Sex Steroid Hormone Signaling Tunes Metabolic and Neuronal Programs in Human Cortical Development
This study demonstrates that sex steroid hormones, particularly androgens, act as selective, cell-state-dependent modulators of metabolic and neuronal maturation programs in developing human cortical lineages, offering a potential mechanistic explanation for the male bias in autism spectrum disorder.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Autism spectrum disorder is a condition that affects how people interact with the world, and it is strikingly more common in boys than in girls. For decades, scientists have searched for the biological reason behind this gap. While many genetic factors are known to contribute to autism, they do not fully explain why the condition appears so much more frequently in males. One long-standing idea is that sex hormones—the chemical messengers like testosterone and estrogen that guide the development of male and female bodies—might also shape the developing brain in ways that influence this risk. In reproductive tissues, these hormones are known to turn genes on and off, but their role in the human brain during pregnancy has remained a mystery. Understanding whether these hormones act as subtle tuners of brain development or as powerful rewirers of the brain's genetic code is essential to understanding the origins of sex differences in neurodevelopmental disorders.
A team of researchers set out to solve this puzzle by looking directly at human brain tissue and laboratory models of the developing brain. They focused on the cortex, the outer layer of the brain responsible for complex thinking, during the middle of pregnancy when the brain is building its basic structure. Using advanced tools to read the genetic instructions inside individual cells, they first mapped where the receptors for sex hormones are located. These receptors are like locks that hormones must fit into to send a signal. The researchers found that these locks are present in the developing human brain, but they are not everywhere. The receptors for androgens, the class of hormones that includes testosterone, were found mostly in the cells that act as the brain's construction crew, known as radial glia and intermediate progenitors. These are the cells that divide to create new neurons. The receptors for estrogen were found more widely across different cell types, but they were also most abundant in these same construction cells. This distribution suggests that hormones might have their strongest influence on the cells that are still growing and dividing, rather than on the mature neurons that have already finished their work.
To see what happens when these hormones are present, the scientists grew human brain cells in the lab, creating tiny, three-dimensional models of the cortex called organoids. They exposed these models to physiological levels of dihydrotestosterone, a potent form of androgen, and estradiol, a form of estrogen, for a single day. The results showed a clear difference in how the brain cells responded. The androgen exposure triggered a much stronger reaction than the estrogen exposure. When the cells were exposed to androgens, they shifted their internal programming. The genes responsible for helping neurons mature, grow long connections, and form synapses were turned down. At the same time, genes related to energy production and cell growth were turned up. It was as if the cells were being told to stay in a state of rapid growth and energy consumption rather than settling down to become specialized, mature brain cells. The estrogen exposure had a much weaker effect, though it did also increase energy-related activity.
The researchers then looked at a specific gene called NTRK2, which is crucial for neuron development and is known to be influenced by hormones. They found that in the lab models, androgens reduced the activity of this gene. When they looked back at the actual human brain tissue from the middle of pregnancy, they saw a pattern that matched this finding perfectly. In the construction cells of the developing brain, the NTRK2 gene was significantly more active in females than in males. This aligns with the idea that the higher levels of androgens naturally present in male fetuses act to lower the activity of this gene, while the lower levels in females allow it to remain higher. This difference is most pronounced in the cells that are still dividing and is largely gone once the neurons have matured.
The study also connected these hormonal effects to the risk of autism. The researchers identified a group of genes that are suppressed by androgens and are naturally more active in females. They found that this specific group of genes is heavily enriched with known risk factors for autism. This suggests that the natural variation in hormone levels during development, which subtly tunes these specific genetic programs, could contribute to the higher prevalence of autism in males. The findings indicate that sex hormones do not rewrite the entire blueprint of the brain. Instead, they act as selective modulators, fine-tuning specific biological programs in specific cell types at specific times. By keeping certain cells in a state of growth and delaying their maturation, androgens may create a developmental trajectory that, when combined with other genetic factors, increases the likelihood of autism. This provides a concrete biological mechanism for how small differences in hormone exposure during a critical window of development could lead to the profound sex differences seen in neurodevelopmental disorders.
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