Regulation of aromatase expression in the anterior amygdala of the developing mouse brain depends on ERβ and sex chromosome complement

Abstract

During development sex differences in aromatase expression in limbic regions of mouse brain depend on sex chromosome factors. Genes on the sex chromosomes may affect the hormonal regulation of aromatase expression and this study was undertaken to explore that possibility. Male E15 anterior amygdala neuronal cultures expressed higher levels of aromatase (mRNA and protein) than female cultures. Furthermore, treatment with oestradiol (E2) or dihydrotestosterone (DHT) increased Cyp19a1 expression and aromatase protein levels only in female neuronal cultures. The effect of E2 on aromatase expression was not imitated by oestrogen receptor (ER) α agonist PPT or the GPER agonist G1, but it was fully reproduced by DPN, a specific ligand of ERβ. By contrast, the effect of DHT on aromatase expression was not blocked by the anti-androgen flutamide, but completely abrogated by the ERβ antagonist PHTPP. Experiments using the four core genotype model showed a sex chromosome effect in ERβ expression (XY > XX) and regulation by E2 or DHT (only XX respond) in amygdala neurons. In conclusion, sex chromosome complement governs the hormonal regulation of aromatase expression through activation of ERβ in developing mouse brain.

Hormonal and genetic factors interact to control aromatase expression in the developing brain

“…It was found that selective agonists for ERα or for the membrane ER GPR30 are not able to reproduce the effect of E 2 on aromatase mRNA. However, a selective ERβ agonist fully reproduced the effect of E 2 and DHT on aromatase expression . In concordance with a possible ERβ involvement in aromatase regulation by E 2 or DHT, a selective antagonist for ERβ in combination with E 2 or DHT prevented the hormonal effects …”

“…47 Surprisingly, 3β-diol treatment increased aromatase expression in neuronal cultures derived from the amygdala of female FCG mice. 48 These findings could shed light on our previous results of hormonal regulation in neuronal cultures. Because aromatase mRNA expression was regulated by both E 2 and DHT and the magnitude of this effect was almost equivalent, 22 we can hypothesise that E 2 and 3β-diol bind to ERβ to regulate aromatase expression in amygdala neurones of the developing mouse brain.…”

“…One of these products is 3β‐diol, which preferentially binds to ERβ and not AR . Surprisingly, 3β‐diol treatment increased aromatase expression in neuronal cultures derived from the amygdala of female FCG mice . These findings could shed light on our previous results of hormonal regulation in neuronal cultures.…”

“…However, a selective ERβ agonist fully reproduced the effect of E 2 and DHT on aromatase expression. 48 In concordance with a possible ERβ involvement in aromatase regulation by E 2 or DHT, a selective antagonist for ERβ in combination with E 2 or DHT prevented the hormonal effects. 48…”

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…The interaction between the sex chromosome complement and gonadal hormones also determines the expression of aromatase and estrogen receptors (Cisternas et al, 2015(Cisternas et al, , 2017Cambiasso et al, 2017) in the brain and, therefore, may contribute to the different effects of estrogen therapy in males and females. However, this possibility needs to be experimentally explored.…”