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

Abstract

Metabolic dysfunction-associated steatotic liver disease is among the most prevalent chronic liver diseases worldwide. Its increasing incidence is typically linked to over-nutrition and metabolic syndrome. However, this account remains insufficiently detailed, particularly regarding diseases in lean individuals and the generational acceleration of metabolic illnesses. The exposome encompasses the entirety of the environmental exposure throughout an individual’s life and provides a complementary framework. The liver is a pivotal organ given that it is the primary location for the biotransformation of xenobiotics. This study synthesized data suggesting that environmental chemical exposure may be a plausible and controllable factor in steatotic liver disease while distinguishing associations from causation. We reviewed the main exposure classes, including per- and polyfluoroalkyl substances, micro- and nanoplastics, endocrine-disrupting plasticizers, persistent organic pollutants, hazardous metals, and air pollution. We assessed the strength of human evidence and delineated the potential mechanisms shared by these agents, including nuclear receptor disruption, mitochondrial and oxidative injury, inflammasome activation, stellate cell fibrogenesis, gut microbiota-bile acid disruption, and developmental reprogramming, along with their documented associations with steatosis, steatohepatitis, fibrosis, and hepatocellular carcinoma. The recognition of environmental exposure redefines metabolic dysfunction-associated steatotic liver disease as chemical environment-driven. These findings have implications in risk assessment, treatment, and prevention.

Key Words: Exposome; Steatotic liver disease; Metabolic dysfunction-associated steatotic liver disease; Per- and polyfluoroalkyl substances; Microplastics; Endocrine-disrupting chemicals; Environmental pollutants; Hepatocellular carcinoma; Environmental hepatology

Core Tip: Metabolic dysfunction-associated steatotic liver disease is typically a result of overnutrition and metabolic syndrome; the phenomenon of lean disease and its increasing prevalence remain inadequately elucidated. This review analyzes the hepatic exposome, focusing on environmental chemicals such as per- and polyfluoroalkyl substances, phthalates, bisphenols, persistent organic pollutants, toxic metals, and air pollution as potential modifiable factors contributing to steatosis, steatohepatitis, fibrosis, and hepatocellular carcinoma, while also noting that micro- and nanoplastics remain an emerging and unverified exposure. We incorporated shared mechanisms, human and experimental evidence assessed by strength, sex-specific susceptibility, and the tools necessary to implement environmental hepatology in practice.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognized as the most prevalent chronic liver disease, affecting approximately 38% of adults worldwide and an increasing number of children. Projections indicate that more than half of all adults will be affected by 2040[1]. It has emerged as a major indication for liver transplantation, with a growing number of patients developing hepatocellular carcinoma (HCC) in conjunction with other liver disease[1,2]. MASLD was reclassified by the 2023 Multisociety Guidelines as the presence of one of five cardiometabolic risk factors, emphasizing the systemic metabolic foundation of hepatic steatosis[3]. The relationship between MASLD and non-hepatic diseases reinforces its systemic features; MASLD is a predictor of type 2 diabetes, chronic renal disease, sarcopenia, and extrahepatic neoplasia. The leading cause of death in patients with MASLD is cardiovascular disease and not hepatic disease. It also places considerable and growing economic costs on society owing to poor quality of life, decreased productivity, and increased healthcare usage[1].

Such a disease requires causal analysis that moves beyond an individual’s diet and exercise to the shared environments in which the entire population lives. The dominant model ascribed the epidemic to excessive caloric intake, lack of physical activity, obesity, and insulin resistance. The model was accurate within its scope; however, it was incomplete. This does not explain the large proportion of non-obese patients, the geographical and individual variability in disease characteristics after adjustment for metabolic risk, or the rate of change, reflecting a generational acceleration of the disease that is greater than any conceivable alteration in the human genome[4]. The current understanding of the etiology of MASLD has developed from the simple “two-hit” model to a more sophisticated “multi-hit” model. In this model, insulin resistance, adipose signaling, nutritional status, gut microbial composition, and genetic and epigenetic vulnerabilities interact with the at-risk liver[5]. This framework allows the consideration of environmental chemicals as additional modifiable factors. Diet and activity are not the sole factors that changed during the epidemic; growing evidence indicates that the chemical environment to which individuals are consistently exposed.

