image: The distinct parental origins of the X chromosome lead to X-specific lower methylation in female embryos (at least in TE lineage), which, combined with the incomplete X chromosome inactivation and sex-specific cell-cell communications, contributes to the sex-differential transcription and development. These include 1) the differentiation advantage towards CTBs, more active cell cycle, enhanced mitochondrial function, stronger vasculogenesis signals, and higher immunotolerance potentials in the female TE lineage, and the differentiation advantage towards STBs and stronger hormone-secreting function in the male TE lineage; 2) the higher proliferation potential and differentiation advantage towards AVE in the male PE lineage; and 3) the higher proliferation potential in male EPI lineage. These differences may serve as the underlying cause for the sex-differential development of the embryos/fetuses, with males prioritizing fetoplacental growth and females tending to ensure resilience to damage. EPI, epiblast. PE, primitive endoderm. TE, trophectoderm. XCI, X chromosome inactivation. AVE, anterior visceral endoderm. CTB, cytotrophoblast. STB, syncytiotrophoblast.
Credit: ©Science China Press
This study is led by Prof. Peng Yuan, Prof. Jie Qiao, and Prof. Liying Yan from Peking University Third Hospital. The researchers conducted an in-depth analysis of the transcriptional characteristics of 8,455 cells from 65 human embryos (Day 6 - Day 14) and the methylation characteristics of some of these cells. "The large number of embryos and cells ensures the reliability of the analysis, " said senior author Prof. Peng Yuan.
The research team found that sex chromosomes play a dominant role in the sex differences of pre-gastrulation embryonic development, but their contribution gradually diminishes with development, which is associated with the progression of X chromosome inactivation (XCI) and lineage differentiation.
"We are surprised to discover that by the second week of embryonic development, male and female embryos already exhibit significant differences in the development of various lineages. Compared to female embryos, male trophectoderm exhibits a differentiation advantage and higher expression levels of placental hormone genes, but lower cell cycle activity, poorer mitochondrial function, and weaker vasculogenesis and immunotolerance signals. The primitive endoderm in male embryos initiates the differentiation of anterior visceral endoderm earlier, and the male epiblast has higher proliferative activity," said Dr. Yongjie Lu, the lead author.
Sex differences in trophectoderm development have been further validated in over 7,000 women undergoing assisted reproductive treatment. Pregnant women carrying male fetuses exhibit higher serum β-hCG levels, thereby providing compelling clinical phenotypic evidence for sex differences in embryonic development.
"These differences align with the sex differences observed in human fetal development, where male fetuses grow faster but are more prone to adverse pregnancy events, while female fetuses have a stronger potential to resist adverse intrauterine environments. Hence, our findings shed light on the origins of sex differences in human fetal development," said senior author Prof. Jie Qiao.
The research team further explored the causes of these differences and found that X-chromosome-specific hypomethylation and incomplete X chromosome inactivation in female embryos, along with sex-specific cell-cell communication patterns, collectively contribute to the observed transcriptional and developmental sex differences.
"These findings reveal the underlying mechanisms of sex differences in human embryonic and fetal development, elucidating the roles of the X chromosome and the intricate cell-cell communication patterns. This is significant for understanding the principles of early human embryonic development," said senior author Prof. Liying Yan.
In summary, this study provides unparalleled insights into the sex differences in human pre-gastrulation embryos and their prospective correlation with the sex differences observed in human fetuses.
See the article:
Sex differences in human pre-gastrulation embryos
https://doi.org/10.1007/s11427-024-2721-y
Journal
Science China Life Sciences