Sex Hormones in Autism: Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism

Tewarit Sarachana, Minyi Xu, Ray-Chang Wu, Valerie W. Hu*

Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, D.C., United States of America


Autism, a pervasive neurodevelopmental disorder manifested by deficits in social behavior and interpersonal
communication, and by stereotyped, repetitive behaviors, is inexplicably biased towards males by a ratio of ,4:1, with no clear understanding of whether or how the sex hormones may play a role in autism susceptibility. Here, we show that male and female hormones differentially regulate the expression of a novel autism candidate gene, retinoic acid-related orphan receptor-alpha (RORA) in a neuronal cell line, SH-SY5Y. In addition, we demonstrate that RORA transcriptionally regulates aromatase, an enzyme that converts testosterone to estrogen. We further show that aromatase protein is
significantly reduced in the frontal cortex of autistic subjects relative to sex- and age-matched controls, and is stronglycorrelated with RORA protein levels in the brain. These results indicate that RORA has the potential to be under both negative and positive feedback regulation by male and female hormones, respectively, through one of its transcriptional targets, aromatase, and further suggest a mechanism for introducing sex bias in autism.

Citation: Sarachana T, Xu M, Wu R-C, Hu VW (2011) Sex Hormones in Autism: Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel
Candidate Gene for Autism. PLoS ONE 6(2): e17116. doi:10.1371/journal.pone.0017116
Editor: Mark Mattson, National Institute on Aging Intramural Research Program, United States of America
Received December 1, 2010; Accepted January 21, 2011; Published February 16, 2011
Copyright:  2011 Sarachana et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The project described was supported in part by a grant from Autism Speaks Grant # 2381 (VWH), by a joint intramural GWU and Clinical and
Translational Science Institute-Children’s National Award for development of Novel Clinical and Translational Methodologies (VWH), and by Award Number
S10RR025565 from the National Center for Research Resources (P.I.: Anastas Popratiloff, Ph.D.). The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. TS is a predoctoral student in the Institute for Biomedical Sciences at The George Washington University, who is supported by a Higher Educational Strategic Scholarship for Frontier Research from the Office of the Commission on Higher Education of the Royal Thai Government, Thailand. This work is part of his dissertation research to be presented in partial
fulfilment of the requirements for the PhD No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: bcmvwh@gwumc.edu