Investigations of methylmercury-induced alterations in neurogenesis.
Investigations of methylmercury-induced alterations in neurogenesis.
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DOI：
10.1289/ehp.02110s5859
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发表时间：
2002-10
影响因子：
10.4
通讯作者：
Kavanagh T
中科院分区：
文献类型：
--
作者：
Faustman EM;Ponce RA;Ou YC;Mendoza MA;Lewandowski T;Kavanagh T
50多年来，甲基汞（MeHg）一直是公共卫生和监管机构关注的环境问题，因为它对人类神经系统具有毒性。它与日本水俣湾附近成人和婴儿神经系统毒性的关联，在20世纪50年代引发了持续至今的环境健康研究调查。与成年暴露相比，妊娠期暴露的神经毒性更大，这表明发育中的神经系统对甲基汞具有独特的易感性。尽管在过去的半个世纪里进行了广泛的研究，但尚未确定甲基汞观察到的神经毒性作用的确切分子机制。本文总结了MeHg对神经上皮细胞增殖影响的一系列实验结果，这是其对神经发生选择性作用的一种假设作用模式。MeHg对细胞周期进入和进展的影响与多种细胞周期调节分子的改变有关，包括p21信号通路。我们将这些研究置于其他涉及信号转导的细胞反应的背景下，包括氧化应激、蛋白质磷酸化改变和细胞内钙稳态改变。虽然现有的信息表明，没有单一的机制可以解释甲基汞诱导的发育性神经毒性相关的各种效应，但我们证明了甲基汞对细胞信号传导的特征性影响，有助于观察到对细胞增殖的影响。通过实验获得的细胞周期动力学和细胞毒性数据，可以建立基于生物学的甲基汞诱导神经发育改变的剂量反应模型，这可以形成信息合成和假设检验的基础，并用于评估环境暴露风险。
Methylmercury (MeHg) has been an environmental concern to public health and regulatory agencies for over 50 years because of its toxicity to the human nervous system. Its association with nervous system toxicity in adults and infants near Minamata Bay, Japan, in the 1950s initiated environmental health research inquiries that continue to this day. Observations of greater neurotoxicity with gestational compared with adult exposure suggest a unique susceptibility of the developing nervous system to MeHg. Despite extensive research conducted over the last half century, determination of definitive molecular mechanisms underlying the observed neurotoxic effects of MeHg have not been identified. This paper summarizes results of a series of experiments conducted to examine the effects of MeHg on neuroepithelial cell proliferation, a hypothesized mode of action for its selective effects on neurogenesis. Observed effects of MeHg on cell cycle entry and progression were associated with alterations in a variety of cell cycle regulatory molecules, including p21 signaling pathways. We place these studies in the context of other cellular responses involved in signal transduction, including oxidative stress, altered protein phosphorylation, and altered intracellular calcium homeostasis. Although existing information suggests that no single mechanism underlies the diverse array of effects associated with MeHg-induced developmental neurotoxicity, we demonstrate characteristic effects of MeHg on cell signaling that contribute to observed effects on cell proliferation. Experimentally derived cell cycle kinetic and cytotoxicity data allowed development of a biologically based dose-response model of MeHg-induced alterations in neurodevelopment, which can form the basis for information synthesis and hypothesis testing and for use in assessing risks from environmental exposures.
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DOI：
10.1007/bf03159968
发表时间：
1992-02-01
期刊：
MOLECULAR AND CHEMICAL NEUROPATHOLOGY
影响因子：
--
作者：
ETO, K;OYANAGI, S;SUDA, I
通讯作者：
SUDA, I
影响因子：
6.3
作者：
CLARKSON, TW;NORDBERG, GF;SAGER, PR
通讯作者：
SAGER, PR
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
12.7
作者：
GEELEN, JAG;DORMANS, JAMA;VERHOEF, A
通讯作者：
VERHOEF, A
影响因子：
10.4
作者：
CLARKSON, TW
通讯作者：
CLARKSON, TW