Novel Biomarker to Identify Critical Windows of Susceptibility to Metal Mixture

 描述（由申请人提供）：神经发育和认知功能是公共卫生中最重要的结果之一，特别是随着知识经济的兴起。虽然人们普遍认为，同时接触几种有毒物质会改变中枢神经系统的发育轨迹，但旨在解决混合化学品接触问题的研究很少，这是公共卫生领域的一项迫切需要。进行混合物研究有许多固有的障碍，如果这一领域要取得进展，就必须克服这些障碍。明显的障碍包括需要大样本量和前瞻性数据来评估暴露时间（即关键的发育窗口）。另外两个障碍包括暴露分类错误和缺乏可用于更高风险的统计方法。 维度互动我们的提案直接解决了所有这些障碍，并将为研究可广泛应用于环境健康的化学混合物建立一个框架。我们开发了一种新的生物标志物，可以客观地重建使用乳牙的过去化学暴露的剂量和时间。这种生物标志物不同于标准的牙齿生物标志物，因为它结合了复杂的组织学和化学分析，以精确地对对应于特定生命阶段的牙本质层进行采样，从而在第二个和第三个三个月以及儿童早期产生综合的纵向每周暴露估计。作为第一步，我们的建议将解决混合金属暴露问题。然而，我们注意到，我们的方法可以并将在未来应用于有机化学品，我们正在同时开发用于牙齿分析的方法。在另一方面，我们还将应用最先进的统计机器学习方法。在这项研究中，我们将重点关注五种具有公共卫生意义的金属/类金属，锰（Mn），铅（Pb），砷（As），锌（Zn）和镉（Cd）。我们将在Mexico和神经毒理学（ELEMENT）的早期生命暴露中进行这项研究，这是一项前瞻性的出生队列研究，使用社会科学，遗传学和毒理学的先进方法来评估影响神经发育的跨学科风险因素。

 DESCRIPTION (provided by applicant): Neurodevelopment and cognitive function are among the most important outcomes in public health, particularly with the rise of knowledge-based economies. While it is widely believed that the simultaneous presence of several toxic exposures can alter developmental trajectories of the central nervous system, studies designed to address mixed chemical exposures are rare, and represent a critical need in the field of public health. Multiple barriers are inherent to conducting mixtures research and must be overcome if this field is to progress. Obvious barriers include the need for large sample sizes and prospective data to assess exposure timing (i.e. critical developmental windows). Two additional barriers include exposure misclassification and lack of statistical approaches available for higher dimensional interactions. Our proposal addresses all of these barriers directly and will establish a framework for the study of chemical mixtures that can be applied broadly in environmental health. We have developed a novel biomarker that can objectively reconstruct the dose and timing of past chemical exposure using deciduous teeth. This biomarker differs from standard tooth biomarkers as it combines sophisticated histological and chemical analyses to precisely sample dentine layers corresponding to specific life stages, generating integrated, longitudinal weekly exposure estimates in the second and third trimesters and during early childhood. Our proposal will address mixed metal exposure, as a first step. We note, however, that our approach can and will be applied to organic chemicals in the future, and we are in parallel developing methods for their analysis in teeth. On another front, we will also apply cutting-edge statistical machine learning methods. In this study, we will focus on five metals/metalloids that are of public health significance, manganese (Mn), lead (Pb), arsenic (As), zinc (Zn) and cadmium (Cd). We will conduct this study in the Early Life Exposures in MExico and NeuroToxicology (ELEMENT), a prospective birth cohort using advanced methods in social science, genetics and toxicology to assess transdisciplinary risk factors impacting neurodevelopment.