Ashby J, Tinwell H, Stevens J, Pastoor T, Breckenridge C B
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom.
Regul Toxicol Pharmacol. 2002 Jun;35(3):468-73. doi: 10.1006/rtph.2002.1571.
The mammalian hazard assessment of the herbicide atrazine (ATR) has focused on the induction of mammary tumors and accelerated reproductive aging of adult rats, and the relationship of these effects to the inhibition of leutinizing hormone (LH) release from the pituitary, an effect itself caused by inhibition of GnRH signaling by the adult rat hypothalamus. In earlier studies, Laws et al. (Toxicol. Sci., 58, 366-376, 2000) demonstrated a delay in female rat sexual maturation induced by ATR, effects that could equally have been caused by inhibition of hypothalamic GnRH release. The present studies were designed to compare the doses that interfere with GnRH signaling seen in previous studies in adult Sprague-Dawley (SD) rats (LH surge suppression) with doses that impair GnRH signaling in peripubertal rats, as indicated by delayed sexual maturation. The studies evaluated the effects of ATR treatment on the timing of uterine growth and vaginal opening (VO) in peripubertal female Wistar (Alderley Park, AP) and SD rats. Doses of 10, 30, and 100 mg/kg ATR were administered daily from postnatal day (pnd) 21 to up to pnd 46. Determinations of uterine weight were made at pnd 30, 33, 43 (AP), and 46 (SD) and the timing of VO was also assessed in the last two of these experiments. The centrally acting GnRH antagonist Antarelix (ANT) was used as a positive control agent as it has previously been shown to prevent uterine growth and to delay VO in peripubertal AP rats. Uterine growth and VO were completely prevented in AP rats exposed to ANT. Uterine growth was delayed at pnd 30 and 33 in AP rats exposed to 100 mg/kg ATR, but this growth inhibition had been overcome by pnd 43. VO was significantly delayed in AP rats for the 100 mg/kg ATR dose. By pnd 46, VO was significantly delayed in SD rats exposed to both 30 and 100 mg/kg ATR, but uterine weights were unaffected by that time (as for AP rats). It is concluded that the no-effect level for the effects of ATR on sexually immature rats (10 mg/kg in SD; 30 mg/kg AP) is approximately the same as reported previously by Laws et al. in peripubertal Wistar rats (25 mg/kg). However, the no-effect level in peripubertal female SD rats is nearly an order of magnitude greater than the no-observed effect level observed in female SD rats fed ATR for 6 months (1.8 mg/kg) where LH suppression was used as an indicator of effect on the pituitary/hypothalamic axis (USEPA, Atrazine-DACT Fourth Report of the Hazard Identification and Review Committee, April 5, 2002). These results support the conclusion that the pituitary/hypothalamic axis in peripubertal female SD rats is less sensitive than that in adult female SD rats.
除草剂阿特拉津（ATR）的哺乳动物危害评估主要集中在成年大鼠乳腺肿瘤的诱导、生殖衰老加速，以及这些影响与垂体促黄体生成素（LH）释放抑制之间的关系，而这种抑制作用本身是由成年大鼠下丘脑对促性腺激素释放激素（GnRH）信号传导的抑制所引起的。在早期研究中，劳斯等人（《毒理学科学》，第58卷，第366 - 376页，2000年）证明了ATR可导致雌性大鼠性成熟延迟，这种影响同样可能是由下丘脑GnRH释放受抑制引起的。本研究旨在比较先前在成年斯普拉格 - 道利（SD）大鼠研究中干扰GnRH信号传导的剂量（LH峰抑制）与损害青春期前大鼠GnRH信号传导的剂量（以性成熟延迟为指标）。这些研究评估了ATR处理对青春期前雌性Wistar（奥尔德利公园，AP）和SD大鼠子宫生长时间和阴道开口（VO）的影响。从出生后第21天（pnd）至第46天，每天给予10、30和100 mg/kg的ATR剂量。在第30、33、43天（AP）和第46天（SD）测定子宫重量，并在其中最后两个实验中评估VO时间。中枢作用的GnRH拮抗剂安他瑞克（ANT）用作阳性对照剂，因为先前已证明它可防止青春期前AP大鼠的子宫生长并延迟VO。暴露于ANT的AP大鼠子宫生长和VO完全被抑制。暴露于100 mg/kg ATR的AP大鼠在第30天和第33天子宫生长延迟，但到第43天时这种生长抑制已被克服。对于100 mg/kg ATR剂量，AP大鼠的VO显著延迟。到第46天，暴露于30和100 mg/kg ATR的SD大鼠VO显著延迟，但此时子宫重量未受影响（与AP大鼠相同）。得出的结论是，ATR对性未成熟大鼠影响的无作用水平（SD大鼠为10 mg/kg；AP大鼠为30 mg/kg）与劳斯等人先前报道的青春期前Wistar大鼠（25 mg/kg）大致相同。然而，青春期前雌性SD大鼠的无作用水平比以LH抑制作为垂体/下丘脑轴影响指标、喂食ATR 6个月的雌性SD大鼠的未观察到影响水平（1.8 mg/kg）几乎高一个数量级（美国环境保护局，《阿特拉津 - DACT危害识别与审查委员会第四次报告》，2002年4月5日）。这些结果支持以下结论：青春期前雌性SD大鼠的垂体/下丘脑轴比成年雌性SD大鼠的敏感性更低。
