Abstract
BackgroundAutism spectrum disorders (ASD) are much more common in males than in females. Molecular alterations within the estrogen receptor (ER) signaling pathway may contribute to the sex difference in ASD, but the extent of such abnormalities in the brain is not known.MethodsPostmortem middle frontal gyrus tissues (13 ASD and 13 control subjects) were used. The protein levels were examined by western blotting. The gene expression was determined by qRT-PCR.ResultsGene expression analysis identified a 35% decrease in ERβ mRNA expression in the middle frontal gyrus of ASD subjects. In addition, a 38% reduction in aromatase (CYP19A1) mRNA expression was observed in ASD subjects. We also found significant decreases in ER co-activators that included a 34% decrease in SRC-1, a 77% decrease in CBP, and a 52% decrease in P/CAF mRNA levels in ASD subjects relative to controls. There were no differences in the mRNA levels of TIF-2, AIB-1 (ER co-activators), ER co-repressors (SMRT and nCoR) and ERα in the middle frontal gyrus of ASD subjects as compared to controls. We observed significant correlations between ERβ, CYP19A1, and co-activators in the study subjects. Immunoblot analysis further confirmed the changes in ERβ and aromatase at the protein level in the control and ASD subjects.ConclusionsThese results, for the first time, provide the evidence of the dysregulation of ERβ and co-factors in the brain of subjects with ASD.Electronic supplementary materialThe online version of this article (doi:10.1186/2040-2392-5-46) contains supplementary material, which is available to authorized users.
Highlights
Autism spectrum disorders (ASD) are much more common in males than in females
Subjects The mRNA levels of Estrogen receptor alpha (ERα), Estrogen receptor beta (ERβ), and Cytochrome P450 (CYP19A1) in the middle frontal gyrus of control and ASD subjects were determined by Quantitative reverse transcriptase PCR (qRT-PCR)
We have identified dysregulation of ERβ, CYP19A1, and co-activators associated with estrogen receptor (ER) signaling in the middle frontal gyrus of ASD subjects with a significant association between these molecules
Summary
Autism spectrum disorders (ASD) are much more common in males than in females. Molecular alterations within the estrogen receptor (ER) signaling pathway may contribute to the sex difference in ASD, but the extent of such abnormalities in the brain is not known. The major co-regulators involved in estrogen signaling are steroid receptor co-activator 1 (SRC-1), transcriptional mediators/intermediary factor 2 (TIF-2), nuclear receptor co-repressor 1 (nCoR), CREB-binding protein (CBP), p300/CREB-binding protein-associated protein (P/CAF), amplified in breast 1 (AIB-1), and silencing mediator of retinoid and thyroid hormone receptors (SMRT) [8]. Among these co-factors, SRC-1, TIF-2, CBP, AIB-1, and P/CAF are transcriptional co-activators, whereas SMRT and nCoR are transcriptional repressors. In the rapid or “non-genomic” pathway, activation of the membrane ER by estrogen leads to a rapid change in various intracellular signaling molecules including kinases, which in turn regulate gene transcription [9]
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