The exposome and meet-in-the-middle as tools in addressing open questions in air pollution research
The exposome and meet-in-the-middle as tools in addressing open questions in air pollution research
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暴露组和中间会面作为解决空气污染研究中开放问题的工具
DOI：
10.1093/eurpub/ckaa166.081
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发表时间：
2020
影响因子：
4.4
通讯作者：
Demetriou C
中科院分区：
文献类型：
--
作者：
Demetriou C
环境颗粒物是对全球疾病负担和死亡率贡献最大的环境因素。关于低剂量的因果关系和特定污染物的影响，仍然存在悬而未决的问题。建立与空气污染有关的因果关系在方法上具有挑战性，影响了监管政策的制定。为了解决这个问题，我们建议将暴露组的概念与中间相遇的方法(MITM)结合起来。这种方法包括测量分子指纹，并将其与外部暴露的测量和预期的健康结果相关联。与暴露于疾病连续体的两端密切相关的标记物证实了因果假设5。在癌症发生的背景下，这种方法允许建立癌症特征的中间到结果性质与致癌物关键特征的从底部到中间的方法之间的关系。我们最近证明了这种方法的原理，从癌症病理标本(分支突变光谱)的角度研究了癌症特征的时间序列，然后通过考虑致癌物苯并(A)芘的关键特征。受影响的主要癌症途径遵循一个普遍的顺序：抵抗细胞死亡，对抗生长信号不敏感，持续增殖(几乎同时)，去调节能量，复制永生，以及激活侵袭和转移。血管生成和避免免疫破坏在上述序列中显示出不同的位置。同时，BaP的“关键特征”被发现与癌症的大多数特征相关，支持其致癌性。MITM方法，使用暴露证据，是一种很有前途的方法，可以成功地解决与空气污染毒理学和监管政策的必要性有关的因果关系。关键信息研究肿瘤突变谱和致癌物的作用机制，揭示癌症特征和致癌的关键特征之间的重叠。这项调查提供了原则证据，证明暴露组/中间相遇的方法可以解决空气污染毒理学中的问题，并为支持监管政策提供证据。
Ambient particulate matter is the environmental factor with the highest contribution to global disease burden and mortality. Open questions remain regarding causality at low doses and the effects of specific pollutants. Establishing causality in regards to air pollution is methodologically challenging, affecting the establishment of regulatory policies.In an effort to address this problem, we suggest combining the concept of the exposome with the Meet-in-the-Middle approach (MITM). This approach consists of measuring molecular fingerprints and relating them retrospectively to measurements of external exposure and prospectively to a health outcome. Markers robustly associated with both ends of the exposure-to-disease continuum, validate a causal hypothesis5. In the context of carcinogenesis, this approach allows establishing the relationship between the middle-to-outcome nature of the hallmarks of cancer with the bottom-to-middle approaches of the key characteristics of carcinogens. We recently demonstrated proof of principle of this approach, by investigating the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (branched mutational spectra), and then by considering the key characteristics of the carcinogen, benzo(a)pyrene. The main cancer pathways affected follow a generally common sequence: resisting cell death, insensitivity to anti-growth signals, sustained proliferation (almost simultaneous), deregulated energetics, replicative immortality, and activation of invasion and metastasis. Angiogenesis and avoiding immune destruction display a varying position in the above sequence. At the same time, “key characteristics” of BaP were found associated with most hallmarks of cancer, supporting its carcinogenicity.A MITM approach, using exposomic evidence, is a promising approach that can successfully address causality concerns in regards to air-pollution toxicology and the need for regulatory policies.Key messagesInvestigation of tumour mutational spectra and of the mechanisms of action of a carcinogen, reveals an overlap between the hallmarks of cancer and the key characteristics of the carcinogen.This investigation provides proof of principle that the exposome/meet-in-the-middle approach can address concerns in air-pollution toxicology and provide evidence to support regulatory policies.