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

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15590110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: SHIRASAKI Tetsuya Kumamoto University, Graduate school of Pharmaceutical Sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (30264047)
• Co-Investigator(Kenkyū-buntansha): TAKAHAMA Kazuo Kumamoto University, Graduate school of Pharmaceutical Sciences, Professor, 大学院・医学薬学研究部, 教授 (80150548) ; SOEDA Fumio Kumamoto University, Graduate school of Pharmaceutical Sciences, Research Associate, 大学院・医学薬学研究部, 助手 (10336216)
• Project Period (FY): 2003 – 2004
• Keywords: endocrine disrupters / diethylstilbestrol / estrogen receptors / synaptic plasticity / LTP / LTD / hippocampus / proteome analysis

Research Abstract

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.