The exposome, analogous to the genome, encompasses all environmental exposures encountered by an individual from conception onward, along with the biological responses elicited by these exposures[6]. Recent population-based analyses have quantified the effects of environmental exposure. In a large prospective cohort, these factors contributed significantly more than polygenic risk to the variation in mortality and incidence of cardiac, pulmonary, and hepatic diseases. This implies that environmental factors, particularly liver health, may be more crucial than hereditary vulnerability[7]. The liver is the most implicated organ because of its predominant function in the detection, biotransformation, and clearance of xenobiotics and in inflammatory responses associated with chemical harm[6]. Studies have shown that the risk of early onset malignancies such as liver and biliary tumors may be modulated by multigenerational changes in exposomes. Factors such as food, microbiome, obesity, and environmental pollutants contribute to this elevated risk[8].

This article focuses on hepatic exposomes and posits that environmental chemical exposure may be an important modifiable factor in the initiation and progression of steatotic liver disease, acknowledging that most human evidence is associational rather than causal. We emphasize the exposure classes for which human and mechanistic evidence is the most developed, namely, polyfluoroalkyl substances (PFAS), micro- and nanoplastics, endocrine-disrupting plasticizers, persistent organic pollutants, toxic metals, and air pollution. We begin with the conceptual framework and the unique role of the liver, followed by an analysis of the mechanisms shared by these structurally diverse agents. We systematically reviewed the evidence by class and examined the relationship between various exposures and the continuum from steatosis to steatohepatitis, fibrosis, and HCC. Finally, we explored the methods for quantifying and addressing hepatic exposure. We aimed to redefine a condition traditionally linked to an individual’s lifestyle as influenced by the chemical environment, which has significant implications for prevention.

METHODOLOGY

This is a narrative review. We searched PubMed, Scopus and Web of Science from inception until June 2026 through combinations of the words “exposome”, “environmental exposure”, “environmental pollutant”, “endocrine-disrupting chemical”, “per- and polyfluoroalkyl substances”, “PFAS”, “microplastics”, “nanoplastics”, “phthalate”, “bisphenol”, “persistent organic pollutant”, “polychlorinated biphenyl”, “dioxin”, “air pollution”, “particulate matter”, “heavy metals”, “cadmium”, “arsenic”, and “aflatoxin” along with “steatotic liver disease”, “metabolic dysfunction-associated steatotic liver disease”, “non-alcoholic fatty liver disease”, “steatohepatitis”, “hepatic fibrosis”, and “hepatocellular carcinoma”. We manually screened the reference lists from the collected articles and pertinent reviews to identify additional materials. Priority was assigned to human cohort and biomonitoring studies, mechanistic studies utilizing physiologically relevant models, and review articles published within the last 5 years, ensuring open access and retrievable full text. Owing to the diverse scope, rapid advancement, and methodological differences in the literature, studies were selected based on their clinical and mechanistic significance rather than following a formal systematic review protocol, and no quantitative synthesis was performed.

THE HEPATIC EXPOSOME: CONCEPTS AND WHY THE LIVER IS A CENTRAL TARGET

The exposome is conceptualized as the environmental counterpart of the genome, encompassing a comprehensive record of all exposures (chemical, physical, dietary, and microbial) that influence a developing organism from conception throughout its life as well as the endogenous responses provoked[6]. Operationally, it is categorized into the following three domains: A general external domain encompassing climate, built environment, and social factors; a specific external domain including diet, pollutants, occupational chemicals, and lifestyle; and an internal domain that involves metabolic, inflammatory, and microbial habitats influenced by these exposures. The strength of this hepatological framework lies in the position of the liver at the intersection of the three domains. The liver serves as the primary site for xenobiotic metabolism and is the initial organ for processing ingested compounds through portal circulation. It exhibits the most extensive array of phases I and II biotransformation enzymes and plays a crucial role in the biliary and metabolic clearance of foreign substances[6]. The machinery that safeguards the organism also makes the liver a site of preferential accumulation and bioactivation. Chronic engagement of inflammatory systems intended to repair chemical insults may, in turn, become a driver of the disease. The magnitude of the pertinent exposure is often underestimated. Tens of thousands of synthetic chemicals are commercially available; however, the majority have not been evaluated for hepatic safety. Furthermore, the global production has increased in parallel with metabolic diseases[4]. Humans are perpetually exposed to various contaminants via food, water, air, and consumer products. Contemporary biomonitoring surveys have identified numerous contaminants in nearly all human samples from birth. Therefore, a pertinent comparison involves assessing greater vs lesser exposure relative to a universal background, rather than contrasting exposed and unexposed subjects. This widespread presence precisely renders even minor individual hepatic effects significant at the population level, and the liver, consistently perfused with all ingested substances, is the organ most likely to incur the cumulative burden of the chemical environment.

