Permanent effects of neonatal estrogen exposure in rats on reproductive hormone levels, Sertoli cell number, and the efficiency of spermatogenesis in adulthood.
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.
Atanassova
N
N
Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology, Edinburgh, Scotland.
McKinnell
C
C
Walker
M
M
Turner
K J
KJ
Fisher
J S
JS
Morley
M
M
Millar
M R
MR
Groome
N P
NP
Sharpe
R M
RM
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D004054:Diethylstilbestrol / Q000494:pharmacology; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000097:blood*; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006727:Hormone Antagonists / Q000494:pharmacology; D007265:Inhibins / Q000097:blood; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012708:Sertoli Cells; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000254:growth & development; D013739:Testosterone / Q000097:blood*
D004967:Estrogens; D006727:Hormone Antagonists; D009842:Oligopeptides; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004997:Ethinyl Estradiol; D007265:Inhibins; D004054:Diethylstilbestrol; D005640:Follicle Stimulating Hormone; C084350:antarelix