Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: Evidence for stimulatory effects of low estrogen levels
Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: Evidence for stimulatory effects of low estrogen levels
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DOI：
10.1210/en.141.10.3898
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发表时间：
2000-10-01
期刊：
影响因子：
4.8
通讯作者：
Sharpe, RM
中科院分区：
文献类型：
--
作者：
Atanassova, N;McKinnell, C;Sharpe, RM
本研究调查了新生雄性大鼠接触雌激素化合物是否会改变青春期精子发生（第 18 天和 25 天），以及观察到的变化是否会导致睾丸大小、交配或生育力（第 90-100 天）的长期变化。新生大鼠接受一系列剂量（0.01-10μg）己烯雌酚（DES；第2-12天每隔一天给药）、高剂量辛基苯酚（OP；第2-12天每天给药2mg）或双酚A（Bis-A；第2-12天每天给药0.5mg）或载体治疗，同时维持标准含大豆饮食。还评估了对采用无大豆饮食饲养对照动物的相同参数的影响，以及给这些动物施用染料木黄酮（从第2-18天每天4毫克/千克/天）的影响。睾丸重量、生精小管管腔形成、生殖细胞凋亡指数（凋亡/存活生殖细胞核体积）和每单位支持细胞核体积的精母细胞核体积用于表征青春期精子发生。与（大豆喂养）对照组相比，DES 给药导致第 18 天青春期精子发生的剂量依赖性延迟，表现为睾丸重量、管腔形成和每单位支持细胞精母细胞核体积的减少以及生殖细胞凋亡指数的升高。然而，两种最低剂量的 DES（0.1 和 0.01 μg）显着增加了每单位支持细胞的精母细胞核体积。同样，OP 或 Bis-A 治疗显着促进了青春期精子发生的这一方面和其他一些方面。与饲喂含大豆饮食的对照动物相比，维持不含大豆饮食的对照动物也显着促进管腔形成和每单位支持细胞的精母细胞核体积。给予金雀异黄酮逆转了无大豆饮食的刺激作用，并显着延迟了青春期精子发生的大多数指标。一般来说，治疗组的血浆 FSH 水平与生精变化平行变化（当青春期生精延迟时降低，当青春期生精提前时升高）。到第 25 天，尽管 FSH 水平的变化基本上持续存在，但第 18 天在各个治疗组中观察到的对精子发生的所有刺激作用不再明显。 在成年期，用 DES 治疗的新生大鼠的睾丸重量呈剂量依赖性下降，但是；只有最低的；剂量组（0.01μg）显示交配证据（6只中的3只）和正常生育力（3窝）。用 OP 或 Bis-A 治疗的新生动物具有正常或增加的 (Bis-A) 睾丸重量，并表现出相当正常的交配/生育力。饲喂无大豆饮食的动物的睾丸显着大于饲喂含大豆饮食的对照组，这一差异在一项超过 24 窝的大型研究中得到了证实，该研究还表明，采用无大豆饮食的雄性血浆 FSH 水平显着降低，体重显着增加。新生儿用金雀异黄素治疗不会改变成年睾丸重量，尽管大多数雄性表现出正常的交配和生育能力，但少数人没有交配或不育。结论是：1) 新生大鼠暴露于低水平雌激素可以促进青春期第一波精子发生，尽管尚不清楚这是由于雌激素的直接影响还是与 FSH 水平相关的升高所致； 2）高剂量的OP和Bis-A对这些过程的影响本质上是良性的； 3) 饮食中是否存在大豆或染料木黄酮对男性具有显着的短期（青春期精子发生）和长期（体重、睾丸大小、FSH 水平以及可能的交配）影响。
This study investigated whether neonatal exposure of male rats to estrogenic compounds altered pubertal spermatogenesis (days 18 and 25) and whether the changes observed resulted in long-term changes in testis size, mating, or fertility (days 90-100). Rats were treated neonatally with a range of doses (0.01-10 mu g) of diethylstilbestrol (DES; administered on alternate days from days 2-12), a high dose of octyl-phenol (OP; 2 mg administered daily from days 2-12) or bisphenol A (Bis-A; 0.5 mg administered daily fi om days 2-12), or vehicle, while maintained on a standard soy-containing diet. The effect on the same parameters of rearing control animals on a soy-free diet was also assessed as was the effect of administering such animals genistein (4 mg/kg/day daily from days 2-18). Testis weight, seminiferous tubule lumen formation, the germ cell apoptotic index (apoptotic/viable germ cell nuclear volume), and spermatocyte nuclear volume per unit Sertoli cell nuclear volume were used to characterize pubertal spermatogenesis. Compared with (soy-fed) controls, DES administration caused dose-dependent retardation of pubertal spermatogenesis on day 18, as evidenced by decreases in testis weight, lumen formation, and spermatocyte nuclear volume per unit Sertoli cell and elevation of the germ cell apoptotic index. However, the two lowest doses of DES (0.1 and 0.01 mu g) significantly increased spermatocyte nuclear volume per unit Sertoli cell. Similarly, treatment with either OP or Bis-A significantly advanced this and some of the other aspects of pubertal spermatogenesis. Maintenance of control animals on a soy-free diet also significantly advanced lumen formation and spermatocyte nuclear volume per unit Sertoli cell compared with controls fed a soy-containing diet. Administration of genistein reversed the stimulatory effects of a soy-free diet and significantly retarded most measures of pubertal spermatogenesis. In general, plasma FSH levels in the treatment groups changed in parallel to the spermatogenic changes (reduced when pubertal spermatogenesis retarded, increased when pubertal spermatogenesis advanced). By day 25, although the changes in FSH levels largely persisted, all of the stimulatory effects on spermatogenesis seen on day 18 in the various treatment groups were no longer evident.In adulthood, testis weight was decreased dose dependently in rats treated neonatally with DES, but; only the lowest; dose group (0.01 mu g) showed evidence of mating (3 of 6) and normal fertility (3 litters). Animals treated neonatally with OP or Bis-A had normal or increased (Bis-A) testis weights and exhibited reasonably normal mating/fertility. Animals fed a soy-free diet had significantly larger testes than controls fed a soy-containing diet, and this difference was confirmed in a much larger study of more than 24 litters, which also showed a significant decrease in plasma FSH levels and a significant increase in body weight in the males kept on a soy-free diet. Neonatal treatment with genistein did not alter adult testis weight, and although most males exhibited normal mating and fertility, a minority did not mate or were infertile. It is concluded that 1) neonatal exposure of rats to low levels of estrogens can advance the first wave of spermatogenesis at puberty, although it is unclear whether this is due to direct effects of the estrogen or to associated elevation of FSH levels; 2) the effect of high doses of OP and Bis-A on these processes is essentially benign; and 3) the presence or absence of soy or genistein in the diet has significant short-term (pubertal spermatogenesis) and long-term (body weight, testis size, FSH levels, and possibly mating) effects on males.