Multiple lines of evidence indicate that the environment should be considered a primary rather than secondary factor in the etiology of steatotic liver disease. Population-scale modeling suggests that exposomes explain a greater proportion of the variation in liver disease incidence than polygenic risk scores, a trend not observed in several other organ systems[7]. Although this finding underlines the statistical significance of the assessed exposures, it should not be considered proof of direct causality. These correlations have been quantified in a systematic review and meta-analysis of 27 studies. A strong positive correlation was found between population exposure to several endocrine-disrupting chemicals, such as phthalates, cadmium, and bisphenol A (BPA), and the risk of fatty liver disease[9]. Metabolomic profiling of human liver tissue has demonstrated that exposure to contaminants produces measurable alterations, specifically in bile acid and lipid pathways affected by MASLD[10]. This relationship is bidirectional: A steatotic liver can dysregulate the cytochrome P450 (CYP) system and nuclear receptors responsible for xenobiotic handling. Consequently, fatty liver and chemical exposure may influence each other by modulating the disposition and toxicity of both factors[11]. The obesogen hypothesis is at the core of these observations and proposes that some environmental chemicals act as endocrine disruptors to alter the development and function of adipose tissue, liver, pancreas, gut, and brain, thereby shifting the metabolic setpoint toward fat storage[4]. Vulnerability is heterogeneous. Factors such as sex, life phase, nutritional status, and coexisting metabolic diseases influence the hepatic response to specific exposures, with the most significant associations frequently observed in women[12]. The hepatic exposome should be understood not as a collection of individual toxins, but as a dynamic, host-dependent system in which structurally unrelated agents interact with a common set of metabolic vulnerabilities. The primary exposure classes relevant to steatotic liver disease along with their key mechanisms and supporting evidence are presented in Table 1.

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

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

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

MECHANISMS LINKING ENVIRONMENTAL EXPOSURES TO STEATOTIC LIVER DISEASE

A key characteristic of hepatic exposomes is that various chemically diverse pollutants operate via a limited number of conserved injury pathways. Identifying these common mechanisms allows individual associations to be interpreted as coherent biological processes rather than mere coincidences, with the overall pathway from exposure to disease as illustrated in Figure 1.

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

Nuclear receptor hijacking and disordered xenobiotic metabolism

Numerous environmental hepatotoxicants bind to and disrupt the activity of ligand-activated nuclear receptors that play critical roles in lipid metabolism and xenobiotic elimination, specifically peroxisome proliferator-activated receptors (PPARs), pregnane X receptors, constitutive androstane receptors, and aryl hydrocarbon receptors (AhRs). PFAS serve as structural surrogates for fatty acids and are significant activators of PPARα. Perfluorooctanoic acid and perfluorooctane sulfonic acid have been shown to induce a PPARα-dependent program in humans, rodents and in vitro models that increases the expression of acyl-CoA oxidase 1 and alters hepatic lipid metabolism, resulting in lipid accumulation[13]. AhR is a major regulator of AhR. Its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin causes hepatic steatosis by boosting hepatic lipid absorption and esterification, decreasing very-low-density lipoprotein release, and impairing fatty acid synthesis and oxidation. It also alters the metabolism of polyunsaturated fatty acids and eicosanoids, creating a proinflammatory environment that favors the progression of steatohepatitis to fibrosis[14,15]. The plasticizer di-2-ethylhexyl phthalate also disrupts hepatic lipid homeostasis through the liver X receptor-sterol regulatory element-binding protein 1c lipogenic axis and PPARα, with effects exacerbated by pre-existing obesity[16]. Persistent organic pollutants interact with the same receptor networks. Polychlorinated biphenyl (PCB) 153 is a diet-dependent obesogen that activates the pregnane X receptors, constitutive androstane receptor, and PPAR signaling pathways, causing steatosis[17]. These receptors modulate CYP enzymes, demonstrating an interaction between exposure and preexisting steatosis. Fatty livers demonstrate an altered induction of CYP2B6 and CYP2C9, which modify the response to subsequent chemical and pharmacological challenges[11].

