Gohlke J M, Griffith W C, Faustman E M
Institute for Risk Analysis and Risk Communication, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA.
Toxicol Sci. 2005 Aug;86(2):470-84. doi: 10.1093/toxsci/kfi209. Epub 2005 May 25.
Investigations into the potential mechanisms for ethanol-induced developmental toxicity have been ongoing for over 30 years since Fetal Alcohol Syndrome (FAS) was first described. Neurodevelopmental endpoints are particularly sensitive to in utero exposure to alcohol as suggested by the more prevalent alcohol-related neurodevelopmental disorder (ARND). The inhibition of proliferation during neurogenesis and the induction of apoptosis during the period of synaptogenesis have been identified as potentially important mechanisms for ARND. However, it is unclear how these two mechanisms quantitatively relate to the dose and timing of exposure. We have extended our model of neocortical neurogenesis to evaluate apoptosis during synaptogenesis. This model construct allows quantitative evaluation of the relative impacts on neuronal proliferation versus apoptosis during neocortical development. Ethanol-induced lengthening of the cell cycle of neural progenitor cells during rat neocortical neurogenesis (G13-G19) is used to compute the number of neurons lost after exposure during neurogenesis. Ethanol-induced dose-dependent increases in cell death rates are applied to our apoptosis model during rat synaptogenesis (P0-P14), when programmed cell death plays a major role in shaping the future neocortex. At a human blood ethanol concentration that occurs after 3-5 drinks ( approximately 150 mg/dl), our model predicts a 20-30% neuronal deficit due to inhibition of proliferation during neurogenesis, while a similar exposure during synaptogenesis suggests a 7-9% neuronal loss through induction of cell death. Experimental in vitro and in vivo dose-response research and stereological research on long-term neuronal loss after developmental exposure to ethanol is compared to our model predictions. Our computational model allows for quantitative, systems-level comparisons of mechanistic hypotheses for perturbations during specific neurodevelopmental periods.
自首次描述胎儿酒精综合征（FAS）以来，对乙醇诱导发育毒性潜在机制的研究已持续了30多年。如更为常见的酒精相关神经发育障碍（ARND）所示，神经发育终点对子宫内酒精暴露尤为敏感。神经发生过程中增殖的抑制以及突触发生期细胞凋亡的诱导已被确定为ARND的潜在重要机制。然而，尚不清楚这两种机制如何在数量上与暴露剂量和时间相关。我们扩展了新皮质神经发生模型，以评估突触发生过程中的细胞凋亡。该模型构建允许对新皮质发育过程中神经元增殖与细胞凋亡的相对影响进行定量评估。大鼠新皮质神经发生（G13 - G19）期间乙醇诱导的神经祖细胞细胞周期延长用于计算神经发生期间暴露后损失的神经元数量。乙醇诱导的细胞死亡率剂量依赖性增加应用于大鼠突触发生（P0 - P14）期间的凋亡模型，此时程序性细胞死亡在塑造未来新皮质中起主要作用。在饮用3 - 5杯酒（约150mg/dl）后出现的人体血液乙醇浓度下，我们的模型预测由于神经发生期间增殖受抑制会导致20 - 30%的神经元缺失，而在突触发生期间类似暴露表明通过诱导细胞死亡会导致7 - 9%的神经元损失。将发育性乙醇暴露后长期神经元损失的体外和体内实验剂量反应研究及体视学研究与我们的模型预测进行比较。我们的计算模型允许对特定神经发育时期扰动的机制假设进行定量的、系统水平的比较。
