42 non-reproductive adult tissues from GTEx. Results We identify 268 and 53 sex-differentially expressed genes in the uncomplicated late first trimester and term placentas, respectively. Of the 53 sex-differentially expressed genes observed in the term placentas, 31 are also sex-differentially expressed genes in the late first trimester placentas. Furthermore, sex differences in gene expression in term placentas are highly correlated with sex differences in the late first trimester placentas. We found that sex-differential gene expression in the term placenta is significantly correlated with sex differences in gene expression in 42 non-reproductive adult tissues (correlation coefficient ranged from 0.892 to 0.957), with the highest correlation in brain tissues. Sex differences in gene expression were largely driven by gene expression on the sex chromosomes. We further show that some gametologous genes (genes with functional copies on X and Y) will have different inferred sex differences if the X-linked gene expression in females is compared to the sum of the X-linked and Y-linked gene expression in males. Conclusions We find that sex differences in gene expression are conserved in late first trimester and term placentas and that these sex differences are conserved in adult tissues. We demonstrate that there are sex differences associated with innate immune response in late first trimester placentas but there is no significant difference in gene expression of innate immune genes between sexes in healthy full-term placentas. Finally, sex differences are predominantly driven by expression from sex-linked genes.

Sex-Specific Alterations in Placental Proteomics Induced by Intrauterine Hyperglycemia

“…Many studies have demonstrated that placenta is a sexually dimorphic organ. 35 Olney et al 36 suggested that the early placenta exhibited sexual differences in the innate immune system but not in healthy term placenta. However, our data showed that male GDM placenta showed more altered pathways related to the immune system during late pregnancy (E18.5), suggesting that the deleterious effects of the intrauterine hyperglycemic environment might have a sexually dimorphic effect.…”

Sex differences in innate and adaptive immunity impact fetal, placental, and maternal health

“…Sexually dimorphic placental gene expression of several of these genes has also been reported. DDX3X is upregulated in female first-trimester and term placental cells compared with male [56, 57, 68]. Another study found that TMSB4X is significantly higher in female trophoblast cells of the first-trimester placenta [57].…”

“…PARs are often enriched with genes that code for immune signaling. CD99 is found on a PAR and is significantly higher in the undifferentiated, multipotent progenitor cells of the placenta, the cytotrophoblast (CTB) cells, of males at all points in gestation [68, 72, 73]. An additional study observed clusters of X-linked genes biased toward male overexpression on placental PARs [74].…”