Screening of ToxCast Chemicals Responsible for Human Adverse Outcomes with Exposure to Ambient Air

Air
pollution poses a major threat to global public health. Although
there have been a few investigations into the relationships between
organic pollutants and adverse outcomes, the responsible components
and molecular mechanisms may be ignored. In this study, a suspect
screening method combining comprehensive two-dimensional gas chromatography–time-of-flight
mass spectrometry (GC × GC–TOF MS) with the Toxicity Forecaster
(ToxCast) database was applied to analyze complex hydrophobic compounds
in ambient air and prospectively figure out toxicologically significant
compounds. Seventy-six ToxCast compounds were screened, including
seven pollutants receiving less attention and five chemicals never
published in the air previously. Given the concentrations, bioactivities,
as well as absorption, distribution, metabolism, and excretion properties
in vivo, 29 contaminants were assigned high priority since they had
active biological effects in the vascular, lung, liver, kidney, prostate,
and bone tissues. Phenotypic linkages of key pollutants to potential
mechanistic pathways were explored by systems toxicology. A total
of 267 chemical–effect pathways involving 29 toxicants and
31 molecular targets were mapped in bipartite network, in which 12
key pathogenic pathways were clarified, which not only provided evidence
supporting the previous hypothesis but also provided new insights
into the molecular targets. The results would facilitate the development
of pollutant priority control, population intervention, and clinical
therapeutic strategies so as to substantially reduce human health
hazards induced by urban air.