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. Author manuscript; available in PMC: 2023 Aug 24.
Published in final edited form as: J Hepatol. 2023 Mar 6;79(2):492–505. doi: 10.1016/j.jhep.2023.02.034

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

Robert Barouki 1,*, Michel Samson 2, Etienne B Blanc 1, Massimo Colombo 3, Jessica Zucman-Rossi 4, Konstantinos N Lazaridis 5, Gary W Miller 6, Xavier Coumoul 1
PMCID: PMC10448911  NIHMSID: NIHMS1922583  PMID: 36889360

Summary

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, hepatocellular carcinoma, viral hepatitis, biliary disease, exposomics, metabolomics, mutational signature, toxicological pathways, microbiota, xenobiotic metabolism

Introduction to the exposome

Although, there have been substantial advances over the past few decades in our understanding of the contribution of genetics to human diseases, the role of exposures to different environmental stressors has remained elusive. In a seminal article in 2005, Chris Wild elaborated a new concept, the exposome, which he defined as the totality of exposures from conception to death.1 The aim of the proposal was to integrate, in a single framework, different types of exposures including chemical, physical, biological, and psycho-social stressors, and to take into consideration the temporal dimension. Within this definition, the exposome can be viewed as the complement of the genome and can be used to improve our understanding of disease determinants. Since the initial definition, different contributions have been made to further develop the concept and to delineate the approaches that support its practical implementation. Much of the focus has been on developing analytical tools to characterise the exposome.2,3 Also, a significant effort has been devoted to better link the exposome to health, in particular through the integration of chemical, biological and computational approaches.4,5 Exposomics can be defined as the study of the exposome, which relies on the application of internal and external exposure assessment methods. Recently, exposomics has been further integrated with the other omics, leading to the concept of functional exposomics, which has been defined as the biological translation of the exposome and its multiple exposures and the characterisation of mechanisms of action, much as functional genomics refers to the functional expression of the genome.6

Initial studies of the exposome have been primarily methodological and global, recent work has been more disease-oriented,7,8 e.g. targeting the exposome relevant for cancer,911 lung disease12 or liver disorders.13 These developments have been supported by the integration of exposomics within omics approaches and subsequently the characterisation of the mechanistic links between various stressors and disease-relevant biological pathways.4,5 These disease-oriented health studies enable a more realistic evaluation of the most relevant determinants and allow for gene-environment interaction studies. Importantly, these developments contribute to bringing the exposome concept to the clinic and should support an improved understanding of disease determinants and ultimately improved prevention.14

In the present review, we have analysed studies linking a variety of exposures to different liver diseases. Most of these studies did not use a non-targeted large-scale exposomics approach, yet they were included in order to enable a more comprehensive assessment of environmental determinants of liver diseases. We will first describe different biological pathways relevant to liver diseases, then we will discuss the implication of exposome components in different liver diseases, including metabolic, infectious, cholestatic diseases and cancer, highlighting specific or shared mechanistic aspects as well as clinical implications. In the conclusion, we identify the most promising approaches and tools to further develop this rapidly growing field.

Biological pathways in the liver

There are several physiological functions of the liver that are known to be modulated by environmental factors. Endogenous metabolism is a major function of the liver, and several metabolic pathways are either specific or highly represented in this organ, e.g. gluconeogenesis and the urea cycle as well as lipid metabolism (as discussed below). Exposure studies coupled with metabolomics studies in human biological fluids have suggested specific dysregulation of liver functions. This is the case for urea cycle intermediates which, when dysregulated in body fluids after exposure to a mix of metals and phthalates, point to a possible liver injury and specifically mitochondrial dysfunction (a part of the urea cycle occurs in the mitochondria).15 It is expected that, with the development of coupled exposomics and metabolomics studies, such associations will be more frequently observed.16 Yet, since endogenous metabolism is dependent on the interaction between several organs, it is critical to integrate the data at the organism level.

Xenobiotic metabolism is another major liver function, although it is not unique to the liver. Hepatocytes express a large number of genes involved in this function such as cytochromes P450, phase 2 enzymes, transporters and xenobiotic receptors.17,18 It has been known for a long time that many of these genes are highly inducible by xenobiotics, in line with their adaptive biological functions.19,20 Yet, the impacts of combined environmental chemicals have been less well studied.21 The regulation of xenobiotic metabolism is not restricted to exogenous chemicals, since endogenous effectors such as hormones, microbiome metabolites, and inflammatory mediators are also implicated. A critical point is that while xenobiotic metabolism displays adaptive functions, it is also the source of toxic intermediates and reactive oxygen species and thus is also potentially involved in pathogenic pathways.19 Thus, there is a clear relationship between the regulation of xenobiotic metabolism and different liver pathologies. Another important point is that because of the anatomy of the vascular system, the liver is the first organ to be exposed to a large number of xenobiotics, microbiome metabolites and dietary compounds. It filters many of these substances, but by protecting the rest of the body, it is also a privileged target.

There are several biliary functions in the liver which are involved in food digestion, metabolic fluxes and regulation, as well as waste and xenobiotic elimination.22 The biliary system is integrated in the gastro-intestinal system, e.g. through the secretion of biliary salts (whose production depends on the metabolism of cholesterol), and any dysfunction leads to food intake anomalies. Furthermore, the biliary system is involved in the elimination of degradation products of endogenous compounds, such as haemoglobin. It is also critical for the elimination of exogenous toxicants and is thus part of the detoxification machinery of the liver. Thus, any dysfunction of the biliary system leads to the accumulation of waste and toxicants and therefore to both liver and systemic toxicity. These functions of the biliary system explain why it is so critical for the link between environmental exposures and health.

The immune functions of the liver are diverse.23 First during the foetal period, the liver is a haematopoietic organ and thus contributes to the development of immune cells. Second, the liver includes Kupffer cells (liver-resident macrophages) which contribute to the organism’s immune defence system. In addition, a large number of inflammatory proteins are synthesised by the liver and contribute considerably to the global inflammatory response. For all these reasons, the liver is both a target of the immune system and also a contributor to certain functions of this system, e.g. local and central inflammatory processes.

The liver is also a storage site for a variety of metabolites and signalling compounds. In addition to the classical homeostatic functions of glycogen and to its role in the synthesis and transport of lipids, the liver stores important mediators such as retinoic acid in stellate cells.24

All these liver functions explain why there is a close interaction between this organ and the exposome. The different activities described above explain why the liver is the site where reactive and possibly genotoxic metabolites, as well as biologically active non-genotoxic compounds, are generated. They also explain why infectious agents, as well as endogenous metabolites, are likely to interact with exogenous compounds in disease development. Depending on the mechanisms involved, these diseases could be cancer, fibrosis, inflammation, metabolic dysregulation, or biliary diseases. In this review, we will attempt to establish such links and to identify gaps in knowledge.

Metabolic diseases, integration of contaminants and microbiome effects

As stated above, the central role played by the liver in endogenous and xenobiotic metabolism is based on a dialogue with other key organs. A typical example of such an inter-organ collaboration is the “pancreas-liver” crosstalk which takes place through the secretion of glucagon and insulin, two strategic drivers of the hepatic metabolism of carbohydrates and lipids. While any interference in such a crosstalk is thought to contribute to the development of several chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), these processes are also modulated by the “gut-liver” axis including the gut microbiota that integrates exposome responses to both food contaminants and dietary composition.25 This crosstalk and its metabolic consequences are further discussed in this chapter and are illustrated by specific examples.

The liver plays a central role in the maintenance of lipid homeostasis, and this is accomplished through several functional activities which span from membrane composition and subcellular organelle compartmentalisation, trafficking, energy storage and production, to signal transduction in the modulation of hormone activity and response to hazardous stimuli (Fig. 1).26 Several receptors regulate lipid metabolism (transport, synthesis, lipolysis). Indeed, despite some controversial observations, it has been shown that activation of the Aryl hydrocarbon receptor (AhR), a bHLH/PAS family member, is linked to increased fat accumulation in the liver.27,28 Moreover, several nuclear receptors regulate lipid metabolism, leading to adverse outcomes in some cases. The pregnane X receptor (PXR, alias NR1I2) and constitutive androstane receptor (CAR, alias NR1I3) have been shown in some studies to have opposite effects on lipid metabolism; indeed, while CAR activation leads to lower triglyceride accumulation in the liver,29 PXR triggers liver steatosis through an increase in lipid accumulation.30 However, these conclusions still need to be supported by additional evidence. Furthermore, these effects may be ligand-dependent because of the functional plasticity of those receptors (AhR, PXR, CAR), the biological outcome of their activation being highly dependent on the nature of their ligands.31,32 Central to the liver’s signal transducing role in lipid metabolism is the farnesoid X receptor (FXR, alias NR1H4), another member of the nuclear metabolic receptor superfamily which, among many functions, regulates the synthesis and enterohepatic circulation of bile acids and directly modulates the expression of genes involved in lipid and glucose metabolism, thereby having clear implications for atherosclerotic risk and hepatic fat content.33 The peroxisome proliferator-activated receptors (PPARs: especially PPAR-α, alias NR1C1), which are also nuclear receptors, play key functions in the regulation of lipid synthesis and degradation; their dysregulation has been linked to hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver cancer.34 Whenever the storage capacity of liver cells is overburdened, the accumulation of lipid intermediates like diacylglycerol, ceramides and fatty acyl-CoAs may lead to cell dysfunction and necroinflammation (lipotoxicity). While the process leading to liver injury following hepatocellular accumulation of fat is complex and its turning point not fully unravelled, liver damage appears to be fuelled by the shift of fat storage from subcutaneous to visceral adipose tissue in most patients, with the expansion of visceral adipose tissue being a powerful predictor of metabolic dysfunction-associated fatty liver disease (MAFLD).35

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

Fig. 1.

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.

