Particulate metal exposures induce plasma metabolome changes in a commuter panel study

Abstract

IntroductionAdvances in liquid chromatography-mass spectrometry (LC-MS) have enabled high-resolution metabolomics (HRM) to emerge as a sensitive tool for measuring environmental exposures and corresponding biological response. Using measurements collected as part of a large, panel-based study of car commuters, the current analysis examines in-vehicle air pollution concentrations, targeted inflammatory biomarker levels, and metabolomic profiles to trace potential metabolic perturbations associated with on-road traffic exposures.MethodsA 60-person panel of adults participated in a crossover study, where each participant conducted a highway commute and randomized to either a side-street commute or clinic exposure session. In addition to in-vehicle exposure characterizations, participants contributed pre- and post-exposure dried blood spots for 2-hr changes in targeted proinflammatory and vascular injury biomarkers and 10-hr changes in the plasma metabolome. Samples were analyzed on a Thermo QExactive MS system in positive and negative electrospray ionization (ESI) mode. Data were processed and analyzed in R using apLCMS, xMSanalyzer, and limma. Features associated with environmental exposures or biological endpoints were identified with a linear mixed effects model and annotated through human metabolic pathway analysis in mummichog.ResultsHRM detected 10-hr perturbations in 110 features associated with in-vehicle, particulate metal exposures (Al, Pb, and Fe) which reflect changes in arachidonic acid, leukotriene, and tryptophan metabolism. Two-hour changes in proinflammatory biomarkers hs-CRP, IL-6, IL-8, and IL-1β were also associated with 10-hr changes in the plasma metabolome, suggesting diverse amino acid, leukotriene, and antioxidant metabolism effects. A putatively identified metabolite, 20-OH-LTB4, decreased after in-vehicle exposure to particulate metals, suggesting a subclinical immune response.ConclusionsAcute exposures to traffic-related air pollutants are associated with broad inflammatory response, including several traditional markers of inflammation.

Perturbations of the arginine metabolome following exposures to traffic-related air pollution in a panel of commuters with and without asthma

“…Fifty-eight pollutant species were measured in all exposure sessions using a specially–designed mobile monitoring platform (Golan et al 2018; Ladva et al 2018). For this analysis, however, we restricted the pollutant analytic database to 3 groups or factors, a priori , based on a published ACE–2 analysis of pollutant source attribution (Krall et al 2018).…”

“…High-resolution metabolomics (HRM), a high-throughput method involving the identification and quantitation of thousands of metabolic features associated with exogenous exposure and endogenous processes, has emerged as a powerful tool to improve exposure estimation to complex environmental mixtures (Bundy et al 2009; Miller and Jones 2014). Several studies have previously demonstrated that metabolomics sensitively reflect internal metabolic perturbations following exposures to urban air pollution (Huang et al 2018; Jeong et al 2018; Ladva et al 2018; Liang et al 2018b; van Veldhoven et al 2019; Vlaanderen et al 2017). These initial findings are promising and have led us to hypothesize that TRAP-specific metabolic markers of exposure and response may be detectable, especially in individuals thought to most susceptible to risk from this pollutant source (i.e., asthma).…”

“…In our previous ACE–2 analyses (Golan et al 2018), we observed modest, albeit transient, increases in systemic inflammation and acute respiratory response, using several known traditional targeted biomarkers, following on-road commutes and in association with several common traffic pollutant components. In addition, perturbations of the metabolome were found to be associated with in-vehicle particulate exposure and traditional markers of inflammation (Ladva et al 2018).…”

Toxicity of airborne particles—established evidence, knowledge gaps and emerging areas of importance

“…Notwithstanding such challenges, identifying metabolite perturbations caused by air pollution exposure is a particularly relevant and promising approach in characterizing the interactions of living organisms with their environment by identifying disregulated molecular pathways and predicting health endpoints [60]. It is not surprising, therefore, that to address issues such as differential toxicity, workers have adopted such an approach in both toxicological and epidemiological studies [61][62][63][64][65][66][67]. Experimental studies have investigated shifts in the metabolite profiles of bronchial wash (BW) and bronchoalveolar lavage (BAL) of healthy volunteers following exposure to biodiesel exhaust (BDE) compared with filtered air [61,62].…”

“…Notably, BDE-induced shifts in metabolite profiles of the BW versus BAL fluids differed appreciably, and a stronger response was detectable for peripheral regions of the lungs. Incorporation into epidemiological research has also been demonstrated to sensitively detect internal metabolic perturbations in healthy subjects, pregnant women and people with asthma following complicated exposures such as those present in urban environments [ 64 , 65 , 67 – 69 ]. A key finding from these studies has been the identification of several oxidative stress and inflammation-related pathways (including leukotriene, cytochrome P450, vitamin E, tyrosine, methionine and tryptophan metabolism) that were consistently associated with elevated pollution exposures.…”