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Biol Sex Differ. 2014 Jun 13;5:8. doi: 10.1186/2042-6410-5-8. eCollection 2014.

The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging.

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Department of Human Genetics, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
Laboratory of Neuroendocrinology of the Brain Research Institute, UCLA, Los Angeles, CA 90095, USA.
Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan.
Interdepartmental PhD Program in Bioinformatics, UCLA, Los Angeles, CA 90095, USA.
Department of Molecular, Cellular, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
Department of Integrative Biology and Physiology, UCLA, Los Angeles, CA 90095, USA.
Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA.
Department of Human Genetics, UCLA, 695 Charles Young Drive South, Gonda Room 5506, Los Angeles, CA 90095-7088, USA.
Contributed equally



The biological basis for sex differences in brain function and disease susceptibility is poorly understood. Examining the role of gonadal hormones in brain sexual differentiation may provide important information about sex differences in neural health and development. Permanent masculinization of brain structure, function, and disease is induced by testosterone prenatally in males, but the possible mediation of these effects by long-term changes in the epigenome is poorly understood.


We investigated the organizational effects of testosterone on the DNA methylome and transcriptome in two sexually dimorphic forebrain regions-the bed nucleus of the stria terminalis/preoptic area and the striatum. To study the contribution of testosterone to both the establishment and persistence of sex differences in DNA methylation, we performed genome-wide surveys in male, female, and female mice given testosterone on the day of birth. Methylation was assessed during the perinatal window for testosterone's organizational effects and in adulthood.


The short-term effect of testosterone exposure was relatively modest. However, in adult animals the number of genes whose methylation was altered had increased by 20-fold. Furthermore, we found that in adulthood, methylation at a substantial number of sexually dimorphic CpG sites was masculinized in response to neonatal testosterone exposure. Consistent with this, testosterone's effect on gene expression in the striatum was more apparent in adulthood.


Taken together, our data imply that the organizational effects of testosterone on the brain methylome and transcriptome are dramatic and late-emerging. Our findings offer important insights into the long-term molecular effects of early-life hormonal exposure.


Brain sexual differentiation; DNA methylation; Epigenetic modifications; Organizational effects; Testosterone

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