Many factors influence the occurrence of NAFLD or more generally MAFLD36, including diet, sedentary lifestyle, dysregulated circadian homeostasis, alcohol abuse and tobacco consumption. They impact pathophysiological processes such as metabolism, fibrosis, and inflammation. Alcohol, even at moderate consumption, is also known to accelerate the course of MAFLD, leading to an increased risk of patients developing cirrhosis, clinical decompensation and liver cancer.37 Interestingly, environmental pollutants which include metals, persistent organic pollutants (POPs: dioxins, polychlorinated biphenyl, or per- and polyfluoroalkyl substances [PFASs]) and particulate matter (PM) also influence such mechanisms. During the last few years, there has been a major focus on PFASs, which represent a large class of POPs; several of these compounds are highly persistent and are stored in the liver. Exposure to several of these substances is associated with health outcomes including immunotoxicity, metabolic diseases, reproductive and developmental toxicity, and cancer.38 A recent systematic review and meta-analysis of the literature concluded that there was evidence for liver toxicity in rodents and associations with markers of liver disease in human studies.39 There is also evidence for an impact of these substances on carbohydrate, amino acid, biliary and lipid metabolism under certain conditions.40,41 In a recent metabolomics study in humans and rodents, PFAS exposure was associated with alterations in a variety of metabolic pathways which appeared to be more severe in females.42 PPAR-α is one of the best identified molecular targets of PFASs.43

Moreover, epidemiological studies have recently shown that long-term exposure to ambient pollution (a source of metals and PM) can trigger MAFLD in humans.44 Vulnerability to the development of liver diseases can be increased in males, in obese individuals, and in consumers of a high-fat diet, alcohol, or tobacco.44 Several air pollutants are incriminated, including PM but also NO2 and polyaromatic hydrocarbons (PAHs). NO2 can indeed react with antioxidant molecules (decreasing their levels) and lipids, leading to a lower defence against pro-oxidants. NO2-associated oxidative stress can lead to bron-choconstriction in the lungs but also to remote effects on other organs such as the heart or the immune system, whose functions are significantly reduced. Regarding PAHs, epidemiological and experimental studies suggest that the activation of AhR leads to an inflammatory phenotype accompanied by an epithelial-mesenchymal transition which, in the case of exposure to a high-fat diet, translates into fibrosis. Such an effect is not observed with single exposures alone (high-fat diet or PAHs).27,44,45 This highlights the importance of considering the exposome and integrating the effects of multiple stressors on the development of MAFLD.

The “gut-liver” axis is one of the most historically studied systems in physiology. The intestine absorbs a large quantity of nutrients after digestion, which are taken up by the liver, such as glucose stored in the form of glycogen during the postprandial period. An unbalanced diet, for example one rich in fats, modifies the intestinal mucus, which alters the intestinal barrier46 and results in the penetration of bacterial metabolites into the portal circulation, leading to hepatic inflammation.47 Moreover, certain dietary deficiencies such as choline can lead to NAFLD. Choline is converted to phosphatidylcholine (lecithin) and plays a role in the assembly and secretion of very low-density lipoproteins by the liver. This step prevents the formation of hepatic steatosis due to triglycerides.48 Choline deficiency is associated with a decrease in very low-density lipoprotein production and release, and thus triglyceride accumulation in the liver; this can be easily observed in mouse models.49 In addition, the intestinal microbiota transforms choline into trimethylamine, which decreases the bioavailability of choline and leads to the supply of trimethylamine to the liver, where it is transformed into trimethylamine N-oxide, a metabolite with potent steatogenic effects.50 In addition to the effects of an unbalanced diet, the uptake of several drugs (such as metformin or digoxin) also impacts the activity and composition of the microbiome and can lead to metabolic disruption in the liver.51,52 Finally, if the intestine supplies the liver with the products of digestion (but also certain deleterious metabolites in case of loss of intestinal permeability), the liver influences the functioning of the intestine by secreting bile acids which can further modify the composition of the gut microbiota.

Indeed, trillions of bacteria, fungi, viruses, archaea, and protozoa residing in the distal segments of the gastrointestinal tract form the gut microbiota. When stressed by various disease processes, the human intestinal microbiome undergoes dysbiosis, which accelerates liver fibrosis development through upregulation of inflammation.53 Dysbiosis-related liver injury may be driven either by an excessive immune response, by gut barrier alterations, or by the production of metabolites that modulate signalling pathways following the interaction with receptors in host cells. Some of these metabolites can target the liver due to altered epithelial barrier permeability. For example, short-chain fatty acids, lipopolysaccharide (a pathogen-associated molecular pattern), bioactive lipids and bile acids, as well as many other metabolites, act as regulators of the host metabolism, gut barrier, and inflammation.54 Yet, owing to the lack of cogent investigations demonstrating causality between gut dysbiosis and liver disease, effective therapeutic interventions aimed at modulating the gut microbiome have lagged behind.

During the last few years, the links between exposure to environmental chemicals and dysbiosis of the gut microbiota have been extensively studied. Indeed, the composition and function of the gut microbiota, which is responsible for the production of diverse biologically active molecules, can be altered by a variety of dietary contaminants, ultimately leading to dysbiosis. For example, in several models (mouse, zebrafish and dog), bisphenol A (BPA), a widely used compound in the plastic industry and in food packaging, causes dysbiosis by increasing the populations of two bacterial phyla (Protobacteria and CKC4),55,56 while decreasing Bacteroides, Flexispiraphyla, Oscillospira and Ruminococcaceae.57,58 Such patterns of dysbiosis are reminiscent of those observed in animals fed a high-fat diet (e.g., the imbalance of Protobacteria populations); this raises the possibility that the combined exposure to BPA and a high-fat diet may have additive or synergistic effects. Moreover, recent evidence indicates that exposure to BPA may have sequential effects, leading to dysbiosis and therefore to the accumulation of hepatic lipids and steatosis.59,60 In fact, the attenuated diversity of the intestinal microbiota results in the accumulation of phyla that release endotoxins responsible for increased intestinal permeability. In turn, these events promote extensive inflammation of the liver characterised by the accumulation of IL-1β and IL-6, and tumour necrosis factor-α, leading to the onset of NAFLD.61 All in all, these findings are reminiscent of previous experiments in mice which demonstrated impaired glucose tolerance caused by increased insulin resistance and peripheral tissue inflammation after BPA exposure.62

Along the same line, chemical contaminants such as phthalates (e.g., diethylphthalate or mono(2-ethylhexyl)phta-late), parabens (e.g., methylparaben), biocides (triclosan), pesticides (carbemazine, dichlorodiphenyldichloroethylene [DDE], beta-hexachlorohexane, or pentachlorophenol) have clearly been shown to cause dysbiosis.6369 Among these molecules, DDE and beta-hexachlorohexane are POPs. DDE causes a dysbiosis which strongly correlates with altered blood levels of phospholipids (phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine) and triacylglycerols.69 There are more insights into the mechanisms of action of other POPs, notably the Seveso dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]). TCDD leads to dysbiosis related to the disruption of the enterohepatic cycle, characterised by a significant depletion of faecal bile acids, increased intestinal permeability and delayed transit (due to the depletion of bile acids).70 TCDD also binds to AhR, thereby hijacking the detection of tryptophan metabolites (some of which are endogenous metabolites produced by the microbiota), contributing to altered gut permeability and, subsequently, to the onset of metabolic syndrome in mice.7072 Likewise, a disruption of the metabolome is also observed at the intestinal or blood levels with BPA and the insecticide chlorpyrifos: BPA increases plasma bicarbonate concentrations in association with disruptions of Bacteroides populations,58 while chlorpyrifos alters concentrations of short-chain fatty acids (such as propionate), which are known to prevent NAFLD by reducing transcription of several enzymes involved in de novo lipogenesis.73

Liver infectious diseases with focus on multiple stressors and interaction with chemical stressors

With regards to the global exposome, the liver is an organ particularly exposed to numerous external biological factors such as viruses, parasites, or pathogenic bacteria. Viral hepatitis is caused by five different viruses (hepatitis A, B, C, D, and E virus)74 and these viruses are responsible for hundreds of millions of acute and chronic liver diseases worldwide, especially in Asia and Africa. Parasites can also infect the liver and activate the immune response, resulting in symptoms of acute or chronic hepatitis.74 Among the protozoans, Trypanosoma cruzi, Leishmania species, and the malaria-causing Plasmodium species can all cause liver inflammation.74 Concerning worm-based parasites, the cestode Echinococcus granulosus infects the liver and forms characteristic hepatic hydatid cysts. Fasciola hepatica and Clonorchis sinensis live in the bile ducts and cause progressive hepatitis and fibrosis.74 Bacterial infections of the liver commonly result in pyogenic liver abscesses, acute hepatitis or granulomatous liver disease mainly involving enteric bacteria such as Escherichia coli and Klebsiella pneumoniae, but many other bacteria can induce acute hepatitis.74 The intrahepatic interactions between chemical substances and the biological factors presented above are numerous since the liver is an obligatory pathway for the detoxification of chemical compounds.

