Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Sep;25(9):2175-2188.
doi: 10.1038/s41380-018-0198-y. Epub 2018 Aug 13.

Sex-specific impact of prenatal androgens on social brain default mode subsystems

Michael V Lombardo #  1   2 , Bonnie Auyeung #  3   4 , Tiziano Pramparo #  5 , Angélique Quartier  6   7   8   9 , Jérémie Courraud  6   7   8   9 , Rosemary J Holt  3 , Jack Waldman  3 , Amber N V Ruigrok  3 , Natasha Mooney  3 , Richard A I Bethlehem  3 , Meng-Chuan Lai  3   10   11 , Prantik Kundu  12 , Edward T Bullmore  13   14   15 , Jean-Louis Mandel  6   7   8   9   16 , Amélie Piton #  6   7   8   9 , Simon Baron-Cohen #  3   14
Affiliations

Sex-specific impact of prenatal androgens on social brain default mode subsystems

Michael V Lombardo et al. Mol Psychiatry. 2020 Sep.

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.

PubMed Disclaimer

Conflict of interest statement

ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline (GSK). The other authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Sex-differential relationship between FT and DMN subsystem connectivity. a, b show axial montages of the two DMN components (IC01, IC09). c Shows a scatterplot of the relationship between FT and IC01-IC09 connectivity
Fig. 2
Fig. 2
Synaptic enrichments of DHT-dysregulated genes and genes with high levels of spatially expression similarity to rsfMRI DMN IC01 map (a) and plots of specific genes contributing to these enrichments (b–h). Whole-brain maps showing expression for each gene are composite maps averaging across all donors. These composite maps are shown for visualization purposes only. They are not meant to reflect directly the hierarchical statistical testing as implemented with Neurosynth Gene Expression Decoding. The coloring in the enrichment plot in a represents terms from different Gene Ontology (GO) clusters
Fig. 3
Fig. 3
a Shows spatial pattern of MEF2C expression compared to spatial rsfMRI map for IC01. The whole-brain MEF2C expression maps shown is a composite map averaging across all donors. This composite map is shown for visualization purposes only. It is not meant to reflect directly the hierarchical statistical testing as implemented with Neurosynth Gene Expression Decoding. b, c Show expression of MEF2C across RNA-seq (b) and qPCR (c) experiments. d Shows the developmental trajectory of MEF2C expression in the Allen Institute BrainSpan atlas (blue, female; red male). e Shows MEF2C expression across induced pluripotent stem cells (iPSC), neural progenitor cells (NPC), and neurons from cases with autism or typically developing controls (TD)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Barker DJ. In utero programming of chronic disease. Clin Sci (Lond) 1998;95:115–28. - PubMed
    1. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359:61–73. - PMC - PubMed
    1. Seckl JR, Holmes MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal ‘programming’ of adult pathophysiology. Nat Clin Pract Endocrinol Metab. 2007;3:479–88. - PubMed
    1. Parikshak NN, Luo R, Zhang A, Won H, Lowe JK, Chandran V, et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell. 2013;155:1008–21. - PMC - PubMed
    1. Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA, et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell. 2013;155:997–1007. - PMC - PubMed

Publication types