Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects

Background: 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. Methods: Postmortem 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. Results: Gene 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. Conclusions: These results, for the first time, provide the evidence of the dysregulation of ERβ and co-factors in the brain of subjects with ASD.