长期双酚A暴露对成年小鼠恐惧记忆的影响

双酚A (bisphenol, BPA)是一种广泛应用于塑料制品的环境内分泌干扰物, 具有弱雌激素和抗雄激素活性, 与雌激素受体有一定的亲和力。本实验探讨长期BPA暴露对成年小鼠恐惧记忆的影响及其神经机制。将9周龄雄性小鼠暴露于BPA (0.4、4、40 mg/kg/d) 90 d, 建立小鼠亚慢性BPA暴露模型后, 进行场景性条件恐惧训练, 然后分别在电击后1 hr及24 hr检测小鼠的僵立时间, 同时在电击前、电击后1 hr及24 hr检测海马相关蛋白表达变化。结果表明, BPA (4、40 mg/kg/d)暴露延长小鼠场景性条件恐惧训练后1 hr及24 hr的僵立时间。Western blot蛋白检测结果显示, 行为训练前, BPA降低了小鼠NMDA受体NR1亚基表达水平, 上调组蛋白去乙酰化酶2表达。行为训练后1 hr及24 hr, BPA促进海马NMDA受体亚基NR1和组蛋白H3乙酰化表达, 抑制组蛋白去乙酰化酶2表达, 同时促进ERK1/2磷酸化水平。以上结果表明, 长期BPA暴露提高成年小鼠恐惧记忆获得的同时延长恐惧记忆的保持; 该作用可能通过激活海马的ERK1/2通路而改变核内组蛋白乙酰化和NMDA受体水平进行。

The Effects of Long-term Exposure to Bisphenol-A on Fear Memory of Adult Mice

Bisphenol-A (BPA), an environmental endocrine disruptor used in the production of plastics, has been reported to possess weakly estrogenic and anti-androgenic properties. The present study aims to investigate the effect of BPA on fear memory of male mice exposed to BPA in adulthood. Nine-week-old male mice were orally exposed (ig) to BPA (0.4, 4, or 40 mg/kg/d) for 90d, and then received contextual fear conditioning test. The total time of freezing was measured 1 h and 24 h after training. At the same time, the hippocampus of mice before or 1 hr, 24 hr after fear conditioning training were dissociated for western blot analyses. The results showed that adulthood exposure to BPA (4 and/or 40 mg/kg/d) increased the freezing time 1 hr and 24 hr after fear conditioning training. Furthermore, western blot analyses showed that BPA exposure decreased the level of N-methyl-D-aspartic acid (NMDA) receptor subunit NR1 and increased the expression of histone deacetylase 2 (HDAC2) before fear conditioning training. One and 24 hr after fear conditioning training, BPA enhanced the increases of the levels of NR1, histone acetylation, and extracellular regulated protein kinases (ERK1/2) phosphorylation in hippocampus induced by fear conditioning training. These results suggest that long term exposure to BPA enhanced acquisition and retention of fear memory by concomitant the increases of histone acetylation and the level of NMDA receptor which may be associated with activation of ERK1/2 signaling pathway.