Hepatic exposome as an emerging contributor to metabolic dysfunction-associated steatotic liver disease

Table 1 Major environmental exposure classes implicated in steatotic liver disease and their principal hepatic effects

Exposure class	Representative sources/examples	Principal hepatic mechanism(s)	Representative human or experimental evidence	Ref.
PFAS	Non-stick coatings, food packaging, firefighting foams; PFOA, PFOS, PFHxS	PPARα activation, ACOX1-mediated peroxisomal oxidative stress, bile-acid and lipid remodeling	NHANES and cohort associations with NAFLD; PFAS track with biopsy steatosis grade and fibrosis; sex-specific liver-metabolome effects; prenatal exposure and child liver injury	[10,13,31,33-35]
Micro- and nanoplastics	Fragmented environmental plastics in water, food, air; polyethylene, polystyrene	Direct hepatotoxicity, ROS/oxidative stress, lipid dysmetabolism; gut-liver axis; vector for adsorbed contaminants	Detected in cirrhotic and other human liver tissue; systemic distribution; hepatotoxicity/steatosis in organoids; fibrosis and aflatoxin synergy in mice	[18,23,24,37-39]
Phthalates	Plasticizers in packaging, medical devices, cosmetics; DEHP, DINP	Endocrine disruption; LXR/SREBP-1c and PPARα lipogenic signaling	Urinary metabolites associated with NAFLD (meta-analytic OR = 1.18); DINP metabolite OR > 4; DEHP worsens steatosis in obesity	[4,9,16,40]
Bisphenols	Polycarbonate plastics, resin linings; bisphenol A and analogs (BPS, BPF)	Gut microbiota remodeling, FXR/TGR5 suppression, ↑bile-acid synthesis and lipogenesis	NHANES urinary BPA associated with NAFLD (OR up to 1.7; meta-analytic OR = 1.43); FMT-transmissible steatosis; analogs also steatogenic	[9,28,41-43]
Persistent and current-use pollutants/pesticides	PCBs, dioxins, organochlorine and glyphosate-based pesticides	PXR/CAR/PPAR and AhR activation; diet-dependent obesogen effect	PCB153 worsens steatosis with high-fat diet; NHANES PCB/Lead/mercury and ALT elevation; dioxin steatohepatitis; ultra-low-dose glyphosate NAFLD signature	[12,14,15,17,44,45,49]
Toxic metals	Arsenic, cadmium, chromium	Hepatic inflammation; gut-FXR-bile acid axis; genotoxic/epigenetic	Metal-induced hepatic inflammation along fibrosis-HCC axis; cadmium dysbiosis-FXR injury (meta-analytic OR = 1.37); arsenic and HCC	[9,25,26,29]
Air pollution	Ambient fine particulate matter (PM2.5), NOx	Pulmonary and hepatic oxidative stress; hepatic lipid reprogramming	UK Biobank: PM/NOx and incident NAFLD/cirrhosis. Rome cohort: Pollutants and incident cirrhosis	[19,46-48]
Dietary mycotoxin	Aflatoxin B1 (contaminated staples)	Genotoxic hepatocarcinogenesis; interaction with HCV/alcohol	Albumin-adduct biomarker prospectively increases HCC risk; synergy with HCV/alcohol	[51]
Industrial volatiles	Vinyl chloride (occupational)	Mitochondrial damage; sensitization to second inflammatory hit (TASH)	80% steatohepatitis and 55% fibrosis in exposed non-obese workers; potentiation of LPS injury	[20,50]

NAFLD: Non-alcoholic fatty liver disease; PFAS: Per- and polyfluoroalkyl substances; PPARα: Peroxisome proliferator-activated receptor alpha; ACOX1: Acyl-CoA oxidase 1; ROS: Reactive oxygen species; PXR: Pregnane X receptor; CAR: Constitutive androstane receptor; AhR: Aryl hydrocarbon receptor; FXR: Farnesoid X receptor; TGR5: Takeda G protein-coupled receptor 5; LXR: Liver X receptor; SREBP-1c: Sterol regulatory element-binding protein 1c; PFOA: Perfluorooctanoic acid; PFOS: Perfluorooctane sulfonic acid; PFHxS: Perfluorohexane sulfonate; DEHP: Di-2-ethylhexyl phthalate; DINP: Di-isononyl phthalate; BPA: Bisphenol A; BPS: Bisphenol S; BPF: Bisphenol F; FMT: Fecal microbiota transplantation; PCB: Polychlorinated biphenyl; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; LPS: Lipopolysaccharide; TASH: Toxicant-associated steatohepatitis; PM2.5: Particulate matter < 2.5 μm; NOx: Nitrogen oxides; ALT: Alanine aminotransferase; OR: Odds ratio; NHANES: National Health and Nutrition Examination Survey.