Defining the Deleterious Effects of Environmental Pollutants at a Mechanistic Level

人类经常暴露在环境中复杂的有害化学物质混合物中。幼儿，特别是未出生的幼儿和老年人最容易受到环境污染物的影响。空气污染是一个特别令人关注的问题，每年与全球370万人的额外死亡有关，柴油机废气排放是一个主要因素。受污染的食品-如受汞污染的海产品-以及砷等重金属对供水的污染也发挥了作用，饮酒和吸烟等生活方式因素也发挥了作用。世界卫生组织（WHO）估计，全球23%的死亡，其中14岁以下儿童的死亡率上升至36%，可归因于这些环境因素。尽管有这些令人震惊的统计数据，但在大多数情况下，我们并不了解污染物如何增加疾病风险。我们缺乏了解意味着我们无法预测暴露于特定污染物可能导致的健康后果。我们也没有能力制定可能减少污染物有害影响的公共卫生干预措施。这项工作将测试一个假设，即与柴油发动机排放物相关的污染物通过对蛋白质、脂肪和DNA（构成我们身体的三种主要化学物质）造成损害而增加疾病风险。我们将使用我们生成的一组模型来实现这一点，这些模型允许在体内暴露后测量对损伤的反应。这项工作将提高我们对柴油机废气的理解，并促进研究有多少其他类型的污染物导致疾病，以及污染物如何加剧哮喘等疾病。它将使我们能够识别受影响的器官和细胞类型，从而预测接触特定化学混合物可能导致的特定健康结果。未来，本研究开发的模型还将使我们能够评估旨在减少有害污染物影响的公共卫生干预措施的有效性。最后，这项工作将为我们提供潜在的生物标志物（可以在人体中轻松安全地测量的化学物质），可用于评估公众暴露于危险水平的污染。

Humans are constantly exposed to a complex mixture of damaging chemicals in the environment. Young children, especially those that are unborn, and the elderly are most at risk from environmental contaminants. Air pollution is a particular concern and has been linked to 3.7 million excess deaths worldwide each year, with diesel exhaust emissions being a major contributor. Contaminated foodstuffs - such as seafood contaminated by mercury - and pollution of water supplies by heavy metals such as arsenic also play a role, as do lifestyle factors, such as drinking and smoking. The World Health Organisation (WHO) estimates that 23% of global deaths, rising to 36% amongst children under 14 years of age, are attributable to environment factors such as these. Despite these alarming statistics, in most cases we do not understand how pollutants increase risk of disease. Our lack of understanding means that we cannot predict the likely health outcomes of exposure to specific pollutants. Nor are we in a position to develop public health interventions that might reduce the harmful impact of pollutants. This work will test the hypothesis that pollutants associated with diesel engine emissions increase disease risk by causing damage to proteins, fats and DNA, the three major types of chemical that make up our bodies. We will do this using a panel of models we have generated that allow responses to damage to be measured following in vivo exposure. This work will improve our understanding of how diesel exhaust fumes, and facilitate studies into how many other types of pollutants cause disease and also how pollutants exacerbate diseases such as asthma. It will allow us to identify affected organs and cell types and thus to predict the specific health outcomes that are likely to result from exposure to specific chemical mixtures. In the future, the models developed during this study will also allow us to evaluate the effectiveness of public-health interventions designed to reduce the impact of harmful pollutants. Finally, this work will provide us with potential biomarkers (chemicals that can be easily and safely measured in humans) that can be used to assess public exposure to dangerous levels of pollution.