Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA, 95060, USA.
Division of Nutritional Sciences and Department of Psychology, Cornell University, Ithaca, NY, 14853, USA.
Neurotherapeutics. 2023 Jan;20(1):3-21. doi: 10.1007/s13311-023-01345-9. Epub 2023 Feb 28.
Behavioral disorders involving attention and impulse control dysfunction, such as ADHD, are among the most prevalent disorders in children and adolescents, with significant impact on their lives. The etiology of these disorders is not well understood, but is recognized to be multifactorial, with studies reporting associations with polygenic and environmental risk factors, including toxicant exposure. Environmental epidemiological studies, while good at establishing associations with a variety of environmental and genetic risk factors, cannot establish causality. Animal models of behavioral disorders, when properly designed, can play an essential role in establishing causal relationships between environmental risk factors and a disorder, as well as provide model systems for elucidating underlying neural mechanisms and testing therapies. Here, we review how animal model studies of developmental lead or manganese exposure have been pivotal in (1) establishing a causal relationship between developmental exposure and lasting dysfunction in the domains of attention, impulse control, and affect regulation, and (2) testing the efficacy of specific therapeutic approaches for alleviating the lasting deficits. The lead and manganese case studies illustrate how animal models can advance knowledge in ways that are not possible in human studies. For example, in contrast to the Treatment of Lead Poisoned Children (TLC) human clinical trial evaluating succimer chelation efficacy to improve cognitive functioning in lead-exposed children, our developmental lead exposure animal model showed that succimer chelation can produce lasting cognitive benefits if chelation sufficiently reduces brain lead levels. In addition, this study revealed that succimer treatment in the absence of lead exposure produces lasting cognitive dysfunction, highlighting potential risks of chelation in off-label uses, such as the treatment of autistic children without a history of lead exposure. Our animal model of developmental manganese exposure has demonstrated that manganese can cause lasting attentional and sensorimotor deficits, akin to an ADHD-inattentive behavioral phenotype, thereby providing insights into the role of environmental exposures as contributors to ADHD. These studies have also shown that oral methylphenidate (Ritalin) can fully alleviate the deficits produced by early developmental Mn exposure. Future work should continue to focus on the development and use of animal models that appropriately recapitulate the complex behavioral phenotypes of behavioral disorders, in order to determine the mechanistic basis for the behavioral deficits caused by developmental exposure to environmental toxicants, and the efficacy of existing and emerging therapies.
涉及注意力和冲动控制功能障碍的行为障碍，如 ADHD，是儿童和青少年中最常见的障碍之一，对他们的生活有重大影响。这些障碍的病因尚不清楚，但被认为是多因素的，研究报告了与多基因和环境风险因素的关联，包括毒物暴露。环境流行病学研究虽然善于建立与各种环境和遗传风险因素的关联，但不能确定因果关系。行为障碍的动物模型，如果设计得当，可以在确定环境风险因素与疾病之间的因果关系方面发挥重要作用，并为阐明潜在的神经机制和测试治疗方法提供模型系统。在这里，我们回顾了发育性铅或锰暴露的动物模型研究如何在以下两个方面发挥关键作用：（1）确立发育性暴露与注意力、冲动控制和情感调节领域的持久功能障碍之间的因果关系；（2）测试特定治疗方法缓解持久缺陷的疗效。铅和锰的案例研究说明了动物模型如何以人类研究不可能的方式推进知识。例如，与评估依地酸二钙钠螯合疗法改善暴露于铅的儿童认知功能的“儿童铅中毒治疗”（TLC）人类临床试验相反，我们的发育性铅暴露动物模型表明，如果螯合作用充分降低大脑中的铅含量，依地酸二钙钠螯合疗法可以产生持久的认知益处。此外，这项研究表明，在没有铅暴露的情况下，依地酸二钙钠治疗会产生持久的认知功能障碍，突出了螯合疗法在非适应证中的潜在风险，例如在没有铅暴露史的情况下治疗自闭症儿童。我们的发育性锰暴露动物模型表明，锰可以导致持久的注意力和感觉运动缺陷，类似于 ADHD 注意力不集中的行为表型，从而深入了解环境暴露作为 ADHD 病因的作用。这些研究还表明，口服哌醋甲酯（利他林）可以完全缓解早期发育性 Mn 暴露产生的缺陷。未来的工作应继续专注于开发和使用适当再现行为障碍复杂行为表型的动物模型，以确定发育性暴露于环境毒物引起的行为缺陷的机制基础，以及现有和新兴疗法的疗效。