Mitochondrial and peroxisomal dysfunction with oxidative stress

The second mechanism involves bioenergetic failure accompanied by oxidative stress. PFAS-induced PPARα-acyl-CoA oxidase 1 axis creates reactive oxygen species in peroxisomes, altering mitochondrial activity. Oxidative stress is sufficient to promote fat formation in exposed hepatocytes[13]. Micro- and nanoplastics exhibit a similar pattern, with polystyrene particles in human stem-cell-derived liver organoids inducing the generation of reactive oxygen species, leading to oxidative stress, inflammation, and disrupted lipid metabolism, accompanied by the upregulation of hepatocyte nuclear factor 4α and CYP2E1[18]. Similar to air pollution, fine particulate matter causes oxidative stress and remodels the hepatic transcriptome, stimulating lipogenesis and suppressing mitochondrial and peroxisomal fatty acid oxidation[19]. Metabolites of several industrial pollutants may directly damage mitochondria, thereby increasing the sensitivity of the liver to inflammatory injury[20].

Inflammation, inflammasome activation, and fibrogenesis

Oxidative and metabolic stresses activate innate immune responses that convert simple steatosis to steatohepatitis, and finally, fibrosis. The NOD-like receptor protein 3 (NLRP3) inflammasome is an important effector that detects danger signals, including cholesterol crystals and reactive oxygen species, leading to the production of interleukin-1β in Kupffer cells and recruited macrophages. Targeted NLRP3 suppression in experimental steatohepatitis reduced hepatic inflammation, transaminase levels, and fibrosis, demonstrating that the inflammasome is a link between metabolic or chemical insults and disease development[21]. At the commencement of inflammation, hepatic stellate cell activation is a crucial stage in fibrogenesis during the initiation of inflammation. Stellate cells that store vitamin A transdifferentiate into proliferative myofibroblasts that release collagen. Oxidative stress, endoplasmic reticulum stress, and signals from macrophages, injured hepatocytes, and sinusoidal endothelial cells promote this process[22]. Direct evidence connecting specific pollutants to these processes remains limited and primarily originates from experimental models: Polystyrene micro- and nanoplastics activate hepatic innate immune signaling, notably the toll-like receptor 4-nuclear factor-κB pathway[23,24]; inorganic arsenic enhances lipopolysaccharide-induced hepatic inflammation[25]; and various toxic metals trigger hepatic inflammatory signaling[26]. In the absence of pollutant-specific data, the inflammasome and stellate-cell pathways should be considered convergent downstream mechanisms associated with various environmental exposures, rather than effects specific to individual exposures. Therefore, environmental agents that interact with these shared pathways may plausibly expedite the disease processes they initiate, thereby establishing a mechanistic link between low-level chemical exposure and the definitive outcomes of cirrhosis and cancer.

The second step reinforces this link between endoplasmic reticulum stress and lipotoxicity. Excessive accumulation of lipids and xenobiotics in hepatocytes leads to an unfolded protein response, which enhances hepatic oxidative stress, inflammasome priming, and stellate cell activation. Numerous environmental contaminants interact with stress stress-response system[10,22]. Together with the inflammasome and stellate cell pathways mentioned above, lipotoxic stress signaling facilitates the transformation of transient chemical insults into more enduring pro-steatotic and pro-fibrotic states. The developmental and epigenetic factors that extend these effects are discussed below.

