The exposome and liver disease - how environmental factors affect liver health

Abstract

Since the initial development of the exposome concept, much effort has been devoted to the characterisation of the exposome through analytical, epidemiological, and toxicological/mechanistic studies. There is now an urgent need to link the exposome to human diseases and to include exposomics in the characterisation of environment-linked pathologies together with genomics and other omics. Liver diseases are particularly well suited for such studies since major functions of the liver include the detection, detoxification, and elimination of xenobiotics, as well as inflammatory responses. It is well known that several liver diseases are associated with i) addictive behaviours such as alcohol consumption, smoking, and to a certain extent dietary imbalance and obesity, ii) viral and parasitic infections, and iii) exposure to toxins and occupational chemicals. Recent studies indicate that environmental exposures are also significantly associated with liver diseases, and these include air pollution (particulate matter and volatile chemicals), contaminants such as polyaromatic hydrocarbons, bisphenol A and per-and poly-fluorinated substances, and physical stressors such as radiation. Furthermore, microbial metabolites and the "gut-liver" axis play a major role in liver diseases. Exposomics is poised to play a major role in the field of liver pathology. Methodological advances such as the exposomics-metabolomics framework, the determination of risk factors' genomic and epigenomic signatures, and cross-species biological pathway analysis should further delineate the impact of the exposome on the liver, opening the way for improved prevention, as well as the identification of new biomarkers of exposure and effects, and additional therapeutic targets.

Keywords: MAFLD; biliary disease; exposomics; hepatocellular carcinoma; metabolomics; microbiota; mutational signature; toxicological pathways; viral hepatitis; xenobiotic metabolism.

Fig. 1.. Metabolic disruption and liver injury following exposure to contaminants and pollutants.

Exposure to food contaminants is associated with dysbiosis and gut barrier injury, ultimately leading to an alteration of the gut-liver axis and increased inflammation of the liver. Changes in microbial metabolites also impact metabolic pathways in the liver, such as lipid metabolism. A variety of contaminants and pollutants activate several receptors in the liver which also lead to significant metabolic disruption. The combination of these alterations increases the risks of developing liver diseases, such as NAFLD, NASH and ultimately cirrhosis and cancer. AhR, aryl hydrocarbon receptor; FXR, farnesoid X receptor; LPS, lipopolysaccharide; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PAHs, polyaromatic hydrocarbons; PCDD, polychlorinated dibenzodioxins; PFASs, per- and polyfluoroalkyl substances; PPAR, peroxisome proliferator-activated receptor; TMA, trimethylamine.

Fig. 2.. Network interaction plot of exposures and metabolites in primary sclerosing cholangitis.

For each pathway, the first principal component was tested for association with each identified exposure biomarker; clusters (Cl1–3) were identified using multilevel community detection to identify communities of nodes that are tightly connected with each other, but sparsely connected with the rest of the network. Reproduced with permission from Hepatology Communications, 6: 965–979, 2022. PFOS, perfluorooctane sulfonic acid.

Fig. 3.. Various mutational signatures identified in liver and HCC tissues and related to specific exposure during life.

The mutational signatures refer to the molecular profile of the genetic alterations accumulated in the liver and in HCC and reflect exposome components that triggered the carcinogenic process during life. Each exposure is believed to lead to a relatively specific set of mutations. Identifying such mutational profiles is helpful to determine which exposure is likely to have contributed to the development of the disease. The most frequent nucleotide changes are represented. For more details on the genes and pathways involved, please refer to Schulze et al. HCC, hepatocellular carcinoma.

Fig. 4.. The liver exposome and its impact on major liver diseases.

The central circle represents different liver diseases (steatosis, cirrhosis, hepatocellular carcinoma). It is not exhaustive and it illustrates the one pathway for the progression of these diseases. The outer circle illustrates the major contributors to the liver exposome. Note that there is no correlation between the location of the exposome component and the type of liver disease. Such correlations would be difficult to illustrate since many exposome components contribute to different stages of liver diseases.