Environmental Endocrine-Disrupting Chemicals and Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), represents the most prevalent chronic liver condition worldwide, affecting approximately 25%-30% of the global adult population. Endocrine-disrupting chemicals (EDCs)-including phthalates, bisphenols, per- and polyfluoroalkyl substances (PFAS), persistent organic pollutants (POPs) and heavy metals-are ubiquitous environmental contaminants with established metabolic toxicity. However, the quantitative association between EDC exposure and MASLD prevalence remains incompletely characterised. We conducted a systematic review and meta-analysis to synthesise the current epidemiological evidence on this association.

We systematically searched PubMed, Embase, Web of Science and the Cochrane Library from inception through January 2026, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (PROSPERO: CRD420261298624). Studies were eligible if they reported quantitative associations between measured EDC exposures and MASLD/NAFLD/metabolic-associated fatty liver disease (MAFLD) outcomes in human populations. Two investigators independently screened records, extracted data and assessed methodological quality using a customised Newcastle-Ottawa Scale (NOS). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. Heterogeneity was assessed via the I² statistic. Funnel plot asymmetry and Egger's test were used to evaluate publication bias. Sensitivity analyses were performed using leave-one-out methods.

Of 427 records identified, 42 studies encompassing diverse global populations met inclusion criteria and were incorporated into the quantitative synthesis. The meta-analysis demonstrated that: Phthalates: mono (2-ethyl-5-carboxypentyl) phthalate (MECPP; weighted mean difference [WMD]: 2.40, 95% CI: 0.71-4.09), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP; WMD: 2.46, 95% CI: 0.81-4.10) and monobenzyl phthalate (MBzP; WMD: 1.84, 95% CI: 0.10-3.59) showed significant positive associations with MASLD prevalence; pooled analysis of phthalate mixtures yielded an overall OR of 1.17 (95% CI: 1.13-1.21; I² = 41.4%). Bisphenols: pooled analysis demonstrated a significant positive association with MASLD (OR: 1.29, 95% CI: 1.09-1.50; I² = 73.0%), with bisphenol A (BPA; OR: 1.32, 95% CI: 0.92-1.72), bisphenol S (BPS; OR: 1.47, 95% CI: 0.96-1.98) and bisphenol F (BPF; OR: 1.19, 95% CI: 0.77-1.61) contributing to this effect. PFAS: the overall pooled effect was OR 0.95 (95% CI: 0.91-1.00; I² = 22.9%). POPs: the overall OR was 1.30 (95% CI: 1.22-1.37; I² = 29.2%), with organochlorine pesticides (OCPs; OR: 1.30, 95% CI: 1.19-1.42) and polychlorinated biphenyl (PCB)/OCP combinations demonstrating significant associations. Heavy metals/metalloids: mercury (Hg) demonstrated the strongest positive association (OR: 1.60, 95% CI: 1.15-2.04; I² = 87.3%), followed by lead (Pb; OR: 1.40, 95% CI: 1.02-1.78) and cadmium (Cd; OR: 1.30, 95% CI: 1.09-1.51; I² = 79.2%); the overall metals pooled OR was 1.26 (95% CI: 1.16-1.37; I² = 79.9%). Methodological quality assessed by NOS ranged from 6 to 9 points, with the majority of studies scoring ≥ 7.

This meta-analysis of observational studies suggests that environmental exposure to several major EDC classes-including phthalates, bisphenols, persistent organic pollutants and certain heavy metals-is associated with a higher prevalence of MASLD, although the magnitude and consistency of associations vary substantially across chemical classes and individual compounds. Findings for PFAS were heterogeneous and compound-specific. Given the predominantly cross-sectional nature of the available evidence and the considerable between-study heterogeneity, causal inference cannot be drawn. These findings should be interpreted as hypothesis-generating and underscore the need for prospective multi-pollutant studies and mechanistic investigations to clarify the role of EDCs in MASLD pathogenesis.