Effects of Maternal Exposure to a Low Dose of Diethylstilbestrol on Sexual Dimorphic Nucleus Volume and Male Reproductive System in Rat Offspring

Abstract

-Diethylstilbestrol (DES) was administered subcutaneously at 0.5, 1.5 or 4.5 µg/kg/day (DES 0.5, 1.5 and 4.5 groups, respectively) to pregnant SD rats daily on days 7-21 of gestation, to investigate its effects on the development and functions of the reproductive system in their male offspring. Of the 10 pregnant rats in the DES 4.5 group, only 1 delivered, and this rat could not suckle the pups. Rat pups in the DES 0.5 and 1.5 groups were autopsied at 1, 3, 6 and 15 weeks after birth. The testosterone concentrations in the DES 1.5 and 0.5 groups at 6 weeks were significantly decreased and the plasma LH concentrations were not altered. In the DES 1.5 group, DES treatment did not change the volume of the sexually dimorphic nucleus in the preoptic area (SDN-POA) in the male offspring, although this dose of DES increased the volume of SDN-POA in female offspring. The DES treatment altered frequencies in the cycles of the seminiferous tubules, and suppressed histological maturation in the epididymis and the prostate weight. These observations indicate that prenatally administered DES impairs testicular endocrine function continuously as well as putuitary function, but the induced low level of testosterone disrupts spermatogensis and permanently inhibits the morphological development of epididymis and prostate.

Effects of Maternal Exposure to Low Doses of DES on Testicular Steroidogenesis and Spermatogenesis in Male Rat Offspring

“…In our previous studies [5,27], we determined the effects of various levels of DES (15, 4.5, 1.5 and 0.5 μg/kg/day) considering Boylan's results [30], achieved by administering various doses of DES s.c. to SD rats, showing that 1.5 μg/kg/day is approximately the maximum possible dose. In the present study, the testis/body weight ratio was lower in the DES 0.5 group than in the control group.…”

“…In our previous study [27], DES administration disrupted the spermatogenic cycle at 15 weeks after birth in comparison with 6 weeks of gestation, but only five 15-week-old pups were used to examine spermatogenesis, although ten 6-week-old pups were employed in other analyses. Hess et al [42] employed the testes of 10 pups and demonstrated that classification of more than 200 seminiferous tubules per pup provided sufficiently reliable data.…”

“…The number of ARs is maximal in Sertoli cells at stages VII-VIII of spermatogenesis [19]. Administration of DES in the neonatal period has been reported to suppress both testosterone levels and AR expression [18,20,21] and to induce impaired spermatogenesis [15,20,[22][23][24][25][26]; however, our previous study [27] demonstrated that a fetal DES treatmentinduced low level of testosterone led to little modification of spermatogenesis at 15 weeks.Although many studies involving DES administration during fetal and neonatal periods have been performed, no study employing DES administration during the fetal period alone has investigated hormone-secreting ability after maturation of newborns by measurement of only fetal testicular hormone-secreting ability, hormone levels and steroidogenic enzyme mRNA levels [28]. The only exception to this is a study in which DES was administered at a high dose (10 μg/kg/animal) to pregnant mice at…”

“…The number of ARs is maximal in Sertoli cells at stages VII-VIII of spermatogenesis [19]. Administration of DES in the neonatal period has been reported to suppress both testosterone levels and AR expression [18,20,21] and to induce impaired spermatogenesis [15,20,[22][23][24][25][26]; however, our previous study [27] demonstrated that a fetal DES treatmentinduced low level of testosterone led to little modification of spermatogenesis at 15 weeks.…”

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…Ikeda et al [80] showed that prenatal dioxin exposure decreased SDN-POA volume of male rats but did not influence this parameter in female rats, suggesting a demasculinizing effect. The estrogenic pharmaceutical diethylstilbestrol (DES) also organizes the developing hypothalamus: the SDN-POA region was increased in size in the female rat but was not affected in male littermates, indicating a masculinizing effect [169]. Prenatal ethinyl estradiol, the most common estrogen in oral steroid contraceptives, decreased SDN-POA volume of males but had no effect in females, suggesting a demasculinizing effect [141].…”