Franssen Delphine, Ioannou Yiannis S, Alvarez-real Alexandra, Gerard Arlette, Mueller Johanna K, Heger Sabine, Bourguignon Jean-Pierre, Parent Anne-Simone
Development Neuroendocrinology Unit, GIGA Neurosciences, University of Liege, CHU Sart-Timan, B4000 Liege, Belgium.
Pediatric Endocrinology, University of Hanover, Germany.
Reprod Toxicol. 2014 Apr;44:63-72. doi: 10.1016/j.reprotox.2013.10.006. Epub 2013 Dec 6.
We studied the effects of neonatal exposure to diethylstilbestrol (DES) on pubertal timing in female rats. We examined associated neuroendocrine changes and effects of prenatal food restriction. Age at vaginal opening was advanced after exposure to 10 μg/kg/d of DES and delayed after 1 μg/kg/d (subcutaneous injections). Using this lower dose, pulsatile GnRH secretion was slower at 25 days of age. Both doses reduced KiSS1 mRNA levels at 15 days of age. Using functional Kisspeptin promoter assay, 1 or 10 μM DES reduced or increased KISS1 transcription, respectively. Leptin stimulatory effect on GnRH secretion in vitro (15 days of age) was reduced after prenatal food restriction and neonatal DES exposure (higher dose), both effects being cumulative. Thus, alterations in pubertal timing by DES neonatally are not unequivocally toward precocity, the level of exposure being critical. We provide evidence of neuroendocrine disruption and interaction with prenatal food availability.
我们研究了新生大鼠暴露于己烯雌酚（DES）对雌性大鼠青春期发育时间的影响。我们检测了相关的神经内分泌变化以及产前食物限制的影响。暴露于10μg/kg/d的DES后，阴道开口年龄提前；而暴露于1μg/kg/d（皮下注射）后，阴道开口年龄延迟。使用较低剂量时，25日龄时促性腺激素释放激素（GnRH）的脉冲式分泌较慢。两种剂量均降低了15日龄时的KiSS1 mRNA水平。使用功能性促性腺激素释放激素神经元蛋白（Kisspeptin）启动子分析，1μM或10μM的DES分别降低或增加了KISS1的转录。产前食物限制和新生大鼠DES暴露（较高剂量）后，瘦素对体外（15日龄）GnRH分泌的刺激作用降低，这两种作用具有累积性。因此，新生大鼠暴露于DES对青春期发育时间的改变并非明确地导致早熟，暴露水平至关重要。我们提供了神经内分泌干扰以及与产前食物供应相互作用的证据。