The gut microbiota-bile acid axis

Various pollutants adversely affect the liver indirectly by altering the gut microbiota and bile acid signaling. The gut and liver are physiologically related via portal circulation, and microbial metabolites and bile acids are important regulators of hepatic inflammation and fibrosis[27]. BPA causes hepatic steatosis via microbiota and bile acid pool reconfiguration, and concurrent inhibition of intestinal and hepatic farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 signaling. This process results in an increases bile acid synthesis and lipogenesis. This phenotype can be transmitted via fecal transplantation and eliminated by antibiotics, thereby confirming the causal role of the microbiota[28]. Cadmium (Cd) operates via a parallel mechanism, causing dysbiosis that inhibits intestinal FXR-fibroblast growth factor 15 signaling and promotes hepatic bile acid synthesis, inflammation, and ductular injury, which can be mitigated by an intestinal FXR agonist[29]. Inorganic arsenic disrupts the gut microbiota, leading to an increased translocation of bacterial lipopolysaccharides, which contributes to hepatic inflammation and the progression toward cirrhosis and cancer[25]. Accordingly, the metabolomic signature of contaminant exposure in patients with MASLD was most evident in the bile-acid pathways[10].

Developmental reprogramming and epigenetic memory

The timing of exposure was as significant as its magnitude. Periods of greatest sensitivity occur in utero and in early childhood, during which exposure to endocrine-disrupting chemicals can influence the structure and function of adipose tissue and the liver, with effects that may persist into adulthood[4]. Maternal exposure, nutrition, and the hormonal environment collectively influence offspring adipose biology and the long-term risk of obesity and fatty liver, with these developmental effects exhibiting significant sexual dimorphism[30]. Direct human data indicate a developmental association: In a multi-country European birth-cohort study involving over 1100 mother-child pairs, increased prenatal exposure to mixtures of organochlorine pesticides, brominated flame retardants, PFAS, and metals correlated with a heightened risk of liver injury and elevated cytokeratin-18 levels in children aged 6-11 years, suggesting prenatal chemical exposure as a potential risk factor for pediatric MASLD[31]. Current evidence in humans indicates an association between prenatal or developmental exposure and subsequent liver injury. The mediation of these associations by epigenetic mechanisms, including lasting changes in DNA methylation and histone modifications, is largely inferred from experimental models rather than directly demonstrated in the human liver. Consequently, this interpretation should be considered provisional[4]. This developmental dimension reinterprets the hepatic exposome as a life course phenomenon, wherein early chemical exposure may establish a trajectory that is later influenced by metabolic stressors.

PER- AND PFAS

Per- and PFAS comprise thousands of synthetic compounds that are recognized for their thermal and chemical stabilities. They are used in applications such as non-stick coatings, food packaging, textiles, and firefighting foams. The carbon-fluorine bonds that confer utility also render these substances nearly indestructible in both environmental and biological contexts, leading to their designation as “forever chemicals;” they are present in the serum of a significant portion of the population[32]. The structural similarity of PFAS to fatty acids positions the liver as a direct target, making PFAS the most well-characterized agents within human hepatic exposomes. Human evidence evolved from mere associations to severity-graded mechanistic studies. PFAS have been consistently linked to hepatic steatosis in cross-sectional analyses of national survey data. Integrative studies have identified a strong correlation between perfluorooctanoic acid exposure and an elevated risk of nonalcoholic fatty liver disease (NAFLD), characterized by a nonlinear dose-response relationship and upregulation of inflammatory signaling genes[13,33]. This association also correlates with histological severity. In a cohort of 100 patients with biopsy-confirmed disease, long-chain PFAS levels were associated with steatosis grade, and specific congeners were elevated in individuals with advanced steatosis and significant fibrosis[34]. In adolescents, serum perfluorohexane sulfonate and perfluorooctanoic acid levels have been identified as significant risk factors for NAFLD in a cohort of approximately 1700 individuals. Toxicogenomic and animal studies have suggested the involvement of CYP2E1 in glutathione S-transferase signaling[35]. In addition, prenatal exposure to perfluoroalkyl substances (PFAS) has been prospectively linked to liver injury in childhood[31]. Metabolomic phenotyping of human liver tissue revealed that PFAS exposure modified the hepatic bile acid and lipid pathways that are characteristic of MASLD, with significantly greater effects observed in women. This sex-specific pattern is corroborated in PPARα-humanized mice[10]. The evidence is not uniformly positive, and this complexity warrants attention, as some survey analyses report no association or even inverse relationships between PFAS and specific components of metabolic syndrome. Moreover, a meta-analysis found no general relationship between PFAS and fatty liver disease but confirmed associations with other endocrine disruptors. However, this study reported a significantly increased risk in women exposed to perfluorooctanoic acid[9,36]. These differences indicate that cross-sectional biomonitoring may be subject to reverse causation, altered renal clearance, and confounding and that these effects may be modified in sensitive populations. Nonetheless, the convergence of cohort, biopsy, pediatric, and mechanistic data positions PFAS as a key example of a persistent environmental chemical linked to steatotic liver disease with potential implications for hepatocarcinogenesis, as discussed below[32].

