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Pre-Implantation Sex Differences
Historically sex differences in embryos were though to only manifest during foetal development of gonads and production of sex specific hormones. However, modern technology has revealed that sexual dimorphism between male and female mammalian occurs much earlier at the embryonic preimplantation stage. The preimplantation stage refers to the time of embryo development between zygote formation and the embedding of a blastocyst into the endometrium of the uterus, otherwise known as implantation or nidation.

In humans and other mammals sex differences are largely regulated by the X and Y sex chromosomes. In mammals, females typically have two X-chromosomes (XX) whereas males have an X- and a Y-chromosome (XY). Changes and interactions between these sex chromosomes, the genome, the cell, and the environment all have a role in producing sexually dimorphic traits which can be seen from zygote formation all the way through to adulthood. It is important to investigate the molecular differences between males and females as their biology differs well beyond external sex characteristics such as susceptibility to certain non-communicable diseases all in which can potentially be determined as early as the preimplantation stage.

Genetic Preimplantation Sex Differences
Y-Linked Genes

The expression of Y-linked genes is one of the primary differences between male and female embryo. A Y-linked genes such as the Sry is important in initiating the development of testes during foetal development  Expression of this gene has been reported to occur at the blastocyst stage in mice and even earlier at the 4-8 cell stage in bovine embryos showing evidence of very early sex differentiation.

X-Linked Genes

Although differences in male and female embryos begin to appear quickly after fertilization with the advent of Y-linked gene expression in male cells, the Y-linked gene expression accounts for only a small proportion of pre-implantation sex differences Major differences are due to delayed or incomplete X-inactivation. X-inactivation is when one of the X chromosomes in female cells are transcriptionally silenced in order to equalize the amount of X-linked gene product produced between males and females. In humans, there is a period of time where X-inactivation has not yet occurred. This means that briefly female cells experience biallelic X-linked gene expression doubling the amount of gene product that male embryos will have. Interestingly, mice X-inactivation occurs immediately after fertilization at the 2-4 cell embryonic stage until its reactivation in the late blastocyst stage eliminating any early X-linked gene biallelic expression effects and showing how sex differences can vary at the preimplantation stage between mammals.

Autosomal Genes

Despite their expression levels being largely the same in both male and female pre-implanted embryos, some autosomal genes have been detected as differentially expressed. Evidence for this can be seen in a study by Bermejo-Alvarez et al. identified four differentially expressed genes between male and female bovine balstocysts. A similar study in mice found there to be 15 differentially expressed genes between males and females at the 8-cell stage and found that these expression of these gene changed a lot through continued development. A more recent study in 2017 which used embryonic stem cells from 3.5-day old mice embryos actually showed that majority of differential gene expression is autosomal with only 25% of differential gene expression being attributed to sex chromosomes. Together these results show that differential gene expression can occur between Y-linked, X-linked, and autosomal genes in order to create dimorphic differences in early embryonic stages.

Effects of Sex Based Differential Gene Expression in Early Embryos
Cell states

Differential gene expression can have impacts on cellular state. Double X chromosome gene dosage, which occurs briefly in early embryo development, has been shown to cause an increase in expression of genes associated with a naive pluripotent cell state and thus a slight delay in development compared to XY male cells. In contrast male cells have been shown to have higher expression of cell differentiation genes. This shows that male cells are more suited for cell lineage determination compared to female cells during the early embryo stage before the initiation of cellular differentiation after implantation. These dimorphic qualities between male and female embryos suggest that pre-implanted embryos face different responses to environmental factors.