Toxicology in the 21st Century Program (Tox21) - Genomic Toxicology

Tox21计划是环境保护局(EPA)、食品和药物管理局(FDA)、国家环境健康科学研究所(NIEHS)的国家毒理学计划(NTP)和NCATS为推进体外毒理学测试而进行的多机构合作努力。Tox21计划由三个NCATS团队组成：系统毒理学、基因组毒理学和计算毒理学。基因组毒理学小组开发改进的人类细胞培养模型和方法，以阐明毒理学和人类疾病。例如，我们正在与NIEHS心血管健康效果创新团队合作，评估12种可疑心血管毒物对心脏和血管系统的不良影响。方法：我的实验室正在使用原代人内皮细胞模型和共培养血管模型来阐明环境毒物和药物如何通过影响血管衰竭模式而导致血管毒性和心脏病发作。例如，通过对培养的人内皮细胞进行转录和细胞因子分析，我们发现麻黄抑制tPA和护骨素的分泌，表明有促凝血作用。双酚A使细胞色素P1A1和细胞色素P1B1基因表达增加，而全氟己酸A (PFHxA)引起明显的氧化应激反应。这些反应提示血管衰竭模式的机制基础，如血管活性紊乱、凝血、炎症和动脉粥样硬化。童志斌博士在我的实验室继续推进神经毒性研究，验证了高通量3D LUHMES培养和分化方法，用于筛选1536-well格式的文库。使用这种3D方法，他使用LUHMES MT1G：：荧光素酶报告细胞系筛选了LOPAC文库，并确认命中。这种分析表明，HIT化合物扰乱了金属的分布和/或导致了氧化应激。这项检测的结果是帕金森氏病或其他神经退行性疾病的候选病原体。此外，我继续与艾米·勒布兰斯的团队合作，研究犬类肿瘤发生的特征。我们目前的重点是利用狗了解转移和耐药机制，并确定有希望的药物靶点和药物组合，以便翻译给人类患者。 公众健康影响声明 在人的一生中，大多数人接触到许多不同的环境化学物质。这些物质可以在食物、水、家用清洁产品和其他地方找到。在某些情况下，这些化学物质可能是有毒的，而在另一些情况下，研究人员缺乏足够的安全数据。药物也含有化学物质，事实上，尽管有希望在动物和其他模型上进行临床前研究，但超过30%的有希望的药物在人体临床试验中失败了，因为它们被发现是有毒的。Tox21计划致力于创造比传统方法更便宜、更耗时的化学毒性评估替代方法，这将改善科学家评估环境化学品和开发有利于公众健康的新药的方式。

The Tox21 Program is a multiagency collaborative effort among the Environmental Protection Agency (EPA), Food and Drug Administration (FDA), the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS), and NCATS to advance in vitro toxicological testing. The Tox21 Program is comprised of three NCATS teams: Systems Toxicology, Genomic Toxicology, and Computational Toxicology. The Genomic Toxicology group develops improved human cell culture models and methods to illuminate toxicology and human diseases. For example, we are collaborating with the NIEHS Cardiovascular Health Effects Innovation Team to evaluate twelve suspected cardiovascular toxicants for adverse effects on heart and vasculature. Methods: My lab is using primary human endothelial cell models and co-culture vascular models to elucidate how environmental toxicants and drugs cause vascular toxicity and heart attacks through impacts on vascular failure modes. By transcriptomic- and cytokine-profiling of cultured human endothelial cells, for example, we found that ephedra suppresses tPA and osteoprotegerin secretion suggesting a procoagulant effect. BPA caused increased expression of CYP1A1 and CYP1B1 genes, whereas perfluorohexanoic A (PFHxA)caused a clear oxidative stress response. These responses suggest mechanistic bases for vascular failure modes such as perturbations of vasoactivity, coagulation, or inflammation and atherosclerosis. Dr. Zhi-Bin Tong continues to advance neurotoxicity studies in my lab by validating a high-throughput 3D LUHMES culture and differentiation method for screening libraries in 1536-well format. Using this 3D method he has screened the LOPAC library using a LUHMES MT1G::Luciferase reporter cell line and confirmed 64 hits. This assay implicates hit compounds in disrupting metal distribution and/or causing oxidative stress. Hits from this assay are candidate causative agents for Parkinsons disease or other neurodegenerative diseases. Additionally, I continue to collaborate with Amy Leblancs team to characterize canine tumorigenesis. Our current focus is to understand metastasis and drug resistance mechanisms using dogs, and to identify promising drug targets and drug combinations for translation to human patients. Public Health Impact Statement During the course of a lifetime, most people are exposed to many different environmental chemicals. These substances can be found in food, water, household cleaning products and elsewhere. In some cases, these chemicals can be toxic, and in others, researchers lack sufficient data about safety. Medicines also contain chemicals, and in fact, more than 30 percent of promising pharmaceuticals have failed in human clinical trials because they are found to be toxic, despite promising pre-clinical studies in animal and other models. The Tox21 Program works to create alternative methods for assessing chemical toxicity that are less expensive and time-consuming than traditional approaches will improve how scientists evaluate environmental chemicals and develop new medicines to benefit public health.