Inflammation-Related Biomarkers Linking Environmental Chemical Mixtures and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Population-Based Study from NHANES 1999-2020

Objective: Environmental pollutants are increasingly recognized as potential risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD), yet the effects of mixed exposures and underlying mechanisms remain unclear. We evaluated associations between environmental chemical mixtures and MASLD and the mediating role of inflammation-related biomarkers. Methods: We analyzed 60 environmental chemicals across six categories among 39,061 U.S. adults from the National Health and Nutrition Examination Survey (NHANES) 1999-2020. Principal Component Pursuit with Principal Component Analysis (PCP-PCA) identified latent exposure patterns. MASLD was identified using multisociety Delphi consensus criteria and the Hepatic Steatosis Index (HSI [&ge;] 36). Logistic regression, restricted cubic spline models, and mediation analysis were applied. Results: PCP-PCA generated 5-17 dimensions per chemical category, with first-dimension variance contributions ranging from 30.70% to 98.88%. Six dimensions from four categories were retained, with phthalate esters (PAEs) and organophosphate flame retardants (OPFRs) showing the most consistent associations with MASLD. PAEs Dim.1, explaining 90.71% of variance, showed a significant non-linear dose-response association (P-nonlinear = 0.0001). Significant associations were identified for mono-isobutyl phthalate (MiBP; OR 1.12, 95% CI 1.07-1.19), mono(carboxyoctyl) phthalate (MCOP; OR 1.08, 95% CI 1.02-1.14), mono(carboxynonyl) phthalate (MCNP; OR 1.12, 95% CI 1.03-1.21), and bis(1,3-dichloro-2-propyl) phosphate (BDCP; OR 1.15, 95% CI 1.08-1.23). C-reactive protein (CRP) and red cell distribution width (RDW) were the primary mediators, accounting for 32.42% and 19.62% of the MiBP-MASLD association, respectively (both p < 0.0001). Conclusion: Environmental co-exposure, particularly to PAEs and OPFRs, was associated with higher MASLD risk, with systemic inflammation potentially contributing to these associations.