Biological mechanisms behind health effects of air pollution exposure from childhood to adulthood

BACKGROUND: Early life air pollution exposure impairs respiratory health during childhood and up to young adulthood. The proposed mechanism for air pollution adverse health effects includes systemic inflammation and metabolic dysregulation, which could be explored by the tools of proteomics and metabolomics. However, epidemiological evidence of the role of proteomics and metabolomics in the relationship between air pollution and respiratory health from childhood to young adulthood is mostly unknown.

AIM: The aim of the thesis is to elucidate biological mechanisms behind the negative health effects of air pollution exposure in children and young adults.

METHODS: All four included studies were based on Swedish birth cohorts. Time- weighted average exposure to air pollutants (i.e., particulate matter with diameter ≤10 um (PM10), ≤2.5 um (PM2.5), and nitrogen dioxide (NO2) or nitrogen oxides (NOx)) was estimated using validated dispersion models.

In study I and II, inflammation-related proteins were repeatedly measured in children of the EMIL and Born-into-Life cohorts at 6 months, 1 year and 2 years of age with Olink inflammation panel (n=158). We examined sex-specific longitudinal associations between preceding air pollution exposure and inflammation-related proteins.

Building upon Study I, Study II focused on 6-month-old infants with data on inflammation-related proteins, as well as dynamic spirometry (n=82). We defined individual inflammation-related protein profiles and analyzed the interaction between air pollution and the abnormal inflammation-related protein profile on lung function on the additive scale.

In Study III, urine metabolomics analyses were carried out at 4 years (n=612) and 24 years of age (N=836) in the BAMSE cohort, using non-targeted screening followed by in-house library annotation. We examined age-specific associations between air pollution and urinary metabolites. Pathway enrichment and interaction with genetic variants were also explored.

Based on the results from Study III, Study IV focused on child participants 4 years of age, for whom spirometry was repeatedly measured at 8-, 16- and 24- year-follow-ups (n=584). We grouped metabolites into 11 groups based on the stability, sources and biological types according to Pubchem, and focused on the carnitine profiles related to fatty acids oxidation. We characterized the metabolite profile in each group by counting the number of abnormally low metabolites and the number of abnormally high metabolites. We assessed the interaction between air pollution and metabolic profile in early childhood on lung function in later life.

RESULTS: Our results showed that preceding air pollution exposure was longitudinally associated with inflammation-related proteins during early childhood, in age and sex-specific manner. Further, early life air pollution exposure and abnormal inflammation-related protein profiles interact synergistically towards lower lung function in infants. Next, we observed that both early life and recent air pollution exposures were associated with urinary metabolic profiles in children and young adults. In particular, air pollution was associated with upregulated caffeine metabolism in children, likely due to increased enzyme activity. In addition, our data suggest that carnitine profile in the pathway of oxidation of fatty acids may modify the air pollution exposure - lung function association.

CONCLUSIONS: Our findings indicate that molecular changes related to air pollution exposure can be detected even in environments with relatively low exposure levels as in Stockholm County. This highlights the public health importance of further reducing urban air pollution levels. The identified air pollution-related inflammatory profiles, and metabolic pathways during childhood provide valuable insights for early identification of susceptible subpopulations and prediction of long-term health consequences.

List of scientific papers

I. He S, Klevebro S, Baldanzi G, Pershagen G, Lundberg B, Eneroth K, Hedman AM, Andolf E, Almqvist C, Bottai M, Melén E, Gruzieva O. Ambient air pollution and inflammation-related proteins during early childhood. Environ Res. 2022 Dec;215(Pt 2):114364. Epub 2022 Sep 17. https://doi.org/10.1016/j.envres.2022.114364

II. He S, Lundberg B, Hallberg J, Klevebro S, Pershagen G, Eneroth K, Melen E, Bottai M,* Gruzieva O.* Joint association of air pollution exposure and inflammation-related proteins in relation to infant lung function. Int J Hyg Environ Health. 2024 Jan;255:114294. Epub 2023 Nov 10. https://doi.org/10.1016/j.ijheh.2023.114294

III. He S,* Habchi B,* Chaleckis R, Hernandez-Pacheco N, Bergström A, Merritt AS, Kull I, Eneroth K, Bottai M, Pershagen G, Merid SK, Björkander S, Yu Z, Melén E, Gruzieva O, Wheelock CE,* Klevebro S .* Long-term exposure to air pollution is associated with urinary metabolite shifts in children and young adults in a Swedish birth cohort. [Submitted]

IV. He S, Habchi B, Chaleckis R, Hernandez-Pacheco N, Bergström A, Merritt AS, Kull I, Eneroth K, Pershagen G, Björkander S, Yu Z, Wheelock CE, Klevebro S, Bottai M, Melén E,* Gruzieva O.* Air pollution exposure, metabolomic markers, and lung function in children and young adults: findings from a Swedish birth cohort. [Manuscript]

* These authors contributed equally