During prenatal development, sex hormones can determine whether the brain acquires feminine or masculine characteristics. Masculinization, for example, has been thought to be a fairly straightforward process, the direct induction of transcription by ligand-activated nuclear steroid receptors. Now, however, it appears the masculinization process is more indirect. According to research conducted at the University of Maryland School of Medicine (UM SOM), sex hormones appear to relieve the epigenetic repression of masculinizing genes.

The finding appeared March 30 in Nature Neuroscience, in an article entitled, “Brain feminization requires active repression of masculinization via DNA methylation.” The article described how estradiol, a testosterone derivative, can trigger a mechanism by which certain genes in the brain are “unsilenced,” allowing them to initiate the process of masculinization.

This work was accomplished in rats, which like other mammals—including humans—develop specifically male or female brain characteristics. For example, in most species, some portions of male and female brains are a different size, and often have a different number of neurons and synapses.
“Nobody has ever shown that this is how the process works,” said Margaret McCarthy, Ph.D., a professor and chairman of the department of pharmacology at UM SOM. “This gives us a new understanding of how gender is determined in the brain.”

In their experiments, the UM SOM scientists found that a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression.

The researchers injected Dnmt inhibitors into the POA, a brain area known to be involved in governing male sexual behavior, after the first week of birth, after the window for brain sexual differentiation was thought to have been closed. Despite this, the POA in the animals was transformed, and took on structural characteristics of a male rat. The female rats also behaved differently, displaying sexual behavior typical of male rats.

In another experiment, they scientists deleted the Dnmt gene in female mice; these animals also showed male behavior patterns. “Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in female rats,” the authors of the Nature Neuroscience article wrote. “Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice.”

In previous research, Dr. McCarty’s group found sex and gender differences in levels of a protein associated with language acquisition and development. This finding may be associated with higher levels of communication among females in some species.

Intriguingly, the latest study also found that inflammatory immune cells known as microglia appear to play a role in masculinization, in part through their production of prostaglandins, a neurochemical normally associated with illness. In recent years, scientists have increasingly realized that the immune system is integral to the development of the brain; Prof. McCarthy and her group are the first to show that it is also important for establishment of sex differences in the brain. The current discovery is another piece in that puzzle; they showed that Dnmt enzymes control expression of genes that play a role in inflammation and immunity, and also in the sexual differentiation of the brain.

“Physically, these animals were females, but in their reproductive behavior, they were males,” said Nugent. “It was fascinating to see this transformation.”

“RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females,” the authors concluded. “Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation.”

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