Several features have enhanced its significance in hepatology. Serum elimination half-lives, measured in years, indicate that the body’s burden accumulates throughout an individual’s life. Consequently, populations that are no longer exposed to long-chain legacy compounds retain them. Additionally, longer-chain congeners are typically the most hepatotoxic and are strongly correlated with disease severity[34]. The regulatory response involving the phase-out of perfluorooctanoic acid and perfluorooctane sulfonic acid has, similar to the situation with plasticizers, led to a shift towards shorter-chain and “GenX” alternatives, whose hepatic safety is largely uncharacterized. Given that the liver serves as both a target and reservoir and considering the universal nature of exposure, even a modest effect per individual may result in a significant population-attributable contribution to the burden of MASLD[9].

MICRO- AND NANOPLASTICS

Although PFAS are the most well-studied hepatic exposure agents, micro- and nano-plastics are the most rapidly emerging contaminants. These particles, resulting from the fragmentation of larger plastics in the environment, are pervasive in water, food, and air and enter the body through ingestion, inhalation, and dermal contact[37]. A significant advancement in hepatology is the direct identification of plastic particles within the human liver tissue. In a proof-of-concept case series, microplastic polymers were detected in the livers of patients with cirrhosis but were absent in those without prior liver disease. This observation raises the unresolved question of whether hepatic accumulation contributes to fibrogenesis or is a consequence of the altered hemodynamics and clearance associated with established cirrhosis[38]. Recent multi-method analyses have confirmed the presence of micro- and nanoplastics in human organs, including the liver, identified their predominant composition as polyethylene, and documented increasing tissue concentrations over time[39]. These particles are distributed throughout human organs, including the brain, suggesting that the liver serves as a central node in the systemic plastic burden that the gut-liver axis is poised to detect early[39].

The mechanistic likelihood of the hepatic effect has been substantiated by experimental research conducted on human-relevant systems. Exposure of human pluripotent stem cell-derived liver organoids to polystyrene microplastics at environmentally relevant concentrations results in hepatotoxicity and disrupts lipid metabolism. This exposure leads to the generation of reactive oxygen species, oxidative stress, and inflammation while upregulating hepatocyte nuclear factor 4α and CYP2E1. These changes indicate an adverse outcome pathway that may contribute to steatosis, fibrosis, and potentially malignant transformation[18]. In addition to their inherent toxicity, plastics serve as vectors by adsorbing and transporting a variety of additives and environmental contaminants, such as phthalates, bisphenols, and other carcinogenic substances that may be released during the processing of particles within biological tissues[37]. Human data are critically limited to tissue detection and experimental toxicity, and direct evidence linking micro- and nano-plastics to human MASLD is absent. Consequently, they should be considered biologically plausible yet unverified exposures rather than confirmed risk factors. This caution is illustrated in Figure 2, and is evident in our abstract, core tips, and conclusion. The particle size is likely to be a determining factor. In contrast to larger microplastics, nanoscale plastics can traverse the intestinal epithelium and other biological barriers, subsequently entering the portal circulation and being assimilated by hepatocytes and resident macrophages. Their elevated surface-area-to-volume ratios enhanced the generation of reactive oxygen species and facilitated the leaching of adsorbed additives[37,39]. Significant uncertainties persist, including the actual internal doses attained in the human liver, the relative contributions of the particles and their chemical cargo, and the causal direction implied by their accumulation in cirrhotic tissues. Addressing these questions requires the use of standardized, contamination-controlled analytical methods and longitudinal human studies that connect the measured hepatic particle burden to histological and clinical outcomes, in contrast to the cross-sectional detection prevalent in the existing literature[38]. In vivo studies have progressed beyond mere detection: In murine models, orally administered polystyrene microplastics induced systemic and hepatic inflammation, facilitated hepatic fibrosis, altered the liver metabolome, and compromised the intestinal barrier and gut microbiota. Furthermore, fecal microbiota transplantation from affected animals replicated the inflammatory phenotype, suggesting the gut-liver axis as a pathway and microbiota as a potential intervention target, particularly as a green tea polyphenol, alleviated injury[23].