Alcohol is undoubtedly the most frequently involved exogenous compound that interacts with biological factors in the liver. Alcohol alone is an important risk factor for chronic liver diseases including fibrosis, but combined with other biological factors, it increases the risk of developing liver pathologies.75,76 Thus, alcohol adversely affects individuals infected with HBV or HCV by promoting viral replication, increasing oxidative stress, and suppressing viral immune responses. The interaction of alcohol with viral hepatitis contributes to an increased risk of developing HBV- or HCV-induced liver fibrosis, end-stage cirrhosis, and even deadly liver cancer. For example, heavy alcohol intake (>80 ml ethanol per day, as defined by IARC, https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Alcohol-Drinking-1988) and concomitant chronic viral hepatitis (HBV or HCV) were associated with a multivariate odds ratio for hepatocellular carcinoma (HCC) of 53.9.77

The exposure to aflatoxin B1 which is a mycotoxin produced by particular fungi (such as Aspergillus species) proliferating on certain foodstuffs increases the risk of HCC associated with both HBV and HCV infections. The co-exposure to aflatoxin B1 and HBV is particularly observed in sub-Saharan Africa and South-East Asia.78 Several studies suggest that exposures to the still commonly used organophosphorus and carbamate pesticides, are additive risk factors to current HCV and HBV infections among males in a rural setting.79 In the south of Vietnam, a study shows that exposure for 10 years or more to organophosphorus pesticides was associated with an increased risk of HCC.80

Although tobacco smoking can cause lung cancer by itself, its association with chronic hepatitis B and C infections is a strong risk factor for liver cancer. A meta-analysis has recently shown that tobacco smoking and HBV infection interact additively in the development of liver cancer.81 Chemical compounds in tobacco smoke have cytotoxic potential that increases necroinflammation and liver fibrosis. Additionally, smoking increases the production of pro-inflammatory cytokines involved in liver cell damage.82 In contrast, several studies report that there is no evidence of an association between marijuana (cannabis) smoking and HCV or HBV infection in leading to significant liver fibrosis progression or to HCC.83

Metals such as arsenic (As), lead (Pb), mercury (Hg), cobalt (Co), copper (Cu), palladium (Pd), iron (Fe) and manganese (Mn) can be very toxic and some are known to cause pathological changes within organs which ultimately lead to cancer.84 Regarding the co-exposure to toxic metals and viral agents inducing hepatitis, it is known that HCV-related hepatitis is associated with altered regulation of metal metabolism; such a deregulation can cause inflammatory changes and oxidative stress, which leads to enhanced HCV replication and reduces the efficacy of antiviral therapy in patients with chronic hepatitis C.85 In addition, copper accumulation in fibrotic livers may contribute to hepatic injury and increase the impacts of HCV infection.85 In contrast, zinc levels in the serum of patients with HCV are associated with a decrease in the severity of disease. An American cross-sectional human health survey based on 70,000 individuals suggests that the toxic effects of lead and cadmium may be associated with an increased susceptibility to chronic HBV infections.86

Cholestatic liver disease

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare cholestatic diseases of the liver, which affect the large- and small-to medium-sized bile ducts, respectively.87,88 Both diseases are characterised by an accumulation of bile acids that likely serves to promote an inflammatory and tissue remodelling cascade, which ultimately leads to hepatic dysfunction and often progresses to end-stage liver disease.22 The overarching pathogeneses of either PSC and PBC are complex and likely involve both genetic and environmental elements that are currently poorly understood. Both diseases are associated with co-morbid autoimmunity and about 70% of patients with PSC have concurrent inflammatory bowel disease.87 From an exposome standpoint, the high incidence of inflammatory bowel disease in these populations is likely of high importance.89 The intestine serves as a barrier to many of the chemicals ingested through the diet. Disruption of that barrier due to inflammation or disrupted microbial homeostasis may increase absorption of and exposure to more exogenous chemicals. This emphasises the importance of assessing intestinal integrity and microbial composition in future studies.

In the past decade, several genome-wide association studies have improved our understanding of the mechanisms underlying PSC and PBC pathogenesis and development, i.e. emphasising the contribution of immunity in disease processes.90 Although genome-wide association studies provide key direction into factors involved in the development of these rare cholestatic diseases, they do not fully account for their exact pathogeneses, nor are they able to identify features of disease progression. Currently, treatments for PBC are primarily focused on altering the bile acid pool and two such treatments, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) have been shown to be beneficial, although many patients do not respond adequately.91 No medical therapy exists for PSC. Therefore, elucidating the pathophysiology of these diseases is essential to improve their management and treatment. To this end, recent attention has been focused on the combined study of exposomics-metabolomics in PSC, with the aim of identifying likely pathogenic environmental exposures along with the metabolic alterations that may contribute to these diseases (Fig. 2).

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

Fig. 2.

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.

In a recent study, an exposomics-metabolomics framework was applied in 40 patients with PSC, 40 patients with PBC and corresponding controls using high-resolution mass spectrometry (HRMS) capable of detecting several tens of thousands of features in plasma samples.16 This approach employs gas chromatography HRMS for detection of semi-volatile compounds and environmental chemicals and liquid chromatography HRMS to measure endogenous metabolites (there is overlap between the two platforms). The study carried out separate exposome-wide and metabolome-wide association studies of PSC and PBC (results for PSC can be seen inFig. 2). Subsequently, these analyses reported chemicals and pathways associated with each disease. These elements were then integrated after applying an exposome-metabolome correlation matrix to describe for the first time exposure-response networks in PSC and PBC.16 The study revealed many environmental chemicals with known hepatotoxic properties and endogenous metabolic pathways potentially underlying liver malfunction. The authors reported 54 compounds associated with PSC while none were associated with PBC. Attempted annotation of the 54 PSC-associated compounds using data available in the NIST 2017 library identified only one high-confidence match, underscoring a major challenge to gaining biological insight using untargeted gas chromatography HRMS. This chemical was terbucarb, a carbamate pesticide, a class of insecticide widely used in household, agricultural, and industrial applications.92 The study also identified two fungicides, fenpropimorph and spiroxamine, that were elevated in patients with PSC and PBC, respectively.16 These chemicals inhibit cholesterol metabolism in mammalian cells, leading to accumulation of polar sterols.93 Subsequently, pathway enrichment analysis found the bile acid biosynthesis pathway included the greatest number of disease-associated metabolites in both PSC and PBC, consistent with known mechanisms of cholestatic liver disease.94 Finally, an integrative network analysis that evaluated the correlation between disease-associated chemicals identified in exposome-wide association studies and the enriched metabolic pathways from metabolome-wide association studies, showed that the largest cluster in PSC centred on aldicarb sulfone, a commercial-use carbamate pesticide that is classified as an extremely hazardous substance in the United States and is no longer being distributed. Of note, this cluster did involve 17 of 27 PSC-associated pathways16

This recent report supports a role for environmental chemicals in contributing to the pathogenesis of PSC and PBC and presents a novel move towards adapting exposomic methodologies for precision medicine approaches to the study of liver disease. It should be noted that this was a relatively small sample size. A larger follow-up study of plasma-based exposomics-metabolomics, which includes 1,600 patients with PSC, PBC and controls is currently underway and will likely fill some knowledge gaps and provide the framework for new therapies for these enigmatic cholestatic liver diseases.

Liver cancers

The predominant primary liver cancers are HCC and cholangiocarcinoma. Both cancers are usually diagnosed at an advanced stage, which may explain their poor prognoses despite some progress in treatment. In this section we will focus on HCC, which is the most frequent liver cancer. In the vast majority of cases, HCC develops on a background of cirrhosis after a long evolution of chronic liver disease, mainly caused by HBV or HCV infection, alcohol consumption or toxins like aflatoxins, aristolochic acid and cyanotoxins, as well as drugs and occupational chemicals.95 Whatever the risk factors, cirrhotic high-grade dysplastic nodules are the most frequent pre-neoplastic lesion from which HCC develops. However, HCC can also develop on a non-cirrhotic liver, this is particularly frequent in the context of NASH or HBV infection. Exceptionally, HCC can also occur in a normal liver through the malignant transformation of a hepatocellular adenoma with specific risk factors: high oestrogen exposure, including oral contraception, androgen intake, genetic metabolic diseases (such as glycogenosis), or high alcohol consumption96 Therefore, the known exposome associated with HCC is diverse and it has expanded considerably over the years.

The mechanisms leading to HCC following exposure to environmental stressors are mostly indirect and related to the inflammation generated by the evolution of chronic liver disease, during which inflammation and metabolic pressures favour the accumulation of epigenetic and genetic alterations in hepatocytes.95,97,98 Toxin exposure can also directly induce genomic alterations in cancer driver genes in hepatocytes before the malignant transformation: DNA viruses (HBV and adeno-associated virus type 2) can activate oncogenes through viral insertional mutagenesis, while aflatoxin B1 exposure, tobacco smoking and alcohol consumption induce DNA damage during life – mutational signatures specific for each risk factor have been observed in HCC and in normal tissues.97,99101 Moreover, the individual genetic background can modulate the risk and the severity of either chronic liver disease or cancer.102,103 Genetic polymorphisms in several genes (PNPLA3, TM6SF2 and HSD17B13) that encode for proteins involved in lipid metabolism modulate the severity of NASH and alcohol-related chronic liver diseases. These gene polymorphisms also modulate the risk of HCC associated with either one of these risk factors.102105 Other genetic polymorphisms in WNT3A/WNT9A or in TERT modulate the risk of HCC without impacting on the chronic liver disease. Finally, alongside genetic polymorphisms, exposure to different risk factors can have additive or synergistic effects on liver cancer development. The most demonstrative example is the co-occurrence of aflatoxin B1 exposure, with HBV viral infection and the null-polymorphism in GSTM1 (glutathione-S-transferase mu), coding for an enzyme that detoxifies aflatoxin B1. Interestingly, these three risk factors cooperate together to drastically increase the risk of HCC in Africa and in East Asia by more than 90-fold compared to individuals without any of these risk factors.106,107

During the last few years, several behavioural and environmental exposures have been shown to increase the risk of liver cancers in humans. Smoking was shown to increase the risk of HCC by more than 80%.108 Interestingly the increased risk of HCC tended to decrease considerably in former smokers and was absent or negligible after 30 years of smoking cessation. The increased risk of HCC related to smoking is of a similar magnitude as that of alcohol abuse. Also, both alcohol abuse and smoking increase the risk of biliary tract cancers.109 In contrast, coffee consumption and aspirin intake were associated with a decreased risk of HCC.110,111

Evidence for environmental exposure and increased HCC has also increased considerably lately. Air pollution has been shown to be associated with a moderate increase in the risk of HCC (15% increase).112 Associations were strongest with air pollution components NO2, PM2.5 (particulate matter with a radius smaller than 2.5 μm) and black carbon.113 It should be noted that PM, including PM2.5, carry (in their compositions or by adsorption) a variety of compounds that are carcinogenic, such as metals and PAHs. Exposure to other environmental stressors has also been associated with increased risk of HCC: metals including arsenic and cadmium, polychlorinated biphenyl, PAHs, pesticides, organic solvents, and PFASs.79,114117 In a recent case-control study involving 100 individuals, high blood levels of a major PFAS, perfluorooctane sulfonic acid, were associated with a 4.5-fold increase in the risk of HCC.118 A metabolome-wide association study and pathway-enrichment analysis showed that disruption of key metabolic pathways by perfluorooctane sulfonic acid may contribute to such an outcome. While the weight of evidence linking these exposures to HCC may be different, the global conclusion is that the extent of the exposome linked to HCC risk is much larger than previously thought.

