The antiestrogen ICI 182,780 induces early effects on the adult male mouse reproductive tract and long-term decreased fertility without testicular atrophy

Abstract

BackgroundEstrogen receptors (ER) have important physiological roles in both the female and male reproductive systems. Previous studies using the estrogen receptor-α knockout mouse (αERKO) or antiestrogen treatment in adult rodents have shown that ERα is essential for normal function of the male reproductive tract. In the present study, time-response effects of the antiestrogen ICI 182,780 were determined to better understand ERα function in the adult male.MethodsAdult male mice, 30 days old, were injected subcutaneously with ICI 182,780 (5 mg) once per week for 17 weeks. Tissues were fixed by vascular perfusion to study the time responses from day 2 to 125 post treatment.ResultsNo difference was seen in body weight due to treatment. Testis weight was decreased 18% on day 59 and 21.4% on day 125. Other significant treatment-related effects included the following: 1) dilation of rete testis and efferent ductule lumen; 2) decreased height of the rete testis and efferent ductule epithelium; 3) decreased height of the supranuclear epithelial cytoplasm in efferent ductules; 4) decreased height of the efferent ductule epithelial microvilli, particularly in the proximal ductules; 5) decrease in the PAS-positive granules and endocytotic vesicles in nonciliated epithelial cells of efferent ductules; 6) capping and vesiculation of narrow cells in the initial segment of the epididymis; 7) accumulation of PAS-positive granules in apical cells of the caput epididymis; 8) increase in lysosomal granules in clear cells of the corpus and cauda epididymis; 9) limited induction of atrophic seminiferous tubules and abnormal spermatogenesis; and 10) decreases in the concentration of cauda sperm, progressive sperm motility and decreased fertility.ConclusionsAntiestrogen treatment of the pubertal male mouse resulted in reproductive effects similar to those observed in the αERKO mouse as early as day 4; however, testis weight did not increase substantially and total atrophy was not observed with extended treatment.

Estrogen in the male: a historical perspective†

“…However, epithelial morphology in Slc9a3 KO ductules was normal, suggesting that key genes involved in maintenance of endocytosis, motile cilia, and the microvillus border were also regulated by ESR1 activity, as these were significantly reduced in the Esr1 KO male, but not in the Slc9a3 KO mice [ 100 , 141 ]. ESR1’s regulation of this key gene has been consistent in all Esr1 KO mice (Table 1 ) generated thus far [ 100 , 112 , 141–144 ], as well as in the ICI-treated adult mice and rats [ 129 , 130 ].…”

“…Adult mice and rats treated with ICI have an undifferentiated efferent ductule epithelium, with reductions in epithelial height and number and size of microvilli, and loss of lysosomes [ 129–131 ]. However, a full anti-estrogen response requires between 50 and 100 days, although increases in luminal diameter begin within 8 days.…”

“…However, a full anti-estrogen response requires between 50 and 100 days, although increases in luminal diameter begin within 8 days. Mice respond more rapidly than rats [ 129 , 130 ], indicating species differences in estrogen sensitivity. Large genetic variation in E2 sensitivity was previously shown in mice and appears to be due to differences in estrogen metabolism through sulfotransferase activity [ 132 ].…”

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).…”

“…c Akingbemi et al (2003), Anahara et al (2006), Cho et al (2003), Lee et al (2000, Lucas et al (2008) and Oliveira et al (2001Oliveira et al ( , 2002Oliveira et al ( , 2003Oliveira et al ( , 2005 the past 10 years and thus require that future studies incorporate improved methods for preserving ER for tissue localization. Another novel animal model that has changed our understanding of oestrogen action in the testis came from the combination of ERKO mice and mice having mutations either in the DNA-binding domain or in the ligand-binding domain of ERa (Sinkevicius et al 2008(Sinkevicius et al , 2009).…”