Role of sex chromosome complement in the regulation of aromatase expression in developing mice brain

CISTERNAS, C.D.; CAMBIASSO, M.J.; GARCIA-SEGURA, L.M.; AREVALO, M.A.

San Diego

Congreso; Neuroscience 2016; 2016

During thecritical period of sexual differentiation there are sex differences in brain aromataseexpression that are time and regionally specific. Some of these sex differencescannot be explained by organizational actions of gonadal hormones because theyoccur before exposition to testosterone inutero. Previous results from our group using the four core genotype mousemodel (FCG) demonstrate that XY neurons from amygdala express higher levels ofaromatase and Cyp19a1 than XX neurons of E15 mice independent of gonadal sex.The present study explores the regulation of aromatase in amygdala neurons fromE15 mice brain and the role of estrogen (ERα and ERβ) and androgen receptors(AR) in this regulation. Our results show that E2 (10-10M) ordihydrotestosterone (DHT, 10-10M) in vitro increases aromatase expression in amygdala neurons derivedfrom XX embryos, but not in those derived from XY embryos. This effect wasindependent of gonadal sex and the final outcome was to abolish the basal sex chromosome-inducedsex difference. The effect of hormone treatments was not imitated with aselective ERαagonist-PPT [4,4´,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol]or G1, a ligand of G protein receptor 30 ⁄ Gprotein-coupled ER. By contrast, a selective ERβ agonist-DPN[2,3-bis(4-hydroxyphenyl)-propionitrile] fully reproduced the effect of E2 andDHT on aromatase expression. Moreover treatment with a selective ERβantagonist-PHTPP(4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol)blocked this effect. As E2 and DHT regulate transcription of target genes viaestrogen or androgen receptors we studied if aromatase regulation involves achange in steroid receptor expression. Our results show that in a way thatresembles aromatase expression, amygdala neurons from XY brain have a higherexpression of ERβ mRNA than XXneurons and hormonal treatments increaseERβmRNA only in XX neurons (male and female). No effects were observed on ERα andAR expression. In summary, our findings indicate that sex chromosome complementdetermines a higher expression of aromatase and ERβ in XY neurons fromamygdala. Also, these results indicate that ERβ is involved in aromatase regulationin a mechanism regulated by sex chromosomes. Given that it is a key enzymenecessary for organizational actions of gonadal testosterone these findingsimply that genetic and gonadal factors interact in the generation of sexdifferences in some structures of the developing rodent brain. Ministeriode Economía y Competitividad, Spain (BFU2014-51836-C2-1-R); Secretaría deCiencia y Tecnología (SECYT-UNC), Argentina; CONICET PIP 2013-2015 Nº00597,Argentina.