Lee Jinyoung, Freeman Jennifer L
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
Neurotoxicology. 2014 Jul;43:57-64. doi: 10.1016/j.neuro.2014.03.008. Epub 2014 Mar 31.
Lead (Pb) exposure has long been recognized to cause neurological alterations in both adults and children. While most of the studies in adults are related to higher dose exposure, epidemiological studies indicate cognitive decline and neurobehavioral alterations in children associated with lower dose environmental Pb exposure (a blood Pb level of 10μg/dL and below). Recent animal studies also now report that an early-life Pb exposure results in pathological hallmarks of Alzheimer's disease later in life. While previous studies evaluating higher Pb exposures in adult animal models and higher occupational Pb exposures in humans have suggested a link between higher dose Pb exposure during adulthood and neurodegenerative disease, these newer studies now indicate a link between an early-life Pb exposure and adult neurodegenerative disease. These studies are supporting the "fetal/developmental origin of adult disease" hypothesis and present a new challenge in our understanding of Pb neurotoxicity. There is a need to expand research in this area and additional model systems are needed. The zebrafish presents as a complementary vertebrate model system with numerous strengths including high genetic homology. Several zebrafish genes orthologous to human genes associated with neurodegenerative diseases including Alzheimer's and Parkinson's diseases are identified and this model is starting to be applied in neurodegenerative disease research. Moreover, the zebrafish is being used in developmental Pb neurotoxicity studies to define genetic mechanisms of toxicity and associated neurobehavioral alterations. While these studies are in their infancy, the genetic and functional conservation of genes associated with neurodegenerative diseases and application in developmental Pb neurotoxicity studies supports the potential for this in vivo model to further investigate the link between developmental Pb exposure and adult neurodegenerative disease pathogenesis. In this review, the major factors influencing the pathogenesis of neurodegenerative diseases, Pb neurotoxicity, the developmental origin of adult disease paradigm, and the zebrafish as a model system to investigate the developmental origin of low-dose Pb-induced neurodegenerative diseases is discussed.
长期以来，人们一直认为铅（Pb）暴露会导致成人和儿童出现神经功能改变。虽然大多数关于成人的研究都与高剂量暴露有关，但流行病学研究表明，儿童认知能力下降和神经行为改变与低剂量环境铅暴露（血铅水平为10μg/dL及以下）有关。最近的动物研究也报告称，生命早期铅暴露会导致晚年出现阿尔茨海默病的病理特征。虽然之前评估成年动物模型中高铅暴露和人类职业性高铅暴露的研究表明，成年期高剂量铅暴露与神经退行性疾病之间存在联系，但这些新研究现在表明，生命早期铅暴露与成人神经退行性疾病之间存在联系。这些研究支持了“成人疾病的胎儿/发育起源”假说，并在我们对铅神经毒性的理解方面提出了新的挑战。有必要扩大这一领域的研究，还需要更多的模型系统。斑马鱼作为一种互补的脊椎动物模型系统，具有许多优点，包括高度的基因同源性。已鉴定出几种与包括阿尔茨海默病和帕金森病在内的神经退行性疾病相关的人类基因直系同源的斑马鱼基因，并且该模型已开始应用于神经退行性疾病研究。此外，斑马鱼正被用于发育性铅神经毒性研究，以确定毒性的遗传机制和相关的神经行为改变。虽然这些研究尚处于起步阶段，但与神经退行性疾病相关基因的遗传和功能保守性以及在发育性铅神经毒性研究中的应用，支持了这种体内模型进一步研究发育性铅暴露与成人神经退行性疾病发病机制之间联系的潜力。在这篇综述中，讨论了影响神经退行性疾病发病机制的主要因素、铅神经毒性、成人疾病范式的发育起源以及斑马鱼作为研究低剂量铅诱导的神经退行性疾病发育起源的模型系统。
