Stoker T E, Laws S C, Guidici D L, Cooper R L
Gamete and Early Embryo Biology Branch, and Endocrinology Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Toxicol Sci. 2000 Nov;58(1):50-9. doi: 10.1093/toxsci/58.1.50.
Since atrazine (ATR), a chlorotriazine herbicide, has been shown previously to alter the secretion of luteinizing hormone (LH) and prolactin (PRL) through a direct effect on the central nervous system (CNS), we hypothesized that exposure to ATR in the EDSTAC male pubertal protocol (juvenile to peripubertal) would alter the development of the male rat reproductive system. We dosed intact male Wistar rats from postnatal day (PND) 23 to 53 and examined several reproductive endpoints. ATR (0, 12.5, 25, 50, 100, 150, or 200 mg/kg) was administered by gavage and an additional pair-fed group was added to compare the effects of any decreased food consumption in the high dose group. Preputial separation (PPS) was significantly delayed in the 12.5, 50, 100, 150, and 200 mg/kg ATR dose groups. PPS was also delayed in the pair-fed group, although significantly less than in the high dose-ATR group. The males were killed on PND 53 or 54, and pituitary, thyroid, testes, epididymides, seminal vesicles, and ventral and lateral prostates were removed. ATR (50 to 200 mg/kg) treatment resulted in a significant reduction in ventral prostate weights, as did the reduced food consumption of the pair-fed group. Testes weights were unaffected by atrazine treatment. Seminal vesicle and epididymal weights were decreased in the high dose-ATR group and the control pair-fed group. However, the difference in epididymal weights was no longer significantly different when body weight was entered as a covariable. Intratesticular testosterone was significantly decreased in the high dose-ATR group on PND 45, but apparent decreases in serum testosterone were not statistically significantly on PND 53. There was a trend for a decrease in luteinizing hormone (LH) as the dose of ATR increased; however, dose group mean LH was not different from controls. Due to the variability of serum prolactin concentrations on PND 53, no significant difference was identified. Although prolactin is involved in the maintenance of LH receptors prior to puberty, we observed no difference in LH receptor number at PND 45 or 53. Serum estrone and estradiol showed dose-related increases that were significant only in the 200 mg/kg-ATR group. No differences were observed in thyroid stimulating hormone (TSH) and thyroxine (T4) between the ATR groups and the control; however triiodothyronine (T3) was elevated in the high dose-ATR group. No differences in hormone levels were observed in the pair-fed animals. These results indicate that ATR delays puberty in the male rat and its mode of action appears to be altering the secretion of steroids and having subsequent effects on the development of the reproductive tract, which appear to be due to ATR's effects on the CNS. Thus, ATR tested positive in the pubertal male screen that the Endocrine-Disrupter Screening and Testing Advisory Committee (EDSTAC) is considering as an optional screen for endocrine disrupters.
由于之前已表明，氯三嗪除草剂阿特拉津（ATR）可通过直接作用于中枢神经系统（CNS）来改变促黄体生成素（LH）和催乳素（PRL）的分泌，因此我们推测，在EDSTAC雄性青春期实验方案（从幼年到青春期前期）中暴露于ATR会改变雄性大鼠生殖系统的发育。我们对出生后第23天（PND）至53天的完整雄性Wistar大鼠给药，并检查了多个生殖终点指标。通过灌胃给予ATR（0、12.5、25、50、100、150或200 mg/kg），并额外增加了一对配对喂食组，以比较高剂量组中食物摄入量减少的影响。在12.5、50、100、150和200 mg/kg ATR剂量组中，包皮分离（PPS）显著延迟。配对喂食组的PPS也延迟了，尽管显著低于高剂量ATR组。在PND 53或54处死雄性大鼠，并取出垂体、甲状腺、睾丸、附睾、精囊以及腹侧和外侧前列腺。ATR（50至200 mg/kg）处理导致腹侧前列腺重量显著降低，配对喂食组食物摄入量减少也导致腹侧前列腺重量显著降低。睾丸重量不受阿特拉津处理的影响。高剂量ATR组和对照配对喂食组的精囊和附睾重量降低。然而，当将体重作为协变量纳入时，附睾重量的差异不再显著。在PND 45时，高剂量ATR组的睾丸内睾酮显著降低，但在PND 53时，血清睾酮的明显降低在统计学上并不显著。随着ATR剂量增加，促黄体生成素（LH）有下降趋势；然而，各剂量组的平均LH与对照组无差异。由于PND 53时血清催乳素浓度存在变异性，未发现显著差异。尽管催乳素在青春期前参与维持LH受体，但我们在PND 45或53时未观察到LH受体数量有差异。血清雌酮和雌二醇呈剂量相关增加，仅在200 mg/kg ATR组显著。在ATR组和对照组之间未观察到促甲状腺激素（TSH）和甲状腺素（T4）有差异；然而，高剂量ATR组的三碘甲状腺原氨酸（T3）升高。在配对喂食动物中未观察到激素水平有差异。这些结果表明，ATR会延迟雄性大鼠的青春期，其作用模式似乎是改变类固醇的分泌，并随后对生殖道发育产生影响，这似乎是由于ATR对中枢神经系统的作用。因此，在青春期雄性筛选中，ATR检测呈阳性，内分泌干扰物筛选和测试咨询委员会（EDSTAC）正在考虑将其作为内分泌干扰物的一种可选筛选方法。
