Targetable Preventive Metabolites: Revealing the Pathways from Air Pollution Mixtures to Hypertension Through Integrated Exposure-Metabolomics

Abstract

Although exposure to air pollution mixes is a significant environmental risk for hypertension, it is still unclear how it causes illness through metabolic disruptions. In order to assess the possible preventative advantages of focusing on modifiable metabolites and to comprehensively uncover the metabolic mediators connecting air pollution mixes to hypertension, this work integrates exposomics and metabolomics. Individual long-term exposure to fine particulate matter (PM₂.¹), nitrogen dioxide (NO₂), and ozone (O₃) was evaluated using land use regression models and satellite data based on a prospective cohort study that included individuals without hypertension at baseline (n = 12,456). Ultra-high performance liquid chromatography-tandem mass spectrometry was used for serum untargeted metabolomics, and quantile g-computation was used to assess the cumulative impact of pollutant mixes on the prevalence of hypertension. The average causal mediation fraction of significant mediating metabolites was computed after they were screened using high-dimensional mediation analysis and causal mediation effect models with false discovery rate correction. In order to evaluate possible population-level benefits, treatments on target metabolites were further simulated using a random forest technique. There were 2,847 instances of hypertension over a median follow-up of 7.2 years. The incidence of hypertension rose by 18% for every interquartile range increase in exposure to air pollution mixtures (HR = 1.18, 95% CI: 1.12–1.24). Hexanoylcarnitine (C6-carnitine), tryptophan, and 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PC ae C38:4) collectively mediated 32.6% (95% CI: 24.1%–41.1%) of the mixture exposure effect, independent of conventional risk factors, according to metabolomics. According to theoretical intervention analysis, about 15.3% of instances of pollution-related hypertension may be avoided if C6-carnitine levels in the population were kept below the 25th percentile. C6-carnitine and other preventable metabolites are important biological mediators of air pollution mixture-induced hypertension, partially illuminating the molecular link between environmental exposure and cardiovascular metabolic disorders. In the context of environmental health, these results offer fresh support for metabolite-targeted precision preventive techniques.