Clarification of the effects of diethylstilbestrol, an endocrine disruptors, on synaptic plasticity and its application as an detailed test

从妊娠第11 ~ 17天开始，将己烯雌酚（DES） 100 ng溶于30 μl玉米油或单独玉米油中，每天1次口服给药。在产后6周（PNW）时，DES暴露组海马CA1的长时程增强（LTP）增强。另一方面，DES暴露组在PNW6时消除了长期抑郁（LTD）。LTP的增强与被动回避测试中的学习障碍有关。雌激素受体敲除小鼠的初步数据表明，ERα可能参与des诱导的突触可塑性的影响。为了阐明这种可能性，未来还需要进一步的研究。蛋白质组学分析显示，产前DES暴露组至少有9种蛋白水平改变2倍以上。其中3种可能是乳酸脱氢酶、乳酸脱氢酶2和微管蛋白α。然而，这些物质是否参与突触可塑性尚不清楚。雌性小鼠未观察到产前DES暴露的影响。DES对突触可塑性影响的性别差异有待进一步研究。产前DES暴露对LTP的影响与频率刺激条件有关，即50 Hz 30脉冲的刺激比20 Hz 100脉冲的刺激更能诱发LTP。产前DES暴露对LTP和LTD的影响在PNW6时最为显著。体外实验提示DES对LTP的影响弱于17β-雌二醇，其作用可能通过雌激素受体介导。综上所述，结合50 Hz 30脉冲对LTP的影响和1 Hz 900脉冲对LTD的影响两种实验方案，可能有助于验证具有雌激素活性的环境干扰物（如DES）对突触可塑性的影响。

Diethylstilbestrol(DES) 100 ng dissolved in 30 μl corn oil or corn oil alone was administered orally to ddY mice once a day from gestation day 11 to 17. When performed at post natal week(PNW) 6, long term potentiation(LTP) in the hippocampal CA1 was enhanced in DES exposure group. On the other hand, long term depression(LTD) was abolished at PNW6 in DES exposure group. Enhancement of LTP was related to the learning disability in the passive avoidance test. Preliminary data in estrogen receptor knock out mice showed the possibility that ERα might contribute to the DES-induced effects on the synaptic plasticity. To elucidate this possibility, further studies are necessary in the future. Proteome analysis revealed that the levels of at least 9 proteins were changed by more than 2 times in prenatal DES exposure group. Three of them were possibly lactate dehydrogenase, lactate dehydrogenase 2 and tubulin alpha. Nothing, however, is known about whether or not these substances are involved in the synaptic plasticity. No effect of prenatal DES exposure in female mice was observed. Further studies are needed to clarify the sexual differences in the effect of DES on the synaptic plasticity.The effect of prenatal exposure of DES on the LTP depended on condition of frequency stimulation, that is, stimulation with 50 Hz 30 pulses was more effective to induce LTP than that with 20 Hz 100 pulses. Effects of prenatal DES exposure on LTP and LTD were the most prominent at PNW6. In vitro experiment suggested that the effect of DES on LTP, which may be mediated through estrogen receptors, was weaker than 17β-estradiol. In conclusion, combination of two experimental protocols, effect on the LTP caused by 50 Hz 30 pulses and effect on the LTD caused by 1 Hz 900 pulses, might be useful for verifying effect on the synaptic plasticity of environmental disrupters possessing estrogenic activity such as DES.