Ambient fine particulate matter components and liver fat and stiffness in youth: metabolic vulnerability in PNPLA3 risk carriers.

BACKGROUND & AIMS: Exposure to fine particulate matter (PM2.5) is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), yet responsible chemical constituents and the biological basis of susceptibility remain unclear, limiting source-targeted regulation and precision prevention in vulnerable populations. We examined PM2.5 components - liver outcomes associations in youth, assessed susceptibility by PNPLA3 genotype (the strongest known MASLD genetic determinant), and evaluated genotype-specific metabolic mediation in two independent cohorts.

METHODS

Baseline data from 113 Los Angeles Latino adolescents with obesity (discovery cohort) were analyzed, including magnetic resonance imaging-measured hepatic fat fraction (HFF), liver stiffness (LS), and serum metabolomics and lipidomics. Visit-year average exposures to 15 PM2.5 components were estimated from residential addresses. Linear regression and g-computation assessed individual component and mixture effects, with PNPLA3 genotype as modifier. Moderated mediation analyses identified metabolic mediators, followed by pathway enrichment and total mediation effect estimation. Findings were replicated in 81 young adults of mixed race/ethnicity and body mass index (replication cohort) using level 1 metabolites confirmed by authentic standards.

RESULTS

PM2.5 components and mixture were predominantly positively associated with HFF and LS; simultaneous interquartile range increases in all components were associated with 10.0% higher HFF. Elemental carbon (EC), bromine (Br), copper, potassium, and lead were key contributors. Stronger effects were observed in PNPLA3 GG carriers. GG carriers exhibited more mediating metabolite features (n = 550 vs. 196), with broader pathway enrichment in carbohydrate, lipid, and amino acid metabolism, and signaling/endocrine pathways. Significant total mediation effects were observed exclusively in GG carriers. Replication confirmed GG-specific associations of EC, Br with HFF, and identified increased fatty acid 16:1, and decreased guanidinosuccinate, proline as candidate mediators.

CONCLUSION

PM2.5 components potentially indicative of combustion and traffic sources (i.e. EC, Br) increase MASLD risk in youth via metabolic pathways, with genotype-specific responses likely heightening susceptibility in PNPLA3 GG carriers.