George Washington University researcher, Dr. Valerie Hu, Professor of Biochemistry and Molecular Biology, and her team at the School of Medicine and Health Sciences, found that male and female sex hormones regulate expression of an important gene RORA through a mechanism that could explain not only higher levels of testosterone observed in some individuals with autism, but also why males have a higher incidence of autism than females.
The gene, RORA, encodes a protein that works as a "master switch" for gene expression, and is critical in the development of the cerebellum as well as in many other processes that are impaired in autism. Dr. Hu’s earlier research found that RORA was decreased in the autistic brain. In this study, the research group demonstrates that aromatase, a protein which is regulated by RORA, is also reduced in autistic brains.
This is significant because aromatase converts testosterone to estrogen. Thus, a decrease in aromatase is expected to lead in part to build up of male hormones which, in turn, further decrease RORA expression, as demonstrated in this study using a neuronal cell model. On the other hand, female hormones were found to increase RORA in the neuronal cells. The researchers believe that females may be more protected against RORA deficiency not only because of the positive effect of estrogen on RORA expression, but also because estrogen receptors, which regulate some of the same genes as RORA, can help make up for the deficiency in RORA.
To find out how RORA is affected by hormones, Hu’s team bathed human brain cells expressing the gene in either oestradiol – a form of the major female sex hormone oestrogen – or the male sex hormone dihydrotestosterone (DHT), which is derived from testosterone. They found that oestradiol enhanced the gene’s expression, whereas DHT suppressed it.
The team also discovered that RORA regulates another gene which controls aromatase, an enzyme that converts testosterone to oestrogen. If RORA is under-expressed, then aromatase cannot function properly and testosterone will accumulate.
In a whole organism, this excess testosterone may in turn further repress the expression of RORA, making matters worse. Elevated levels of testosterone in the womb are thought to contribute to the development of autism. However, if the RORA gene is faulty in a female fetus, it would be less susceptible to a build-up of testosterone because the fetus has higher levels of oestrogen to begin with. What’s more, female sex hormones are likely to promote any RORA that is expressed, rather than further repress it.
"For a long time elevated fetal testosterone has been a proposed as risk factor for autism, but the problem is that there has been no molecular explanation," says Hu. "Now we have evidence for a really exacerbating situation. What we have identified is an inhibitory feedback loop. That is what makes this so fascinating."
"It is well known that males have a higher tendency for autism than females; however, this new research may, for the first time, provide a molecular explanation for why and how this happens. This is just the tip of the iceberg in terms of understanding some of the biology underlying autism, and we will continue our work to discover new ways to understand and, hopefully, to someday combat this neurodevelopmental disorder," said Dr. Hu.