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

ENDOCRINE-DISRUPTING PLASTICIZERS: PHTHALATES AND BISPHENOLS

Phthalates and bisphenols are high-production-volume chemicals used to enhance the flexibility and durability of plastics and resins. They are readily leached from food packaging, medical devices, and consumer products, resulting in near-universal human exposure. Both are representative endocrine-disrupting chemicals that play significant roles in the obesogen hypothesis[4]. Several urinary phthalate metabolites have been linked to NAFLD across various diagnostic criteria, using nationally representative survey data. In fully adjusted analyses, an oxidative metabolite of di-isononyl phthalate was associated with over fourfold increased odds of elastography-defined fatty liver, demonstrating a dose-response gradient[40]. In addition, pooled meta-analytic estimates indicate that the increase in fatty liver risk related to phthalates is approximately 18%[9]. Mechanistic studies reveal how di-2-ethylhexyl phthalate worsens hepatic steatosis by activating the lipogenic liver X receptor-sterol regulatory element-binding protein 1c pathway and PPARα-mediated fatty acid metabolism and exhibits significantly greater effects in obese than in lean animals, providing clear evidence of the interaction between nutrients and toxicants[16]. As the same report noted, the industry is moving to newer phthalate alternatives, which is a classic example of regretted substitution, where a controlled chemical is replaced by a less-studied analog with questionable safety characteristics.

Among the plasticizers, BPA has the clearest mechanistic story. Chronic low-dose exposure causes hepatic steatosis by modifying the gut microbiota and bile acid metabolism, and inhibiting FXR and Takeda G protein-coupled receptor 5 signaling. This leads to an increase in hepatic bile acid synthesis and lipogenesis. Microbiota is an important mediator, as demonstrated by the transfer of phenotypes via fecal transplantation[28]. There is a large body of research on human exposure that is largely based on cross-sectional studies. In a nationally representative sample of > 7600 adults in the United States, people in the highest quartiles of urine BPA had approximately 44%-69% increased chances of NAFLD in fully adjusted models, with a substantial dose-response association[41]. Moreover, meta-analyses have shown that BPA is one of the most consistent endocrine disruptors, with a pooled odds ratio of 1.43[9]. Studies in women with polycystic ovarian syndrome corroborated the relationship between BPA and hepatic steatosis, insulin resistance, and low-grade inflammation[42]. The substitutes are similarly hazardous: A comprehensive analysis of thirteen bisphenol analogs revealed that the prevalent alternatives, bisphenol S, bisphenol F, and bisphenol AF, all prompted hepatic lipid accumulation in human hepatocytes, upregulating lipogenic genes and inhibiting fatty-acid β-oxidation in a manner comparable to the parent compound[43]. The proliferation of these analogs, marketed as safer alternatives, outpaces the toxicological evidence and exemplifies the regrettable substitution problem.

