E.V. is partially funded by the DSD Translational Research Network (NICHD 1R01HD068138). M.S.B. is funded by the Neuroendocrinology, Sex Differences and Reproduction training grant (NICHD 5T32HD007228). The authors have no competing interests to disclose.

The mechanisms by which sex differences in the mammalian brain arise are poorly understood, but are influenced by a combination of underlying genetic differences and gonadal hormone exposure. Using a mouse embryonic neural stem cell (eNSC) model to understand early events contributing to sexually dimorphic brain development, we identified novel interactions between chromosomal sex and hormonal exposure that are instrumental to early brain sex differences. RNA-sequencing identified 103 transcripts that were differentially expressed between XX and XY eNSCs at baseline (FDR = 0.10). Treatment with testosterone-propionate (TP) reveals sex-specific gene expression changes, causing 2854 and 792 transcripts to become differentially expressed on XX and XY genetic backgrounds respectively. Within the TP responsive transcripts, there was enrichment for genes which function as epigenetic regulators that affect both histone modifications and DNA methylation patterning. We observed that TP caused a global decrease in 5-methylcytosine abundance in both sexes, a transmissible effect that was maintained in cellular progeny. Additionally, we determined that TP was associated with residue-specific alterations in acetylation of histone tails. These findings highlight an unknown component of androgen action on cells within the developmental CNS, and contribute to a novel mechanism of action by which early hormonal organization is initiated and maintained.

Infection with Zaire ebolavirus (EBOV) appears to trigger an anti–pan-filovirus response in a small subset of Congolese Ebola virus disease survivors, generating potential neutralizing antibodies against EBOV and Bundibugyo, Taï Forest, Sudan, and Marburg viruses.

While numerous in vivo experiments have sought to explore the effects of sex chromosome composition and sex steroid hormones on cellular proliferation and differentiation within the mammalian brain, far fewer studies as reviewed here, have explored these factors using a direct in vitro approach. Generally speaking, in vivo studies provide the gold standard to demonstrate applicable findings in regards to the role hormones play in development. However, in the case of neural stem cell (NSC) biology, there remain many unknown factors that likely contribute to observations made within the developed brain, specifically in regions where there are abundant sex steroid hormone receptors. For these reasons, using a NSC in vitro model may provide a more controlled and refined system to explore the direct effects of sex and hormone response, limiting the vast array of other influences on NSCs occurring during development and within adult cellular niches. These specific cellular models may have the ability to greatly improve the mechanistic understanding of changes occurring within the developing brain during the hormonal organization process, in addition to other modifications that may contribute to neuro-psychiatric sex-biased diseases.

Sex differences in brain development and postnatal behavior are determined largely by genetic sex and in utero gonadal hormone secretions. In humans however, determining the weight that each of these factors contributes remains a challenge because social influences should also be considered. Cases of disorders of sex development (DSD) provide unique insight into how mutations in genes responsible for gonadal formation can perturb the subsequent developmental hormonal milieu and elicit changes in normal human brain maturation. Specific forms of DSDs such as complete androgen insensitivity syndrome (CAIS), congenital adrenal hyperplasia (CAH), and 5α-reductase deficiency syndrome have variable effects between males and females, and the developmental outcomes of such conditions are largely dependent on sex chromosome composition. Medical and psychological works focused on CAH, CAIS, and 5α-reductase deficiency have helped form the foundation for understanding the roles of genetic and hormonal factors necessary for guiding human brain development. Here we highlight how the three aforementioned DSDs contribute to brain and behavioral phenotypes that can uniquely affect 46,XY and 46,XX individuals in dramatically different fashions. © 2016 Wiley Periodicals, Inc.