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

Figure 1 Hepatic exposome and transition from environmental exposure to steatotic liver disease. Environmental chemicals from the external exposome (per- and polyfluoroalkyl substances, micro- and nanoplastics, phthalates and bisphenols, persistent organic pollutants, toxic metals, air pollution and aflatoxin B1) are absorbed by the body through ingestion, inhalation and dermal contact and are transported to the liver, the key organ for xenobiotic uptake, biotransformation and elimination. They converge on a common set of mechanisms: Nuclear receptor hijacking (peroxisome proliferator-activated receptor alpha, pregnane X receptor, constitutive androstane receptor, arylhydrocarbon receptor), mitochondrial and peroxisomal dysfunction with oxidative stress, inflammasome activation and hepatic stellate cell-driven fibrogenesis, disruption of the gut microbiota-bile acid-farnesoid X receptor axis, and developmental and epigenetic reprogramming. These mechanisms are associated with the clinical progression from normal liver to steatosis and toxicant-associated steatohepatitis, and then to fibrosis, cirrhosis and hepatocellular carcinoma. Two distinct classes of modifiers act upon this pathway and are shown separately: Host-susceptibility factors (sex, life stage, including developmental windows, and nutritional status) that modify the host response to a given exposure (e.g., women exhibit more robust steatogenic responses to several pollutants and in utero and early childhood windows of exposure confer disproportionately high and persistent risk) and exposure-related modifiers (mixture composition, dose, and timing of exposure) that describe the exposure itself, rather than host susceptibility. PPARα: Peroxisome proliferator-activated receptor alpha; PXR: Pregnane X receptor; CAR: Constitutive androstane receptor; AhR: Aryl hydrocarbon receptor; FXR: Farnesoid X receptor; PM2.5: Particulate matter < 2.5 μm; PCBs: Polychlorinated biphenyls; TGR5: Takeda G protein-coupled receptor 5; PFAS: Per- and polyfluoroalkyl substances; incl: Including; TASH: Toxicant-associated steatohepatitis.

Figure 2 Environmental exposure classes mapped to dominant hepatic mechanism, representative human evidence, and current strength of evidence. For each class, this figure lists the dominant mechanism in the liver, a representative study in humans, the study design, approximate sample size, and evidence tier. Evidence tiers describe the strength of human (association) evidence, not proof of causation, and are defined as follows: Strong, consistent associations in large and/or prospective human cohorts, biopsy-based studies, or an established carcinogen classification, consistent with experimental mechanism (per- and polyfluoroalkyl substances, air pollution, aflatoxin B1, and vinyl chloride/toxicant-associated steatohepatitis); emerging, human associations reported but based mainly on cross-sectional biomonitoring or few studies (bisphenols, phthalates, persistent organic pollutants, and toxic metals); and preliminary, human data limited to tissue detection with toxicity demonstrated only experimentally (micro- and nanoplastics). Representative studies and sizes are: Per- and polyfluoroalkyl substances, biopsy cohort (n = 100) and adolescent cohort (n ≈ 1700); air pollution, UK Biobank (n > 450000) and a Rome cohort (n > 1.2 million); bisphenols, National Health and Nutrition Examination Survey (n > 7600); persistent organic pollutants, National Health and Nutrition Examination Survey (n > 4200); aflatoxin B1, prospective nested case-control and International Agency for Research on Cancer group 1 classification; and micro- and nanoplastics, human tissue detection with organoid and rodent toxicity only. PFAS: Per- and polyfluoroalkyl substances; PM2.5: Particulate matter < 2.5 μm; BPA: Bisphenol A; FXR: Farnesoid X receptor; TGR5: Takeda G protein-coupled receptor 5; HCV: Hepatitis C virus. NR: Nuclear receptor; HCC: Hepatocellular carcinoma; NHANES: National Health and Nutrition Examination Survey; OR: Odds ratio; IARC: International Agency for Research on Cancer; TASH: Toxicant-associated steatohepatitis; As: Arsenic; Cd: Cadmium; Cr: Chromium; PPARα: Peroxisome proliferator-activated receptor alpha; ACOX1: Acyl-CoA oxidase 1; ROS: Reactive oxygen species; LXR: Liver X receptor; SREBP-1c: Sterol regulatory element-binding protein 1c.