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

阐明内分泌干扰物己烯雌酚对突触可塑性的影响及其作为详细测试的应用

• 批准号: 15590110
• 负责人: SHIRASAKI Tetsuya
• 金额: $ 2.3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590110/
• 关键词: endocrine disrupters; diethylstilbestrol; estrogen receptors; synaptic plasticity; LTP; LTD; hippocampus; proteome analysis; 内分泌撹乱物質; DES; 長期増強

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.

从妊娠第11天到17日，每天一次向DDY小鼠口服二乙基苯甲醇（DES）100 ng溶解在30μl玉米油或玉米油中。在河马CA1中，在hippocampal ca1中进行长期增强（PNW）6（PNW）6时，在Hippocampal CA1中进行了DES曝光组。另一方面，在DES暴露组的PNW6中，长期抑郁症（LTD）被废除。 LTP的增强与被动回避测试中的学习障碍有关。雌激素受体中的初步数据敲除小鼠表明ERα可能有助于DES诱导的对合成可塑性的影响。为了阐明这种可能性，将来需要进一步的研究。蛋白质组分析表明，在产前暴露组中，至少9种蛋白质的水平超过2倍。其中三个可能是乳酸脱氢酶，乳酸脱氢酶2和微管蛋白α。然而，对于这些物质是否参与突触可塑性，一无所知。在雌性小鼠中未观察到产前暴露的影响。需要进一步的研究来阐明DES对突触可塑性的影响的性差异。 DES对LTP产前暴露的影响取决于频率刺激的条件，即50 Hz 30脉冲的刺激对LTP和LTD的产前暴露对LTP和LTD的影响是PNW6上最突出的。体外实验表明，可以通过雌激素受体介导的DES对LTP的作用弱于17β-雌二醇。总之，两种实验方案的组合，对50 Hz 30脉冲引起的LTP的影响以及由1 Hz 900脉冲引起的LTD的影响，可能有助于验证对具有雌激素活性的环境衰落的突触可塑性的影响。