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Estrogen Receptor (ER) and ERß Are Both Expressed in Human Ejaculated Spermatozoa: Evidence of Their Direct Interaction with Phosphatidylinositol-3-OH Kinase/Akt Pathway

Centro Sanitario (S.Aq., M.G., E.M., S.C.), Department of Cell Biology (A.C., V.R.), Faculty of Pharmacy (D.S., S.An.), University of Calabria 87030 Arcavacata di Rende (Cosenza - Italy)

Address all correspondence and requests for reprints to: Prof. Sebastiano Andò, Faculty of Pharmacy, University of Calabria, Arcavacata di Rende (CS) 87030, Italy. E-mail: sebastiano.ando{at}unical.it. Alternate E-mail: aquisav{at}libero.it.

Human and animal models have evidenced how estrogen insufficiency is associated with abnormal spermatogenesis and male infertility. We previously demonstrated that estradiol is able to influence both capacitation and acrosome reaction in human ejaculated spermatozoa. It remains to be elucidated whether the biochemical changes induced by estradiol, in a rapid nongenomic way, are mediated by a single estrogen receptor (ER) or by the two ER subtypes, ER and ERß. In the present study, we have first demonstrated the concomitant expression of ERß and ER in human ejaculated spermatozoa. By RT-PCR and Southern blot, transcripts of both ERs were detected. Western blot analysis showed ER and ERß proteins at the same size as the "classical" ERs. The localization of ER and ERß with the immunocytochemistry shows a differential distribution of the two ER subtypes, the former being prevalently located in the midpiece, but the latter being in the tail. Estradiol has been associated with sperm longevity; however, the mechanism through which estradiol acts in sperm survival was never investigated. Upon estradiol exposure, we observed an enhanced phosphorylation of the proteins involved in the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway like PDK1, Akt, GSK-3, Bcl-2, together with ERK1/2, which was also involved in cell survival signals. Moreover, such phosphorylations were reduced in the presence of ICI 182, 780, addressing the role of estradiol and ERs in sperm survival. For instance we have provided, for the first time, a different interaction of the two ERs with the PI3K/Akt pathway, because ER interacts with the p55 regulatory subunit of PI3K, whereas ERß interacts with Akt1. However, it still remains to be elucidated whether the functional role of each of the ER subtypes in sperm survival signaling is redundant or distinct.

This work was supported by Grant Prot. Number 2003067201 from the COFIN-MIUR-2003.

S.A. and D.S. contributed equally to this work.

Abbreviations: Dnase, Deoxyribonuclease; E₂, estradiol; ER, estrogen receptor; FITC, fluorescein isothiocyanate; ICI, ICI 182, 780; KO, knockout; LY, LY294002; M-MLV, Moloney murine leukemia virus; PI3K, phosphatidylinositol-3-OH kinase; SDS, sodium dodecyl sulfate; SSC, saline sodium citrate; TBS-T, Tween-20 in Tris-buffered saline.

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