Permanent Effects of Neonatal Estrogen Exposure in Rats on Reproductive Hormone Levels, Sertoli Cell Number, and the Efficiency of Spermatogenesis in Adulthood

Abstract

This study aimed to identify the mechanism(s) for impairment of spermatogenesis in adulthood in rats treated neonatally with estrogens. Rats were treated (days 2-12) with 10, 1, or 0.1 microg diethylstilbestrol (DES), 10 microg ethinyl estradiol (EE), 10 mg/kg of a GnRH antagonist (GnRHa), or vehicle and killed in adulthood. DES/EE caused dose-dependent reductions in testis weight, total germ cell volume per testis, and Sertoli cell volume per testis. Sertoli cell number at 18 days of age in DES-treated rats was reduced dose dependently. GnRHa treatment caused changes in these parameters similar to those in rats treated with 10 microg DES. Plasma FSH levels were elevated (P < 0.001) to similar levels in all treatment groups regardless of differences in Sertoli cell number and levels of inhibin B; the latter reflected Sertoli cell number, but levels were disproportionately reduced in animals treated with high doses of DES/EE. Neonatal estrogen treatment, but not GnRHa, caused dose-dependent reductions (40-80%) in plasma testosterone levels in adulthood, but did not alter LH levels. Preliminary evidence suggests that the decrease in testosterone levels in estrogen-treated rats is not due to reduced Leydig cell volume per testis. GnRHa-treated rats exhibited a significant increase in germ cell volume per Sertoli cell and a reduction in germ cell apoptosis, probably because of the raised FSH levels. Despite similar raised FSH levels, rats treated with DES (10 or 1 microg) or EE (10 microg) had reduced germ cell volume/Sertoli cell and increased germ cell apoptosis, especially when compared with GnRHa-treated animals. The latter changes were associated with an increase in lumen size per testis, indicative of impaired fluid resorption from the efferent ducts, resulting in fluid accumulation in the testis. Rats treated neonatally with 0.1 microg DES showed reduced germ cell apoptosis comparable to that in GnRHa-treated animals. The changes in apoptotic rate among treatment groups occurred across all stages of the spermatogenic cycle. It is concluded that 1) neonatal estrogen treatment results in dose-dependent alterations in Sertoli cell numbers, germ cell volume, efficiency of spermatogenesis, and germ cell apoptosis in adulthood; 2) the relatively poor spermatogenesis in estrogen-treated animals is most likely due to altered testis fluid dynamics and/or altered Sertoli cell function; 3) as indicated by FSH (LH) and testosterone levels, the hypothalamic-pituitary axis and Leydig cells are probably more sensitive than the Sertoli cells to reprogramming by estrogens neonatally; and 4) elevated FSH levels in adulthood may improve the efficiency of spermatogenesis.

Soy, phytoestrogens and their impact on reproductive health

“…It is interesting to note that these two studies were the only ones to assess the effects of life-long exposure (from conception to adulthood). In addition, both studies reported a decrease in litter size (21-40%), whereas the other three studies evaluating litter size effects at precise windows of exposure found no effects (Atanassova et al, 1999;Nagao et al, 2001;Tan et al, 2006). These findings suggest that negative effects on sperm production and male fertility in rodents are only observed during a life-long exposure to soy and phytoestrogens.…”

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.…”

“…Furthermore, long-term changes, including molecular alterations, have been observed after exposure to endocrine disrupting chemicals during these early developmental periods [13,28]. In addition, it has been reported that neonatal exposure of animals to estrogenic compounds caused disorders of the male reproductive tract [24], reduction of testosterone [3], testicular atrophy and carcinoma [17,21], increased rate of breast cancer [8], uterine adenocarcinoma and various cervicovaginal lesions [18,20]. Diethylstilbestrol (DES), a synthetic non-steroidal estrogen, exhibits a high estrogenic activity by binding to the ERs, and is thus a useful model compound for evaluating the potential toxicity of a wide range of chemicals that affect or mimic estrogen activity [7].…”

La exposición prenatal a andrógenos como factor de reprogramación fetal

“…Se sabe que la exposición prenatal o neonatal de fetos machos a altas concentraciones de estradiol resulta en una disminución del número de células de Sertoli, deficiencia de la espermatogénesis y aumento de la apoptosis (dependiente de la concentración) en la etapa adulta 21 . El uso de dietiletilbestrol en la prevención del parto prematuro, se encontró claramente asociado a un aumento de cáncer testicular, criptorquidia e hipospadia en los hijos varones de las mujeres tratadas 22,23 .…”