Interestingly, analysis of the DNA mutational profile of different HCCs has identified mutational signatures associated with specific risk factors, notably viruses, alcohol and toxins.99 Therefore, the molecular profile of the genetic alterations accumulated in the liver and in HCC reflects exposome components that triggered the carcinogenic process during life (Fig. 3). Using such large-scale profiling could improve our knowledge of the environmental determinants of HCCs. The same could be true for epigenetic profiling, such as miRNA profiles or the DNA methylation landscape.119 On the other end of the biological mechanisms, the identification of initial events such as the activation of nuclear receptors or the modulation of xenobiotic metabolising enzyme activities could also be relevant. However, concerning the nuclear receptors implicated in HCC, there are still a lot of discussions and uncertainties, mostly related to the relevance of animal studies to human pathogenesis.120 These controversies particularly concerning the receptors PPAR-α and CAR (whose expression levels and ligand patterns significantly differ in humans and rodents) have considerably delayed our capacity to correctly predict the hepatic carcinogenicity of industrial substances. Yet a cross-species understanding of the biological pathways associated with exposure to stressors on one hand and cellular transformation on the other hand would be extremely useful for predicting the impacts of exposome components.

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

Fig. 3.

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.99 HCC, hepatocellular carcinoma.

Fewer well-organised studies were devoted to the role of environmental exposures on cholangiocarcinoma. Anatomically, cholangiocarcinoma is categorised into three subtypes: perihilar or Klatskin’s tumour, intrahepatic, and extrahepatic. The pathogenesis of each type is likely distinct and better studies are needed to classify these tumours on a molecular basis. Unfortunately, the anatomic classification was not followed properly for a variety of reasons, and thus, past environmental studies should be interpreted with caution.121 Such reported exposures include liver parasites, dioxin and dioxin-like compounds, nitrosamines, tobacco smoking, asbestos, and alcohol consumption as well as several occupational hazards.121 Interestingly psychosocial stress also appears to play a role.122124

Other exposure-related liver diseases

Several liver diseases are fully or partially related to changes in exposures but are usually considered as independent entities. We believe they should be discussed in the context of the exposome and summaries of these conditions and their relation to the exposome are developed below.

Drug-induced liver injury (DILI)

Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event following exposure to toxic doses of a compound (intrinsic DILI) or as an unpredictable event with drugs in common use (idiosyncratic DILI).125 While most of the cases reported in the US and Europe are secondary to conventional medications, traditional/complimentary and dietary supplements are the main causative agents of DILI in Asia.126 Liver harm develops when the offending agents, often lipophilic drugs, are converted to reactive metabolites that have the potential to covalently bind to proteins and cause cellular organelle stress. This process may lead to hepatocyte death, which is mediated either by the collapse of mitochondrial function and necrosis, or by activation of regulated cell-death pathways.127 DILI can present as any recognised pattern of liver enzyme derangement in susceptible individuals in whom the disease process is framed by genetic and environmental risk modulators like advancing age, sex, alcohol intake and underlying liver disease. Accordingly, the diagnosis of DILI is almost invariably challenging, requiring a step-by-step approach with accurate analysis of the temporal sequence of events, exclusion of alternative causes and navigation through the RUCAM (Roussel Uclaf Causality Assessment Method) algorithm or its revised version RECAM (Revised Electronic version of RUCAM). In selected cases, HLA genotyping may improve causality assessment and differential diagnosis with autoimmune hepatitis.128 The overwhelming importance of a prompt assessment of causality relies on the potentially severe outcome of DILI that spans from a trivial illness to acute liver failure and the need for liver transplantation.

Unbalanced homeostasis of iron

Unbalanced homeostasis of iron is a good illustration of genome-exposome interactions in liver diseases. Iron is essential for the production of heme and iron-sulphur components of proteins and enzymes involved in vital biological processes. Its dysregulation may result in either deficiency or overload syndromes. Iron overload has the propensity to damage cell components owing to the fact that iron accepts and releases electrons, i.e. has the ability to cause oxidative stress (like lipid peroxidation) leading to shrunken and electrondense mitochondria and cell death (ferroptosis). Key genes related to ferroptosis include GPX4 (glutathione peroxidase-4), ACSL4 (acyl-CoA synthetase long-chain family member-4), CBR3 (carbonyl reductase [NADPH] 3), and PTGS2 (prostaglandin peroxidase synthase-2). Notably, ferroptosis is involved in different pathological conditions, including neurological and liver and kidney diseases and different cancers.129 Central to iron homeostasis is the liver peptide hepcidin, which regulates serum iron levels through degradation of ferroportin in iron-absorptive enterocytes and in macrophages. Dysregulation of this pathway can be observed in steatohepatitis (NASH), alcohol-related liver disease, DILI, viral hepatitis, and haemochromatosis.130 In haemochromatosis, mutations in genes of the hepcidin-ferroportin axis lead to increased iron absorption, high transferrin saturation and increased toxicity from non-transferrin bound iron species, which favours the onset of cirrhosis, liver cancer and extrahepatic diseases like diabetes, osteoporosis, arthropathy and, in patients with early onset haemochromatosis, hypogonadotrophic hypogonadism, hypothyroidism and heart failure. The commonest form of haemochromatosis in Caucasians is due to homozygous HFE(C282Y) mutations, but the exact disease penetrance is dependent on age and sex.131 Congenital iron overload disease also occurs in individuals with alpha and beta thalassemia, syndromic and non-syndromic congenital sideroblastic anaemia, congenital dyserythropoietic anaemia, hypotransferrinaemia and in diseases related to divalent metal transporter 1 mutations. Genetically driven regional accumulation of iron and ferritin may occur, causing harm to the brain and lenses, whereas acquired iron overload due to chronic blood transfusions, inflammation or anaemia may have multiple clinical consequences.130

Dysregulation of copper homeostasis and Wilson disease

Dysregulation of copper homeostasis and Wilson disease is another relevant example of genome-exposome interactions. Copper is an essential metal required for the function of many metalloproteins that serve numerous metabolic needs of liver cells, including building of nascent ceruloplasmin, which carries more than 95% of the total copper in plasma.132 Copper compounds are also active plant protection products, and it is likely that certain populations are exposed to high levels of copper. As excess hepatic copper is excreted via the biliary pathway into faeces, cholestasis is responsible for both hepatic retention and increased circulating levels of copper. The prototype clinical syndrome caused by excessive retention of copper is Wilson disease, a familial, neurological lethal disease accompanied by cirrhosis, which results from inactivation of the gene encoding a metal-transporting P-type ATPase, ATP7B, found mainly in hepatocytes. When exceeding storage capacity, copper deposits in various organs, especially the brain, kidneys and cornea. The disease may present with a broad spectrum of liver disease that ranges from asymptomatic to cirrhosis and acute liver failure. In teenagers, liver disease usually precedes neurologic manifestations by years, while most adult patients with neurologic symptoms have some degree of liver disease at presentation. Notably, acute liver failure occurs mostly among women. In the US it accounts for up to 12% of all listings for acute liver failure and is almost invariably fatal if not treated with emergency transplantation. Severe liver injury may cause the sudden release of copper into the blood and cause acute intravascular haemolysis with anaemia, haemoglobinuria, jaundice and progression to renal failure.133 Wilson disease should be differentiated from aceruloplasminemia, MDR3 (multidrug resistance protein 3) deficiency, and certain congenital disorders of glycosylation through genetic, laboratory and clinical investigations.

Conclusions and perspectives

The range of external factors that compose the liver exposome is extremely diverse and several of its components have been linked to liver diseases in clinical, epidemiological, and experimental studies (Fig. 4). Some important conclusions can be drawn from the analysis of the impact of various exposures on liver diseases:

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

Fig. 4.

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.

  • One exposure, several pathologies. The analysis of the contribution of the exposome to different liver diseases shows that several exposures are common to different liver pathologies, for example alcohol consumption, smoking, viral infections, and some chemical exposures. This is not surprising as these diseases are linked to each other, for example the progression from MAFLD or viral hepatitis to cirrhosis to HCC.

  • Combination of different exposures. Another important observation is that often a combination of different exposures is involved in disease development or progression, for example the combination of viral agents and chemicals for the progression of viral disease and HCC, or chemicals, dietary imbalance and dysbiosis for the progression of metabolic diseases and the likely contribution of multiple chemicals such as drugs, environmental and occupational chemicals in the progression of liver diseases. Indeed, it is likely that most liver disease results from a combination of multiple factors necessitating an exposome-based approach.

  • Systemic and liver-specific impacts. While some risk factors like smoking, air pollution or obesity display systemic effects at the organism level with liver pathology being one component of a larger disease, other factors such as hepatitis viruses, mycotoxins, certain drugs and chemicals, elicit a more specific liver disease. Obviously both types of stressors could have combined effects.

