Intrauterine Position Affects Estrogen Receptor α Expression in the Ventromedial Nucleus of the Hypothalamus via Promoter DNA Methylation

There is well-established evidence in many mammalian species for effects of the intrauterine position (IUP) (the sex-specific positioning of the embryo) on postnatal brain function and behavior. We found that the IUP affects estrogen receptor (ER)alpha expression in adult female rats in the ventrolateral region of the hypothalamic ventromedial nucleus (vlVMH), which is associated with sexual behavior. The ER alpha expression level in the vlVMH was higher in females that developed in utero between two male siblings (2M females) than in those that developed between female siblings (2F females). We also found that the cytosine methylation status across the ER alpha promoter in the vlVMH was affected by the IUP, with greater methylation in 2F females. These findings showed a negative correlation between ER alpha expression levels in the vlVMH and methylation frequency in the ER alpha promoter. This suggests that genomic methylation sustains the effect of the fetal IUP on ER alpha expression in the vlVMH. (Endocrinology 151: 5775-5781, 2010)