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Abstract
Early-onset neurodevelopmental conditions (e.g., autism) affect males more frequently than females. Androgens may play a role in this male-bias by sex-differentially impacting early prenatal brain development, particularly neural circuits that later develop specialized roles in social cognition. Here, we find that increasing prenatal testosterone in humans is associated with later reduction of functional connectivity between social brain default mode (DMN) subsystems in adolescent males, but has no effect in females. Since testosterone can work directly via the androgen receptor (AR) or indirectly via the estrogen receptor through aromatase conversion to estradiol, we further examined how a potent non-aromatizable androgen, dihydrotestosterone (DHT), acts via the AR to influence gene expression in human neural stem cells (hNSC)—particularly for genes of high-relevance for DMN circuitry. DHT dysregulates a number of genes enriched for syndromic causes of autism and intellectual disability and for genes that in later development are expressed in anatomical patterns that highly correspond to the cortical midline DMN subsystem. DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation-inhibition balance. Androgens have male-specific prenatal influence over social brain circuitry in humans and may be relevant towards explaining some component of male-bias in early-onset neurodevelopmental conditions.
Highlights
It has long been known that events occurring during prenatal development can have long-lasting programming impact on susceptibility for medical conditions that emerge later in life [1,2,3]
Confirming our overall hypothesis that fetal testosterone (FT) exerts sex-specific influence over connectivity between neural circuits underpinning functions affected in male-biased neurodevelopmental conditions, we find only one between-component connection that is differentially related to FT in males vs. females
We have shown that variation in testosterone during midgestational prenatal development has longlasting effects on how specific networks comprising the core of the social brain, the default mode network (DMN), are organized
Summary
It has long been known that events occurring during prenatal development can have long-lasting programming impact on susceptibility for medical conditions that emerge later in life [1,2,3]. Emerging work has shown that events starting during prenatal development can have long-term impact potentially. These authors jointly supervised this work: Amélie Piton, Simon Baron-Cohen. Extended author information available on the last page of the article leading to increased likelihood for atypical neurodevelopmental phenotypes. It is becoming increasingly clear that prenatal brain development is a critical window of importance for understanding factors that increase the likelihood of neurodevelopmental conditions
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