Estrogen Actions in the Male Reproductive System Involve Estrogen Response Element-Independent Pathways

Abstract

The estrogen receptor-alpha (ERalpha) acts through multiple pathways, including estrogen response element (ERE)-dependent (classical) and ERE-independent (nonclassical) mechanisms. We previously created a mouse model harboring a two-amino-acid mutation of the DNA-binding domain (E207A, G208A) that precludes direct binding of ERalpha to an ERE. After crossing heterozygous mutant mice with an ERalpha knockout (ERKO) line, it was possible to assess the degree of physiological rescue by the isolated ERalpha nonclassical allele (-/AA; AA) when compared with ERKO mice (-/-) and to wild type (+/+; WT). In male ERKO mice up to 8 months of age, testosterone levels were high, although LH levels were similar to WT. Testosterone was normal in the AA mice, indicating that the AA allele rescues the enhanced testosterone biosynthesis in ERKO mice. Male ERKO mice exhibited distention of the seminiferous tubules as early as 2-3 months of age as a consequence of decreased water resorption in the efferent ducts. By 3-4 months of age, ERKO mice had impaired spermatogenesis in approximately 40% of their tubules, and sperm counts and motility declined in association with the histological changes. In the AA mice, histological defects were greatly reduced or absent, and sperm counts and motility were rescued. Levels of aquaporins 1 and 9, which contribute to water uptake in the efferent ducts, were reduced in ERKO mice and partially or fully rescued in AA mice, whereas another water transporter, sodium-hydrogen exchanger-3, was decreased in both ERKO and AA mice. We conclude that non-ERE-dependent estrogen pathways are sufficient to rescue the defective spermatogenesis observed in ERKO mice and play a prominent role in ERalpha action in the testis, including pathways that regulate water resorption and androgen biosynthesis.

Oestrogens and spermatogenesis

“…Although effects on the efferent ductules were noted as early as 4 days after treatment (Cho et al 2003), effects on the testis were delayed, similar to those seen in the ERaKO (Eddy et al 1996;Hess et al 1997a;Weiss et al 2008), but seminiferous tubular atrophy was heterogeneous and focal, as seen in ArKO mice Robertson et al 2001Robertson et al , 2002Toda et al 2008), and not due to fluid back-pressure. Others have also found apparent direct effects of ICI 182,780 on seminiferous epithelium (Gancarczyk et al 2004;Anahara et al 2006), including effects within 6 days of treatment (Anahara et al 2006).…”

Induction of spermatogenic cell apoptosis in prepubertal rat testes irrespective of testicular steroidogenesis: a possible estrogenic effect of di(n-butyl) phthalate

“…The intracellular mechanisms of ERs action in the present study and the possible involvement of both ERa and ERb in spermatogenic cell apoptosis are not known, and further studies are required. More recent work has been shown that estrogen action in male reproductive system does not involve EREs pathway (Weiss et al 2008). Moreover, many studies revealed a nongenomic signaling pathway through membrane-associated ERs (Hammes & Levin 2007) and cross-talk between genomic pathways (Revelli et al 1998, Losel et al 2003.…”

Transactivating function (AF) 2–mediated AF-1 activity of estrogen receptor α is crucial to maintain male reproductive tract function

“…Several previous studies have used ERα mutant knock-in mice to evaluate ERα function in male reproduction (26,27). The E207A, G208A mutated ERα knock-in (NERKI) mice were found to lack ERE-mediated transcription, but allowed E2-dependent transcription by ERα tethering with AP-1 (28).…”