Inherited Effects of Low-Dose Exposure to Methylmercury in Neural Stem Cells
Inherited Effects of Low-Dose Exposure to Methylmercury in Neural Stem Cells
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DOI：
10.1093/toxsci/kfs257
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发表时间：
2012-12-01
影响因子：
3.8
通讯作者：
Ceccatelli, Sandra
中科院分区：
文献类型：
--
作者：
Bose, Raj;Onishchenko, Natalia;Ceccatelli, Sandra
甲基汞（MeHg）是一种环境污染物，具有公认的神经毒性作用，特别是对发育中的神经系统。在本研究中，我们表明，纳摩尔浓度的甲基汞可以诱导神经干细胞（NSC）的长期影响。我们研究了短期直接和长期的遗传效应暴露于甲基汞（2.5或5.0纳米）使用原代培养的大鼠胚胎皮层神经干细胞。我们发现，甲基汞对细胞活力没有不良影响，但减少了神经干细胞增殖，改变了细胞周期调节因子（p16和p21）和衰老相关标志物的表达。此外，我们证明了在暴露的细胞中的整体DNA甲基化的减少，表明表观遗传变化可能参与了甲基汞诱导效应的机制。在直接接触甲基汞的细胞（母细胞）和在无甲基汞条件下培养的子细胞中观察到这些变化。与我们的体外数据一致，发现在围产期暴露于低剂量甲基汞的成年小鼠的大脑皮层中的颗粒下区细胞增殖减少的趋势。有趣的是，这种受损的增殖对海马齿状回的神经元总数有可测量的影响。重要的是，这种作用可以通过长期抗抑郁治疗逆转。我们的研究提供了新的证据编程的影响，诱导甲基汞在神经干细胞和支持的想法，发展暴露于低水平的甲基汞可能会导致长期的后果，易患神经发育障碍和/或神经退行性疾病。
Methylmercury (MeHg) is an environmental contaminant with recognized neurotoxic effects, particularly to the developing nervous system. In the present study, we show that nanomolar concentrations of MeHg can induce long-lasting effects in neural stem cells (NSCs). We investigated short-term direct and long-term inherited effects of exposure to MeHg (2.5 or 5.0nM) using primary cultures of rat embryonic cortical NSCs. We found that MeHg had no adverse effect on cell viability but reduced NSC proliferation and altered the expression of cell cycle regulators (p16 and p21) and senescence-associated markers. In addition, we demonstrated a decrease in global DNA methylation in the exposed cells, indicating that epigenetic changes may be involved in the mechanisms underlying the MeHg-induced effects. These changes were observed in cells directly exposed to MeHg (parent cells) and in their daughter cells cultured under MeHg-free conditions. In agreement with our in vitro data, a trend was found for decreased cell proliferation in the subgranular zone in the hippocampi of adult mice exposed to low doses of MeHg during the perinatal period. Interestingly, this impaired proliferation had a measurable impact on the total number of neurons in the hippocampal dentate gyrus. Importantly, this effect could be reversed by chronic antidepressant treatment. Our study provides novel evidence for programming effects induced by MeHg in NSCs and supports the idea that developmental exposure to low levels of MeHg may result in long-term consequences predisposing to neurodevelopmental disorders and/or neurodegeneration.