All these considerations highlight the relevance of the exposome concept for improving our understanding of liver disease pathogenesis, with the aim of guiding prevention, biomarker identification and ultimately treatment.

There are still many unknowns concerning the actual contribution of the exposome to liver pathologies. In this regard, there is huge interest in the development of technologies and approaches that would fill these gaps. As highlighted in different sections of this review, in our view, the most promising technologies and approaches are the following:

  • A combined and integrated exposomics-metabolomics framework to better characterise liver diseases, identify both exogenous exposures and endogenous processes and establish putative links between these two profiles.4

  • Further development of chemical mixture studies to assess the effect of large mixtures of chemicals and their interaction with other stressors.134 While drug-drug interactions have been extensively studied, it is important to extend this research to other types of chemicals and at a much larger scale. Since the liver is the primary organ of xenobiotic metabolism, mixtures studies should encompass parent molecules and their metabolites.

  • Development of genomic and epigenomic mutational signatures correlated with specific exposures. This would help to link the observed molecular description of liver samples (e.g., HCC or hepatocellular adenoma) with likely risk factors and exposures. Such approaches could benefit from both clinical and toxicological studies.

  • A systematic characterisation of the microbiome because of its significant influence on organ metabolomes and since dysbiosis has been associated with a variety of diseases including metabolic and biliary diseases.135 Importantly, disruption of gut permeability is linked to exposure to several chemicals and dysbiosis. Finally, there are sex-specific differences in microbial composition, which could account for differences in disease susceptibility in addition to hormonal effects.136

  • A strategy to better integrate in vivo/in vitro and human studies to improve prediction. Such a strategy could involve a systems biology approach and biological pathway identification in order to better translate experimental approaches into human-relevant knowledge.5

Obviously, all these approaches will benefit from comprehensive clinical studies of liver diseases in which an exposome approach has been integrated. While in many such studies, genomics and other omics technologies have been included, it is time to introduce and integrate exposomics with the other omics.6 This will primarily concern chemical exposomics but, as mentioned earlier, a more extensive microbiological characterisation is also relevant (microbiome, viral and parasitic agents) as well as a more extensive characterisation of physical stressors. The social component of the exposome is also critical for liver diseases, particularly concerning the social determinants of diets, dysbiosis and addictive behaviours.

We should also be aware of the limitations of the exposome framework in epidemiological and clinical studies. Indeed, by increasing the number of biomarkers and of factors influencing liver diseases, very large cohorts or clinical studies are needed to meet statistical requirements. This may not be possible for certain diseases and in all cases may prove to be very costly. Thus, it is critical to assess the cost-effectiveness of each study design. Despite these limitations, exposome studies may prove to be a hypothesis-generating first step. Hypothesis-driven studies will still be needed to confirm and to provide more precision on the causal links between exposures and outcomes.

Liver studies have benefited from the combination of clinical and experimental approaches. This should now be further developed with the exposome concept in mind. Experimental 2-dimensional or 3-dimensional model systems have been used and can still be further developed to link clinical and experimental observations.137 Improving assessment of toxicity using these new methodologies could support preventive measures and protect public health. Furthermore, the combination of clinical and experimental studies could support the development of new biomarkers and lead to the development of new therapies. The latter could consist of dietary or microbial interventions or the development of drugs targeting critical biological pathways.

Supplementary Material

Supp for Main manuscript

Key points.

  • The liver plays an important role in xenobiotic metabolism and elimination and is therefore a target of the chemical exposome.

  • Chemicals, infectious and physical agents are important determinants of different liver diseases.

  • Both traditional targeted studies and non-targeted exposomics studies have revealed the links between exposure to chemicals and liver diseases.

  • The combination of different stressors, e.g. chemical and viral agents, plays a role in liver disease pathogenesis.

  • Liver diseases can be related to exposure to liver-specific stressors, e.g. viral hepatitis, or to stressors displaying more systemic effects, e.g. air pollution.

  • There is increasing concern about the liver toxicity of certain chemicals such as endocrine disruptors, pesticides and per- and polyfluoroalkyl substances.

  • New methodologies including high-resolution mass spectrometry, genomic, epigenomic and metagenomic signature detection and computational approaches will further develop research in this field.

Financial support

This work was supported by NIH RC2 DK 118619 and R01 DK126691 (to KNL and GWM) and U2C ES030163 (to GWM) and by recurrent funding from Université Paris Cité and Inserm unit 1124.

Abbreviations

AhR

aryl hydrocarbon receptor

beta-HCH

beta-hexachlorohexane

BPA

bisphenol A

CAR

constitutive androstane receptor (NR1I3)

DDE

dichlorodiphenyldichloroethylene

DEP

diethylphthalate

DILI

drug-induced liver injury

HRMS

high-resolution mass spectrometry

MEHP

mono(2-ethylhexyl)phthalate

NAFLD

non-alcoholic fatty liver disease

MAFLD

metabolic dysfunction-associated fatty liver disease

PAHs

polycyclic aromatic hydrocarbons

PBC

primary biliary cholangitis

PFASs

per- and polyfluoroalkyl substances

PM

particulate matter

POP

persistent organic pollutant

PPAR

peroxisome proliferator-activated receptor

PSC

primary sclerosing cholangitis

PXR

pregnane X receptor (NR1I2)

TCDD

2,3,7,8-tetrachlorodibenzo-p-dioxin

Footnotes

Conflict of interest

M Colombo: speaker bureau and advisory boards (Target HCC COST Galapagos Exelixis).

Please refer to the accompanying ICMJE disclosure forms for further details.

Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhep.2023.02.034.

