Additional repression of activity-dependent c-fos and BDNF mRNA expression by lipophilic compounds accompanying a decrease in Ca2+ influx into neurons
Additional repression of activity-dependent c-fos and BDNF mRNA expression by lipophilic compounds accompanying a decrease in Ca2+ influx into neurons
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DOI：
10.1016/j.neuro.2004.07.008
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发表时间：
2005-01-01
期刊：
影响因子：
3.4
通讯作者：
Tsuda, M
中科院分区：
文献类型：
--
作者：
Imamura, L;Kurashina, K;Tsuda, M
最近，有人提出，多种环境干扰物（ED）由于其亲脂性特性，会干扰哺乳动物新生儿大脑的发育。因此，在评估 ED 风险时，这些亲脂性化合物的协同作用非常重要。在小鼠小脑颗粒细胞（CGC）中，脑源性神经营养因子（BDNF）基因的活动依赖性表达通过膜去极化引起的钙离子（Ca2+）流入CGC而被激活，这不仅参与小脑的活动依赖性发育，还参与出生后大脑其他区域的活动依赖性发育。在我们之前的研究中，我们报道了氯菊酯和其他一些被怀疑是 ED 的拟除虫菊酯杀虫剂，抑制了 c-fos 和 BDNF mRNA 表达的诱导，同时在对 CGC 无毒的剂量下减少了 Ca2+ 的流入。在本研究中，我们研究了其他亲脂性化合物是否像氯菊酯一样影响 Ca2+ 信号诱导的两个基因的表达，如果是的话，这些影响是否是协同的或额外的。用对,对'-滴滴涕己烯雌酚 (DES) 或双酚 A 预处理可剂量依赖性地抑制这两种基因的诱导以及 CGC 对 Ca2+ 吸收的增加。此外，CGCs 同时暴露于氯菊酯、p,p'-DDT 和 DES，揭示了对基因诱导和 Ca 21 吸收的额外抑制。这些结果表明，即使每种化合物的浓度低于人类的有效剂量，ED 的毒性作用也可能至少另外发生在大脑中。 (C) 2004 Elsevier Inc. 保留所有权利。
Recently, it has been proposed that a variety, of environmental disruptors (EDs) disturb the neonatal development of the brain in mammals because of their lipophilic characteristics. Therefore, the synergism of these lipophilic compounds is important when evaluating the risk from EDs. In mouse cerebellar granule cells (CGCs), the activity-dependent expression of the brain-derived neurotrophic factor (BDNF) gene is activated through an influx of calcium ions (Ca2+) into CGCs caused by membrane depolarization, which is involved in the activity-dependent development of not only the cerebellum but also other regions of the brain after birth. In our previous study, we reported that permethrin and some other pyrethroid insecticides, which are suspected of being EDs, repressed the induction of c-fos and BDNF mRNA expression, accompanying a reduction of Ca2+ influx at doses non-toxic to CGCs. In the present study, we investigated whether other lipophilic compounds influenced the Ca2+ signal-induced expression of both genes as permethrin did and, if so, whether these effects were synergistic or additional. Pretreatment with p,p'-DDT diethylstilbestrol (DES) or bisphenol A dose-dependently repressed the induction of both genes as well as the increase in the uptake of Ca2+ by CGCs. Simultaneous exposure of CGCs with permethrin, p,p'-DDT and DES, in addition, revealed an additional repression on the induction of the genes and the Ca 21 uptake. These results suggest that toxic effects of EDs might, at least additionally, occur in the brain even if the concentration of each compound is lower than the effective dose for humans. (C) 2004 Elsevier Inc. All rights reserved.