生命早期双酚A暴露对子代成年小鼠焦虑和抑郁行为的影响及其神经机制

Early Life Exposure to Bisphenol A Affects Anxiety and Depression Behaviors in Mice and Its Molecular Mechanism

双酚A(bisphenol A,BPA)对脑和行为发育的影响已引起关注,本研究探讨围生期不同发育阶段母体BPA暴露对仔鼠成年后焦虑和抑郁行为的影响。分别在妊娠期(妊娠第7天～出生)和哺乳期(出生第1～14天)将母鼠暴露于BPA(0.4、4mg/kg/day),以旷场、明暗箱、镜子迷宫、高架十字迷宫等多种模型检测生后56天(postnatalday56)仔鼠的焦虑行为,以强迫游泳模型检测其抑郁行为。结果显示,妊娠期BPA暴露的成年雌性仔鼠在所有4种模型中均检测到促焦虑作用,而哺乳期BPA暴露的雌鼠、妊娠期或哺乳期BPA暴露的雄鼠仅在2种模型中检测到促焦虑作用。妊娠期BPA暴露显著加重雌雄仔鼠的抑郁行为,而哺乳期仅高剂量BPA加重仔鼠的抑郁行为。进一步的Westernblot分析显示,妊娠期或哺乳期BPA暴露显著下调成年后雌雄仔鼠海马和杏仁核AMPA受体GluR1亚基的表达,但对NMDA受体NR1亚基的影响不一致。以上结果提示,妊娠期或哺乳期BPA暴露对成年雌雄仔鼠均有不同程度的促焦虑和抑郁作用,其中妊娠期暴露对雌鼠的作用最显著,海马和杏仁核AMPA受体活动的减弱可能与围生期BPA暴露加重仔鼠成年后的焦虑和抑郁行为有关。

The effect of Bisphenol-A on the brain and behavioral development has attracted extensive attention. This study was to investigate the anxiety and depressive behaviors of adult offspring mice following maternal exposed to BPA （0.4 or 4 mg/kg/day） from gestation day 7 （GD 7） to GD 20 or postnatal day （PND） 1 to PND 14 The anxiety behavior of BPA-treated mice on PND 56 were tested using open field, dark-light transition, mirrored maze, and elevated plus maze; and depressive behavior was tested using forced swim task. The results showed that, both gestational and lactational exposure to BPA increased anxiety in both sexes of adult offspring but the effect pattern was different due to the exposure period and gender. The females those gestational exposed to BPA exhibited an increased anxiety in all of the 4 models, while the females those lactational exposed to BPA and the males of gestational or lactational exposure to BPA exhibited an increased anxiety in 2 of the 4 models. Gestational exposure to BPA significantly prolonged the immobile time in the forced swim test of both sexes of offspring, and the same effect was induced by lactational exposure to BPA only at 4 mg/kg/day. Furthermore, Western blot analyses showed that gestational or lactational exposure to BPA significantly inhibited the expression of AMPA receptor subunit GluR1 in the hippocampus and amygdale. These results suggest that both gestational and lactational exposure BPA increased anxiety and depression in both sexes of adult offspring mice, and gestational exposure to BPA has stronger effect on the anxiety and depression. The inhibition of GluR1 level in the hippocampus and amygdale might be associated with the BPA-induced anxiety and depressive behaviors of adult offspring mice.