Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty
Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty
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DOI：
10.1111/j.1471-4159.2007.04882.x
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发表时间：
2007-12-01
影响因子：
4.7
通讯作者：
DiCicco-Bloom, Emanuel
中科院分区：
文献类型：
--
作者：
Falluel-Morel, Anthony;Sokolowski, Katie;DiCicco-Bloom, Emanuel
正常的大脑发育需要对包括增殖、分化和细胞死亡在内的多个过程进行协同调节。来自内源性和外源性的多种因素相互作用，对这些过程产生正向和负向调节。特别是，围产期大鼠的大脑对特定的发育损伤高度敏感，这些损伤会导致后期的认知异常。我们利用该模型研究了一种备受关注的外源性因素——甲基汞（MeHg）的发育影响。7日龄大鼠接受单次注射甲基汞（5微克/克体重）。甲基汞在24小时内使海马中的DNA合成抑制了44%，并降低了细胞周期蛋白D1、D3和E的水平，但在小脑中没有这种情况。毒性与半胱天冬酶依赖性程序性细胞死亡密切相关。甲基汞暴露导致2周后海马体积减小（21%）和细胞数量减少，特别是在通过体视学方法确定的齿状回颗粒细胞层（16%）和门区（50%），这表明神经元可能特别脆弱。与此一致的是，围产期暴露导致幼年期在空间导航任务训练期间海马依赖性学习出现严重缺陷。总之，这些研究表明，围产期暴露于一剂甲基汞会急性诱导细胞凋亡，从而导致后期海马结构和功能的缺陷。
Normal brain development requires coordinated regulation of several processes including proliferation, differentiation, and cell death. Multiple factors from endogenous and exogenous sources interact to elicit positive as well as negative regulation of these processes. In particular, the perinatal rat brain is highly vulnerable to specific developmental insults that produce later cognitive abnormalities. We used this model to examine the developmental effects of an exogenous factor of great concern, methylmercury (MeHg). Seven-day-old rats received a single injection of MeHg (5 mu g/gbw). MeHg inhibited DNA synthesis by 44% and reduced levels of cyclins D1, D3, and E at 24 h in the hippocampus, but not the cerebellum. Toxicity was associated acutely with caspase-dependent programmed cell death. MeHg exposure led to reductions in hippocampal size (21%) and cell numbers 2 weeks later, especially in the granule cell layer (16%) and hilus (50%) of the dentate gyrus defined stereologically, suggesting that neurons might be particularly vulnerable. Consistent with this, perinatal exposure led to profound deficits in juvenile hippocampal-dependent learning during training on a spatial navigation task. In aggregate, these studies indicate that exposure to one dose of MeHg during the perinatal period acutely induces apoptotic cell death, which results in later deficits in hippocampal structure and function.