References

  • [1].Wild CP. Complementing the genome with an « exposome »: the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol Août 2005;14(8):1847–1850. [DOI] [PubMed] [Google Scholar]
  • [2].Rappaport SM. Redefining environmental exposure for disease etiology. NPJ Syst Biol Appl 2018;4:30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Miller GW, Jones DP. The nature of nurture: refining the definition of the exposome. Toxicol Sci Off J Soc Toxicol Janv 2014;137(1):1–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Vermeulen R, Schymanski EL, Barabási AL, Miller GW. The exposome and health: where chemistry meets biology. Science 24 Jan 2020;367(6476):392–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Barouki R, Audouze K, Becker C, Blaha L, Coumoul X, Karakitsios S, et al. The exposome and toxicology: a win-win collaboration. Toxicol Sci Off J Soc Toxicol 28 Févr 2022;186(1):1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Price EJ, Vitale CM, Miller GW, David A, Barouki R, Audouze K, et al. Merging the exposome into an integrated framework for « omics » sciences. IScience 18 Mars 2022;25(3):103976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Niedzwiecki MM, Walker DI, Vermeulen R, Chadeau-Hyam M, Jones DP, Miller GW. The exposome: molecules to populations. Annu Rev Pharmacol Toxicol 6 Jan 2019;59:107–127. [DOI] [PubMed] [Google Scholar]
  • [8].Barouki R, Audouze K, Coumoul X, Demenais F, Gauguier D. Integration of the human exposome with the human genome to advance medicine. Biochimie Sept 2018;152:155–158. [DOI] [PubMed] [Google Scholar]
  • [9].Wild CP, Scalbert A, Herceg Z. Measuring the exposome: a powerful basis for evaluating environmental exposures and cancer risk. Environ Mol Mutagen Août 2013;54(7):480–499. [DOI] [PubMed] [Google Scholar]
  • [10].Vineis P, Fecht D. Environment, cancer and inequalities-The urgent need for prevention. Eur J Cancer Oxf Engl 1990 Nov 2018;103:317–326. [DOI] [PubMed] [Google Scholar]
  • [11].Koual M, Tomkiewicz C, Cano-Sancho G, Antignac JP, Bats AS, Coumoul X. Environmental chemicals, breast cancer progression and drug resistance. Environ Health Glob Access Sci Source 17 Nov 2020;19(1):117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].López-Cervantes JP, Lønnebotn M, Jogi NO, Calciano L, Kuiper IN, Darby MG, et al. The exposome approach in allergies and lung diseases: is it time to define a preconception exposome? Int J Environ Res Public Health 1 Déc 2021;18(23):12684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Cheung AC, Walker DI, Juran BD, Miller GW, Lazaridis KN. Studying the exposome to understand the environmental determinants of complex liver diseases. Hepatol Baltim Md Janv 2020;71(1):352–362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Colombo M, Barouki R. Expanding the liver exposome: should hepatologists care about air pollution? J Hepatol Mars 2022;76(3):495–497. [DOI] [PubMed] [Google Scholar]
  • [15].Papaioannou N, Distel E, de Oliveira E, Gabriel C, Frydas IS, Anesti O, et al. Multi-omics analysis reveals that co-exposure to phthalates and metals disturbs urea cycle and choline metabolism. Environ Res Janv 2021;192:110041. [DOI] [PubMed] [Google Scholar]
  • [16].Walker DI, Juran BD, Cheung AC, Schlicht EM, Liang Y, Niedzwiecki M, et al. High-resolution exposomics and metabolomics reveals specific associations in cholestatic liver diseases. Hepatol Commun Mai 2022;6(5):965–979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Nelson DR, Kamataki T, Waxman DJ, Guengerich FP, Estabrook RW, Feyereisen R, et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol Févr 1993;12(1):1–51. [DOI] [PubMed] [Google Scholar]
  • [18].Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol 20 Janv 2015;28(1):38–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Barouki R Linking long-term toxicity of xeno-chemicals with short-term biological adaptation. Biochimie Sept 2010;92(9):1222–1226. [DOI] [PubMed] [Google Scholar]
  • [20].Barouki R, Coumoul X, Fernandez-Salguero PM. The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett 31 Juill 2007;581(19):3608–3615. [DOI] [PubMed] [Google Scholar]
  • [21].Ambolet-Camoit A, Bui LC, Pierre S, Chevallier A, Marchand A, Coumoul X, et al. 2,3,7,8-tetrachlorodibenzo-p-dioxin counteracts the p53 response to a genotoxicant by upregulating expression of the metastasis marker agr2 in the hepatocarcinoma cell line HepG2. Toxicol Sci Off J Soc Toxicol Juin 2010;115(2):501–512. [DOI] [PubMed] [Google Scholar]
  • [22].Lazaridis KN, LaRusso NF. The cholangiopathies. Mayo Clin Proc Juin 2015;90(6):791–800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Guillot A, Tacke F. Liver macrophages: old dogmas and new insights. Hepatol Commun Juin 2019;3(6):730–743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Shirakami Y, Lee SA, Clugston RD, Blaner WS. Hepatic metabolism of ret-inoids and disease associations. Biochim Biophys Acta Janv 2012;1821(1):124–136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Fernández-Musoles R, García Tejedor A, Laparra JM. Immunonutritional contribution of gut microbiota to fatty liver disease. Nutr Hosp 17 Févr 2020;37(1):193–206. [DOI] [PubMed] [Google Scholar]
  • [26].Enjoji M, Kohjima M, Nakamuta M. Lipid metabolism and the liver. In: Ohira H, éditeur, editors. The liver in systemic diseases [Internet]. Tokyo: Springer Japan; 2016. p. 105–122 [cité 28 Nov 2022] Disponible sur: http://link.springer.com/10.1007/978-4-431-55790-6_6. [Google Scholar]
  • [27].Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, et al. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect 2017;125(3):428–436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Bock KW. Aryl hydrocarbon receptor (AHR) functions: balancing opposing processes including inflammatory reactions. Biochem Pharmacol Août 2020;178:114093. [DOI] [PubMed] [Google Scholar]
  • [29].Yan J, Chen B, Lu J, Xie W. Deciphering the roles of the constitutive androstane receptor in energy metabolism. Acta Pharmacol Sin Janv 2015;36(1):62–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Mackowiak B, Hodge J, Stern S, Wang H. The roles of xenobiotic receptors: beyond chemical disposition. Drug Metab Dispos Biol Fate Chem Sept 2018;46(9):1361–1371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Guyot E, Chevallier A, Barouki R, Coumoul X. The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications. Drug Discov Today Mai 2013;18(9–10):479–486. [DOI] [PubMed] [Google Scholar]
  • [32].Chai SC, Cherian MT, Wang YM, Chen T. Small-molecule modulators of PXR and CAR. Biochim Biophys Acta Sept 2016;1859(9):1141–1154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Panzitt K, Wagner M. FXR in liver physiology: multiple faces to regulate liver metabolism. Biochim Biophys Acta Mol Basis Dis 1 Juill 2021;1867(7):166133. [DOI] [PubMed] [Google Scholar]
  • [34].Wang Y, Nakajima T, Gonzalez FJ, Tanaka N. PPARs as metabolic regulators in the liver: lessons from liver-specific PPAR-null mice. Int J Mol Sci [Internet] 17 Mars 2020;21(6):2061 [cité 28 Nov 2022]. Disponible sur: https://www.mdpi.com/1422-0067/21/6/2061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Bedossa P, Tordjman J, Aron-Wisnewsky J, Poitou C, Oppert JM, Torcivia A, et al. Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity. Gut Sept 2017;66(9):1688–1696. [DOI] [PubMed] [Google Scholar]
  • [36].Fouad Y, Waked I, Bollipo S, Gomaa A, Ajlouni Y, Attia D. What’s in a name? Renaming « NAFLD » to « MAFLD. Liver Int Off J Int Assoc Study Liver Juin 2020;40(6):1254–1261. [DOI] [PubMed] [Google Scholar]
  • [37].Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterol Août 2018;155(2):443–457.e17. [DOI] [PubMed] [Google Scholar]
  • [38].Fenton SE, Ducatman A, Boobis A, DeWitt JC, Lau C, Ng C, et al. Per- and polyfluoroalkyl substance toxicity and human health review: current state of knowledge and strategies for informing future research. Environ Toxicol Chem [Internet] Mars 2021;40(3):606–630 [cité 28 Nov 2022]. Disponible sur: https://onlinelibrary.wiley.com/doi/10.1002/etc.4890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Ducatman A, Fenton SE. Invited perspective: PFAS and liver disease: bringing all the evidence together. Environ Health Perspect [Internet] Avr 2022;130(4):041303 [cité 28 Nov 2022]. Disponible sur: https://ehp.niehs.nih.gov/doi/10.1289/EHP11149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Roth K, Yang Z, Agarwal M, Liu W, Peng Z, Long Z, et al. Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury. Environ Int [Internet] Déc 2021;157:106843 [cité 28 nov 2022]. Disponible sur: https://linskinghub.elsevier.com/retrieve/pii/S0160412021004682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Liu JJ, Cui XX, Tan YW, Dong PX, Ou YQ, Li QQ, et al. Per- and perfluoroalkyl substances alternatives, mixtures and liver function in adults: a community-based population study in China. Environ Int [Internet] Mai 2022;163:107179 [cité 28 nov 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0160412022001052. [DOI] [PubMed] [Google Scholar]
  • [42].Sen P, Qadri S, Luukkonen PK, Ragnarsdottir O, McGlinchey A, Jäntti S, et al. Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease. J Hepatol [Internet] Févr 2022;76(2):283–293 [cité 28 Nov 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0168827821021048. [DOI] [PubMed] [Google Scholar]
  • [43].Behr AC, Plinsch C, Braeuning A, Buhrke T. Activation of human nuclear receptors by perfluoroalkylated substances (PFAS). Toxicol In Vitro [Internet] Févr 2020;62:104700 [cité 28 Nov 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0887233319306289. [DOI] [PubMed] [Google Scholar]
  • [44].Guo B, Guo Y, Nima Q, Feng Y, Wang Z, Lu R, et al. Exposure to air pollution is associated with an increased risk of metabolic dysfunction-associated fatty liver disease. J Hepatol Mars 2022;76(3):518–525. [DOI] [PubMed] [Google Scholar]
  • [45].Larigot L, Benoit L, Koual M, Tomkiewicz C, Barouki R, Coumoul X. Aryl hydrocarbon receptor and its diverse ligands and functions: an exposome receptor. Annu Rev Pharmacol Toxicol 6 Janv 2022;62:383–404. [DOI] [PubMed] [Google Scholar]
  • [46].Liquori GE, Mastrodonato M, Mentino D, Scillitani G, Desantis S, Portincasa P, et al. In situ characterization of O-linked glycans of Muc2 in mouse colon. Acta Histochem [Internet] Nov 2012;114(7):723–732 [cité 28 Nov 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0065128111001929. [DOI] [PubMed] [Google Scholar]
  • [47].Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, Wiest R, et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol [Internet] Déc 2019;71(6):1216–1228 [cité 28 Nov 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0168827819304714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Mehedint MG, Zeisel SH. Cholineʼs role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Metab Care [Internet] Mai 2013;16(3):339–345 [cité 28 Nov 2022]. Disponible sur: http://journals.lww.com/00075197-201305000-00016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Grattagliano P, Caraceni I, Portincasa P, Domenicali M, Palmieri VO, Trevisani F, Bernardi M, et al. Adaptation of subcellular glutathione detoxification system to stress conditions in choline-deficient diet induced rat fatty liver. Cell Biol Toxicol [Internet] Nov 2003;19(6):355–366 [cité 28 Nov 2022]. Disponible sur: http://link.springer.com/10.1023/B:CBTO.0000013341.73139.fc. [DOI] [PubMed] [Google Scholar]
