The exposome and meet-in-the-middle as tools in addressing open questions in air pollution research

Abstract

Abstract 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 messages Investigation 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.