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Differential Expression of Two Estrogen Receptor ß Isoforms in the Human Fetal Testis during the Second Trimester of Pregnancy

MRC Human Reproductive Sciences Unit (T.L.G., L.L.L.R., R.A.A., P.T.K.S.), Centre for Reproductive Biology, Edinburgh EH16 4SB; and School of Biological and Molecular Sciences (N.P.G.), Oxford Brookes University, Headington, Oxford OX3 0PB, United Kingdom

Address all correspondence and requests for reprints to: Dr. Philippa Saunders, MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh Academic Centre, 49 Little France Cresent, Edinburgh EH16 4SB, United Kingdom. E-mail: p.saunders{at}ed.ac.uk.

Testicular cancer is more common in individuals with disorders of the male reproductive tract. It has been suggested that inappropriate exposure to estrogens during fetal life may have an impact on maturation of testicular germ cells that are the cells of origin of the majority of testis cancers. The aim of the present study was to establish whether human fetal germ cells (gonocytes) are a potential target of estrogen action. To address this issue, we used RT-PCR and immunohistochemistry to examine the pattern of expression of estrogen receptors (ER, ERß, and ERß2 variant) in human fetal testes at 12–19 wk gestation. ER, mRNA, and protein were not detected in any of the fetal testes. In contrast, using an antibody directed against the hinge domain of ERß expression was detected in multiple testicular nuclei. RT-PCR with primers specific for full-length wild-type ERß (ERß1) or the ERß2 variant formed by splicing of an alternative eighth exon, was performed on whole-tissue extracts and materials recovered by laser capture and revealed that mRNAs for both isoforms were expressed. Immunohistochemistry with isotype-specific monoclonal antibodies showed that ERß1 was low/undetectable in gonocytes, whereas these cells expressed the highest levels of ERß2, compared with other testicular cell types. Both ERß1 and ERß2 were detected in some but not all Sertoli cells, peritubular cells, and other interstitial cells including those tentatively identified as Leydig cells. Our immunohistochemical results demonstrate that during the second trimester, some but not all somatic cells within the human fetal testis express wild-type ERß (ERß1) protein and/or the variant isoform of ERß (ERß2) that lacks amino acids essential for binding of estradiol. ERß2 protein was readily detectable in fetal gonocytes, whereas ERß1 was not. We did not detect expression of ER. The expression of ERß2, a variant proposed act as a dominant negative receptor, might prevent estrogen action in gonocytes. We suggest that during this period of fetal life, estrogenic ligands are most likely to act on somatic cells that contain ERß1 protein.

Abbreviations: AMH, Anti-Mullerian hormone; ER, estrogen receptor; ERE, estrogen-responsive element; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NRS, normal rabbit serum; TBS, Tris-buffered saline.

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