  • [50].Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterol [Internet] Mars 2011;140(3):976–986 [cité 28 Nov 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0016508510017397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Weersma RK, Zhernakova A, Fu J. Interaction between drugs and the gut microbiome. Gut Août 2020;69(8):1510–1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Lindell AE, Zimmermann-Kogadeeva M, Patil KR. Multimodal interactions of drugs, natural compounds and pollutants with the gut microbiota. Nat Rev Microbiol Juill 2022;20(7):431–443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol Mars 2020;72(3):558–577. [DOI] [PubMed] [Google Scholar]
  • [54].de Vos WM, Tilg H, Van Hul M, Cani PD. Gut microbiome and health: mechanistic insights. Gut Mai 2022;71(5):1020–1032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Makarova K, Siudem P, Zawada K, Kurkowiak J. Screening of toxic effects of bisphenol A and products of its degradation: zebrafish (Danio rerio) embryo test and molecular docking. Zebrafish Oct 2016;13(5):466–474. [DOI] [PubMed] [Google Scholar]
  • [56].Liu Y, Yao Y, Li H, Qiao F, Wu J, Du ZY, et al. Influence of endogenous and exogenous estrogenic endocrine on intestinal microbiota in zebrafish. PLoS One 2016;11(10):e0163895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [57].Reddivari L, Veeramachaneni DNR, Walters WA, Lozupone C, Palmer J, Hewage MKK, et al. Perinatal bisphenol A exposure induces chronic inflammation in rabbit offspring via modulation of gut bacteria and their metabolites. Msystems Oct 2017;2(5):000933–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Koestel ZL, Backus RC, Tsuruta K, Spollen WG, Johnson SA, Javurek AB, et al. Bisphenol A (BPA) in the serum of pet dogs following short-term consumption of canned dog food and potential health consequences of exposure to BPA. Sci Total Environ 1 Févr 2017;579:1804–1814. [DOI] [PubMed] [Google Scholar]
  • [59].Hong T, Jiang X, Zou J, Yang J, Zhang H, Mai H, et al. Hepatoprotective effect of curcumin against bisphenol A-induced hepatic steatosis via modulating gut microbiota dysbiosis and related gut-liver axis activation in CD-1 mice. J Nutr Biochem 30 Juin 2022;109:109103. [DOI] [PubMed] [Google Scholar]
  • [60].Feng D, Zhang H, Jiang X, Zou J, Li Q, Mai H, et al. Bisphenol A exposure induces gut microbiota dysbiosis and consequent activation of gut-liver axis leading to hepatic steatosis in CD-1 mice. Environ Pollut Barking Essex 1987 Oct 2020;265(Pt A):114880. [DOI] [PubMed] [Google Scholar]
  • [61].Feng G, Li XP, Niu CY, Liu ML, Yan QQ, Fan LP, et al. Bioinformatics analysis reveals novel core genes associated with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Gene 5 Juin 2020;742:144549. [DOI] [PubMed] [Google Scholar]
  • [62].Malaisé Y, Menard S, Cartier C, Gaultier E, Lasserre F, Lencina C, et al. Gut dysbiosis and impairment of immune system homeostasis in perinatally-exposed mice to Bisphenol A precede obese phenotype development. Sci Rep 3 Nov 2017;7(1):14472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Hu J, Raikhel V, Gopalakrishnan K, Fernandez-Hernandez H, Lambertini L, Manservisi F, et al. Effect of postnatal low-dose exposure to environmental chemicals on the gut microbiome in a rodent model. Microbiome 14 Juin 2016;4(1):26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [64].Wang C, Yue S, Hao Z, Ren G, Lu D, Zhang Q, et al. Pubertal exposure to the endocrine disruptor mono-2-ethylhexyl ester at body burden level caused cholesterol imbalance in mice. Environ Pollut Barking Essex 1987 Janv 2019;244:657–666. [DOI] [PubMed] [Google Scholar]
  • [65].Jin Y, Zeng Z, Wu Y, Zhang S, Fu Z. Oral exposure of mice to carbendazim induces hepatic lipid metabolism disorder and gut microbiota dysbiosis. Toxicol Sci Off J Soc Toxicol Sept 2015;147(1):116–126. [DOI] [PubMed] [Google Scholar]
  • [66].Zhang Q, Caudle WM, Pi J, Bhattacharya S, Andersen ME, Kaminski NE, et al. Embracing systems toxicology at single-cell resolution. Curr Opin Toxicol [Internet] Août 2019;16:49–57 [cité 14 Nov 2021]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S2468202019300063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Kan H, Zhao F, Zhang XX, Ren H, Gao S. Correlations of gut microbial community shift with hepatic damage and growth inhibition of Carassius auratus induced by pentachlorophenol exposure. Environ Sci Technol 6 Oct 2015;49(19):11894–11902. [DOI] [PubMed] [Google Scholar]
  • [68].Chi Y, Lin Y, Lu Y, Huang Q, Ye G, Dong S. Gut microbiota dysbiosis correlates with a low-dose PCB126-induced dyslipidemia and non-alcoholic fatty liver disease. Sci Total Environ 25 Févr 2019;653:274–282. [DOI] [PubMed] [Google Scholar]
  • [69].Liang Y, Liu D, Zhan J, Luo M, Han J, Wang P, et al. New insight into the mechanism of POP-induced obesity: evidence from DDE-altered microbiota. Chemosphere Avr 2020;244:125123. [DOI] [PubMed] [Google Scholar]
  • [70].Fader KA, Nault R, Zhang C, Kumagai K, Harkema JR, Zacharewski TR. 2,3, 7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: alterations in biosynthesis, enterohepatic circulation, and microbial metabolism. Sci Rep 19 Juill 2017;7(1):5921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [71].Natividad JM, Agus A, Planchais J, Lamas B, Jarry AC, Martin R, et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab 6 Nov 2018;28(5):737–749.e4. [DOI] [PubMed] [Google Scholar]
  • [72].Fader KA, Nault R, Doskey CM, Fling RR, Zacharewski TR. 2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice. Sci Rep 24 Avr 2019;9(1):6514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [73].Guardia-Escote L, Basaure P, Biosca-Brull J, Cabré M, Blanco J, Pérez-Fernández C, et al. APOE genotype and postnatal chlorpyrifos exposure modulate gut microbiota and cerebral short-chain fatty acids in preweaning mice. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc Janv 2020;135:110872. [DOI] [PubMed] [Google Scholar]
  • [74].Talwani R, Gilliam BL, Howell C. Infectious diseases and the liver. Clin Liver Dis Févr 2011;15(1):111–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [75].Tsui JI, Pletcher MJ, Vittinghoff E, Seal K, Gonzales R. Hepatitis C and hospital outcomes in patients admitted with alcohol-related problems. J Hepatol Févr 2006;44(2):262–266. [DOI] [PubMed] [Google Scholar]
  • [76].Sagnelli E, Stroffolini T, Mele A, Imparato M, Sagnelli C, Coppola N, et al. Impact of comorbidities on the severity of chronic hepatitis B at presentation. World J Gastroenterol 14 Avr 2012;18(14):1616–1621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [77].Xu HQ, Wang CG, Zhou Q, Gao YH. Effects of alcohol consumption on viral hepatitis B and C. World J Clin Cases 26 Nov 2021;9(33):10052–10063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [78].Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect Juin 2010;118(6):818–824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [79].Melaram R Environmental risk factors implicated in liver disease: a mini-review. Front Public Health 2021;9:683719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [80].Cordier S, Le TB, Verger P, Bard D, Le CD, Larouze B, et al. Viral infections and chemical exposures as risk factors for hepatocellular carcinoma in Vietnam. Int J Cancer 9 Sept 1993;55(2):196–201. [DOI] [PubMed] [Google Scholar]
  • [81].Liu X, Baecker A, Wu M, Zhou JY, Yang J, Han RQ, et al. Interaction between tobacco smoking and hepatitis B virus infection on the risk of liver cancer in a Chinese population. Int J Cancer 15 Avr 2018;142(8):1560–1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [82].Jain D, Chaudhary P, Varshney N, Bin Razzak KS, Verma D, Khan Zahra TR, et al. Tobacco smoking and liver cancer risk: potential avenues for carcinogenesis. J Oncol 2021;2021:5905357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [83].Mallat A, Hezode C, Lotersztajn S. Environmental factors as disease accelerators during chronic hepatitis C. J Hepatol Avr 2008;48(4):657–665. [DOI] [PubMed] [Google Scholar]
  • [84].Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Exp Suppl 2012 2012;101:133–164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [85].Aslam N, Iqbal MS, Hussain SM, Rizwan M, Naseer QUA, Afzal M, et al. Effects of chelating agents on heavy metals in Hepatitis C Virus (HCV) patients. Math Biosci Eng MBE 15 Févr 2019;16(3):1138–1149. [DOI] [PubMed] [Google Scholar]
  • [86].Krueger WS, Wade TJ. Elevated blood lead and cadmium levels associated with chronic infections among non-smokers in a cross-sectional analysis of NHANES data. Environ Health Glob Access Sci Source 11 Févr 2016;15:16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [87].Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med 22 Sept 2016;375(12):1161–1170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [88].Lleo A, Marzorati S, Anaya JM, Gershwin ME. Primary biliary cholangitis: a comprehensive overview. Hepatol Int Nov 2017;11(6):485–499. [DOI] [PubMed] [Google Scholar]
  • [89].Ho SM, Lewis JD, Mayer EA, Plevy SE, Chuang E, Rappaport SM, et al. Challenges in IBD research: environmental triggers. Inflamm Bowel Dis 16 Mai 2019;25(Suppl 2):S13–S23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [90].Webb GJ, Hirschfield GM. Using GWAS to identify genetic predisposition in hepatic autoimmunity. J Autoimmun Janv 2016;66:25–39. [DOI] [PubMed] [Google Scholar]
  • [91].Goldstein J, Levy C. Novel and emerging therapies for cholestatic liver diseases. Liver Int Off J Int Assoc Study Liver Sept 2018;38(9):1520–1535. [DOI] [PubMed] [Google Scholar]
  • [92].Struger J, Grabuski J, Cagampan S, Sverko E, Marvin C. Occurrence and distribution of carbamate pesticides and metalaxyl in southern ontario surface waters 2007–2010. Bull Environ Contam Toxicol Avr 2016;96(4):423–431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [93].Wages PA, Joshi P, Tallman KA, Kim HYH, Bowman AB, Porter NA. Screening ToxCast for chemicals that affect cholesterol biosynthesis: studies in cell culture and human induced pluripotent stem cell-derived neuroprogenitors. Environ Health Perspect Janv 2020;128(1):17014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [94].Mousa OY, Juran BD, McCauley BM, Vesterhus MN, Folseraas T, Turgeon CT, et al. Bile acid profiles in primary sclerosing cholangitis and their ability to predict hepatic decompensation. Hepatol Baltim Md Juill 2021;74(1):281–295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [95].Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primer 21 Janv 2021;7(1):6. [DOI] [PubMed] [Google Scholar]
