Abnormalities in Functional Development of the Sertoli Cells in Rats Treated Neonatally with Diethylstilbestrol: A Possible Role for Estrogens in Sertoli Cell Development1

Abstract

Diethylstilbestrol (DES) was administered neonatally (Days 2-12; 10 microg on alternate days) to rats, and developmental changes in Sertoli cell function were evaluated at 18, 25, and 35 days of age and compared to those observed in rats administered a GnRH antagonist (GnRHa; Days 2 and 5; 10 mg/kg) or a vehicle (controls). DES and GnRHa treatments resulted in similar reductions in both Sertoli cell numbers (40% for DES, 48% for GnRHa) and suppression of testicular growth at 18 and 25 days, though by 35 days the suppression was more pronounced (p < 0.001) in DES-treated animals. Plasma FSH levels were suppressed markedly at 18 and 25 days, but not at 35 days, in GnRHa-treated rats, whereas in DES-treated rats the FSH levels were suppressed significantly only at 35 days. Both treatments suppressed plasma levels of inhibin B, though this was more pronounced (p < 0.05) in DES- than in GnRHa-treated rats. In controls, Sertoli cell immunoexpression of inhibin alpha, sulfated glycoprotein-1 (SGP-1), and androgen receptor (AR) increased in intensity and changed to an adult, stage-dependent pattern by 25 days. In GnRHa-treated rats these changes were reduced in intensity but were similar to those in controls at 35 days. In DES-treated rats, the increase in intensity and stage-dependent pattern of immunoexpression of inhibin alpha, SGP-1, and AR were virtually absent at 25 days but were present by 35 days. Germ cell volume per Sertoli cell was reduced in GnRHa- and DES-treated rats compared with controls at 18 and 25 days but was significantly greater (p < 0. 001) in DES- than in GnRHa-treated rats at 35 days. The proportion of apoptotic to viable germ cells was increased (p < 0.01) in GnRHa- and DES-treated rats compared with controls at 18 and 25 days; but at 35 days, values in GnRHa-treated rats had declined to control values whereas those for DES-treated rats remained 10-fold elevated (p < 0.001). In adulthood, testis weight and daily sperm production were reduced by 43% and 44%, respectively, in GnRHa-treated rats, but spermatogenesis was grossly normal. Comparable changes were observed in approximately 25% of DES-treated rats, but the majority exhibited > 60% reduction in testis weight with many Sertoli cell-only tubules and very low daily sperm production. Taken together, these data are interpreted as providing evidence for direct modulation of Sertoli cell (maturational) development by DES.

Neonatal Exposure to Genistein Reduces Expression of Estrogen Receptor Alpha and Androgen Receptor in Testes of Adult Mice.

“…Recovery of maturational development of AR immunoexpression patterns by postnatal 35 days has also been reported in DES-treated rats showing delayed patterns between postnatal 18 and 25 days [33]. However, in the present study, the expression levels of ERa mRNA and AR mRNA of DES-treated mice were still lower than those of control in adulthood at 12 weeks.…”

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

“…Previous studies have demonstrated that high doses of potent estrogens, such as DES, are clearly inhibitory to testicular development over both the short and long term [3,25]. The results of the present histological analyses in the groups exposed to DES neonatally showed a thinning of germ cell layers in the seminiferous tubules, which suggests a reduction of spermatogenesis, and the hypoplasia of the Leydig cells and epididymal ducts of the cauda epididymis at 8 weeks of age; however, the groups exposed to DES in utero but not treated neonatally showed no histological changes in the testis or epididymis.…”

Sulfation of “Estrogenic” Alkylphenols and 17β-Estradiol by Human Platelet Phenol Sulfotransferases

“…Man-made xenoestrogens include the alkylphenols, nonylphenol and octylphenol, and bisphenol A; environmental exposure to these compounds has been reported to modify sexual development and reproductive function in amphibians (2,3), crustacea (4,5), and fish (6). In mammals, evidence is less clear, but there is widespread public concern that they may exert similar effects on human reproductive health and be involved in the initiation of some hormone-dependent cancers (7)(8)(9)(10)(11)(12)(13)(14).…”