  • [96].Nault JC, Paradis V, Ronot M, Zucman-Rossi J. Benign liver tumours: understanding molecular physiology to adapt clinical management. Nat Rev Gastroenterol Hepatol 14 Juill 2022;19:703–716. [DOI] [PubMed] [Google Scholar]
  • [97].Ng SWK, Rouhani FJ, Brunner SF, Brzozowska N, Aitken SJ, Yang M, et al. Convergent somatic mutations in metabolism genes in chronic liver disease. Nat Oct 2021;598(7881):473–478. [DOI] [PubMed] [Google Scholar]
  • [98].Brunner SF, Roberts ND, Wylie LA, Moore L, Aitken SJ, Davies SE, et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nat Oct 2019;574(7779):538–542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [99].Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet Mai 2015;47(5):505–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [100].Nault JC, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet Oct 2015;47(10):1187–1193. [DOI] [PubMed] [Google Scholar]
  • [101].Péneau C, Imbeaud S, La Bella T, Hirsch TZ, Caruso S, Calderaro J, et al. Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma. Gut Mars 2022;71(3):616–626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [102].Trépo E, Caruso S, Yang J, Imbeaud S, Couchy G, Bayard Q, et al. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study. Lancet Oncol Janv 2022;23(1):161–171. [DOI] [PubMed] [Google Scholar]
  • [103].Buch S, Innes H, Lutz PL, Nischalke HD, Marquardt JU, Fischer J, et al. Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study. Gut 4 Juill 2022. gutjnl-2022–327196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [104].Trépo E, Valenti L. Update on NAFLD genetics: from new variants to the clinic. J Hepatol Juin 2020;72(6):1196–1209. [DOI] [PubMed] [Google Scholar]
  • [105].Nault JC, Ningarhari M, Rebouissou S, Zucman-Rossi J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gastroenterol Hepatol Sept 2019;16(9):544–558. [DOI] [PubMed] [Google Scholar]
  • [106].Sun CA, Wang LY, Chen CJ, Lu SN, You SL, Wang LW, et al. Genetic polymorphisms of glutathione S-transferases M1 and T1 associated with susceptibility to aflatoxin-related hepatocarcinogenesis among chronic hepatitis B carriers: a nested case-control study in Taiwan . Carcinogenesis Août 2001;22(8):1289–1294. [DOI] [PubMed] [Google Scholar]
  • [107].McGlynn KA, Rosvold EA, Lustbader ED, Hu Y, Clapper ML, Zhou T, et al. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci U S A 14 Mars 1995;92(6):2384–2387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [108].Petrick JL, Campbell PT, Koshiol J, Thistle JE, Andreotti G, Beane-Freeman LE, et al. Tobacco, alcohol use and risk of hepatocellular carci- noma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project. Br J Cancer Avr 2018;118(7):1005–1012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [109].McGee EE, Jackson SS, Petrick JL, Van Dyke AL, Adami HO, Albanes D, et al. Smoking, alcohol, and biliary tract cancer risk: a pooling project of 26 prospective studies. J Natl Cancer Inst 1 Déc 2019;111(12):1263–1278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [110].Petrick JL, Freedman ND, Graubard BI, Sahasrabuddhe VV, Lai GY, Alavanja MC, et al. Coffee consumption and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by sex: the liver cancer pooling project. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol Sept 2015;24(9):1398–1406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [111].Petrick JL, Sahasrabuddhe VV, Chan AT, Alavanja MC, Beane-Freeman LE, Buring JE, et al. NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project. Cancer Prev Res Phila Pa Déc 2015;8(12):1156–1162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [112].Pritchett N, Spangler EC, Gray GM, Livinski AA, Sampson JN, Dawsey SM, et al. Exposure to outdoor particulate matter air pollution and risk of gastrointestinal cancers in adults: a systematic review and meta-analysis of epidemiologic evidence. Environ Health Perspect [Internet] Mars 2022;130(3):036001 [cité 4 Août 2022]. Disponible sur: https://ehp.niehs.nih.gov/doi/10.1289/EHP9620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [113].So R, Chen J, Mehta AJ, Liu S, Strak M, Wolf K, et al. Long-term exposure to air pollution and liver cancer incidence in six European cohorts. Int J Cancer [Internet] Déc 2021;149(11):1887–1897 [cité 4 Août 2022]. Disponible sur: https://onlinelibrary.wiley.com/doi/10.1002/ijc.33743. [DOI] [PubMed] [Google Scholar]
  • [114].Wang W, Cheng S, Zhang D. Association of inorganic arsenic exposure with liver cancer mortality: a meta-analysis. Environ Res [Internet] Nov 2014;135:120–125 [cité 4 Août 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0013935114003041. [DOI] [PubMed] [Google Scholar]
  • [115].VoPham T Environmental risk factors for liver cancer and nonalcoholic fatty liver disease. Curr Epidemiol Rep [Internet] Mars 2019;6(1):50–66 [cite 4 Août 2022]. Disponible sur: http://link.springer.com/10.1007/s40471-019-0183-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [116].Ludewig G, Robertson LW. Polychlorinated biphenyls (PCBs) as initiating agents in hepatocellular carcinoma. Cancer Lett [Internet] Juin 2013;334(1):46–55 [cité 4 Août 2022]. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0304383512007033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [117].Jha G, Kankarla V, McLennon E, Pal S, Sihi D, Dari B, et al. Per- and polyfluoroalkyl substances (PFAS) in integrated crop–livestock systems: environmental exposure and human health risks. Int J Environ Res Public Health [Internet] 28 Nov 2021;18(23):12550 [cité 4 Août 2022]. Disponible sur: https://www.mdpi.com/1660-4601/18/23/12550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [118].Goodrich JA, Walker D, Lin X, Wang H, Lim T, McConnell R, et al. Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort. JHEP Rep Innov Hepatol Oct 2022;4(10):100550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [119].Lambert MP, Paliwal A, Vaissière T, Chemin I, Zoulim F, Tommasino M, et al. Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. J Hepatol Avr 2011;54(4):705–715. [DOI] [PubMed] [Google Scholar]
  • [120].Guyton KZ, Chiu WA, Bateson TF, Jinot J, Scott CS, Brown RC, et al. A reexamination of the PPAR-α activation mode of action as a basis for assessing human cancer risks of environmental contaminants. Environ Health Perspect [Internet] Nov 2009;117(11):1664–1672 [cité 4 Août 2022]. Disponible sur: https://ehp.niehs.nih.gov/doi/10.1289/ehp.0900758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [121].Brandi G, Straif K, Mandrioli D, Curti S, Mattioli S, Tavolari S. Exposure to asbestos and increased intrahepatic cholangiocarcinoma risk: growing evidences of a putative causal link. Ann Glob Health 2022;88(1):41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [122].Suk WA, Bhudhisawasdi V, Ruchirawat M. The curious case of cholangiocarcinoma: opportunities for environmental health scientists to learn about a complex disease. J Environ Public Health [Internet] 9 Août 2018;2018:1–7 [cité 19 Déc 2022]. Disponible sur: https://www.hindawi.com/journals/jeph/2018/2606973/. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [123].National Toxicology Program. Toxicology and carcinogenesis studies of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (cas No. 1746–01-6), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (cas No. 57117–31-4), and 3,3’, 4,4’,5-pentachlorobiphenyl (PCB 126) (cas No. 57465–28-8) in female harlan sprague-dawley rats (gavage studies). Natl Toxicol Program Tech Rep Ser Sept 2006;(526):1–180. [PubMed] [Google Scholar]
  • [124].National Toxicology Program. NTP toxicology and carcinogenesis studies of 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126) (CAS No. 57465–28-8) in female Harlan Sprague-Dawley rats (Gavage Studies). Natl Toxicol Program Tech Rep Ser Janv 2006;(520):4–246. [PubMed] [Google Scholar]
  • [125].European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, clinical practice guideline panel: chair:, panel members, EASL governing board representative: EASL clinical practice guidelines: drug-induced liver injury. J Hepatol Juin 2019;70(6):1222–1261. [DOI] [PubMed] [Google Scholar]
  • [126].Sandhu N, Navarro V. Drug-induced liver injury in GI practice. Hepatol Commun Mai 2020;4(5):631–645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [127].Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, et al. Drug-induced liver injury. Nat Rev Dis Primer 22 Août 2019;5(1):58. [DOI] [PubMed] [Google Scholar]
  • [128].Hayashi PH, Lucena MI, Fontana RJ, Bjornsson ES, Aithal GP, Barnhart H, et al. A revised electronic version of RUCAM for the diagnosis of DILI. Hepatol Baltim Md Juill 2022;76(1):18–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [129].Macías-Rodríguez RU, Inzaugarat ME, Ruiz-Margáin A, Nelson LJ, Trautwein C, Cubero FJ. Reclassifying hepatic cell death during liver damage: ferroptosis-A novel form of non-apoptotic cell death? Int J Mol Sci 28 Févr 2020;21(5):1651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [130].Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica 2020;105(2):260–272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [131].European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European association for the study of the liver. EASL clinical practice guidelines on haemochromatosis. J Hepatol Août 2022;77(2):479–502. [DOI] [PubMed] [Google Scholar]
  • [132].European Association for Study of Liver. EASL clinical practice guidelines: Wilson’s disease. J Hepatol Mars 2012;56(3):671–685. [DOI] [PubMed] [Google Scholar]
  • [133].Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, et al. A multidisciplinary approach to the diagnosis and management of Wilson disease:executive summary of the 2022 practice guidance on Wilson disease from the American association for the study of liver diseases. Hepatol Baltim Md 24 Sept 2022. [DOI] [PubMed] [Google Scholar]
  • [134].Drakvik E, Altenburger R, Aoki Y, Backhaus T, Bahadori T, Barouki R, et al. Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment. Environ Int Janv 2020;134:105267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [135].Lai Y, Liu CW, Yang Y, Hsiao YC, Ru H, Lu K. High-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice. Nat Commun 19 Oct 2021;12(1):6000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [136].Santos-Marcos JA, Haro C, Vega-Rojas A, Alcala-Diaz JF, Molina-Abril H, Leon-Acuña A, et al. Sex differences in the gut microbiota as potential determinants of gender predisposition to disease. Mol Nutr Food Res Avr 2019;63(7):e1800870. [DOI] [PubMed] [Google Scholar]
  • [137].Audouze K, Sarigiannis D, Alonso-Magdalena P, Brochot C, Casas M, Vrijheid M, et al. Integrative strategy of testing systems for identification of endocrine disruptors inducing metabolic disorders-an introduction to the OBERON project. Int J Mol Sci 23 Avr 2020;21(8). [DOI] [PMC free article] [PubMed] [Google Scholar]

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