PERSISTENT ORGANIC POLLUTANTS, TOXIC METALS, AND AIR POLLUTION

In addition to the chemicals directly associated with plastics, three additional exposure classes were included in the hepatic exposome. Persistent organic pollutants, including PCBs, organochlorine insecticides, and dioxins, are lipophilic bioaccumulative substances that persist for decades and are found in the serum of adults. The diet-dependent obesogen PCB 153, which worsens hepatic steatosis and visceral obesity when administered in conjunction with a high-fat diet, has hepatic relevance. This exposure also modified the adipokine profile and redirected hepatic gene expression from fatty acid oxidation to lipogenesis, whereas no such effects were observed with the control diet[17]. The data from the human population were consistent. In an analysis conducted by the National Health and Nutrition Examination Survey, serum PCBs, along with lead and mercury, demonstrated a dose-dependent association with an unexplained increase in alanine aminotransferase. This increase reflects hepatocellular injury rather than steatosis, and is an indirect surrogate marker for suspected NAFLD in adults without other liver diseases[44]. A recent National Health and Nutrition Examination Survey study of more than 4200 adults found combinations of persistent organic pollutants associated with fatty liver disease, with notable sex-specific patterns. Some congeners display inverse connections in women, highlighting the complexity and context dependency of these interactions[45]. Dioxins represent a mechanistic aspect of this class, inducing AhR-mediated steatosis, which advances to steatohepatitis and fibrosis in experimental models[14,15]. A focused review of persistent endocrine-disrupting chemicals and fatty liver disease identified consistent associations between these compounds and NAFLD as well as elevated liver enzymes. This review highlights that the effects are often sex-specific, with more pronounced outcomes observed in women[12]. Toxic metals constitute the second category. Arsenic, Cd, and chromium accumulate in the liver and induce hepatic inflammation, which is a known factor in the progression of steatosis to fibrosis and cirrhosis, ultimately leading to HCC[26]. Cd functions via the gut microbiota-FXR axis[29], whereas inorganic arsenic integrates gut microbial disruption with direct genotoxic and epigenetic effects to facilitate hepatocarcinogenesis[25]. A meta-analysis estimated that the cadmium-related increase in fatty liver risk is approximately 37%[9]. Third, ambient air pollution, which has long been studied for its cardiovascular and respiratory effects, is increasingly linked to liver diseases. Epidemiological evidence from large prospective cohorts has indicated a relatively strong association. Long-term exposure to particulate matter and nitrogen oxides was linked to the incidence of NAFLD and cirrhosis in the UK Biobank cohort of > 450000 people, with hazard ratios of roughly 1.1 to 1.2 per interquartile-range increase[46]. Furthermore, in Rome, a cohort of over 1.2 million administrative inhabitants was found to have a substantial connection between the incidence of cirrhosis and long-term exposure to all evaluated pollutants[47]. Fine particulate matter induces pulmonary and hepatic oxidative stress, which alters hepatic lipid metabolism, thereby supporting the cohort findings[19,48].

Together, these classes expand the hepatic exposome from a limited set of prominent chemicals to a more accurate representation of lifelong low-level exposure to complex mixtures. A recurring theme is the distinction between legacy and current-use agents: Bioaccumulative compounds, such as dioxins and older PCBs, persist in the population and adipose tissue decades after production ceases, whereas current-use pesticides, plasticizers, and combustion products indicate ongoing exposure. Consequently, an individual’s hepatic exposome encompasses both past and present contaminations[44,45]. Occupational cohorts, such as vinyl chloride and plastic workers, smelter and battery workers, and agricultural workers exposed to pesticides, served as significant natural experiments. Their elevated and well-documented exposure demonstrates hepatic effects that are more challenging to identify at doses typical in the general population[26]. Current pesticides are of special concern because of the ongoing nutritional nature of exposure. Chronic administration of an ultra-low, environmentally relevant dose of a glyphosate-based herbicide in a 2-year rodent research resulted in a liver proteome and metabolome that largely overlapped with the molecular signature of NAFLD. This includes markers of peroxisomal proliferation, lipotoxicity, and oxidative stress, suggesting that even previously thought safe levels can disturb hepatic lipid metabolism[49].

FROM STEATOSIS TO STEATOHEPATITIS, FIBROSIS, AND HCC

The clinical relevance of hepatic exposomes depends on whether environmental exposure contributes to the progression of outcomes only by increasing hepatic fat or also in an active manner. The molecular underpinnings are the inflammasome and stellate cell pathways through which chemical damage may contribute to inflammation and fibrogenesis[21,22]. The most striking example of an environmental toxin that may cause steatohepatitis in the absence of obesity and alcohol is toxicant-associated steatohepatitis (TASH). The frequency of steatohepatitis was 80%, whereas the prevalence of fibrosis was 55% in a non-obese cohort high-exposure to vinyl chloride. This correlates with insulin resistance, lower adiponectin levels, elevated pro-inflammatory cytokines, and impaired antioxidant defenses. Serum transaminase levels were normal, indicating that the disease might have been missed by conventional screening procedures[50]. TASH demonstrated that chemical exposure alone can generate a complete histological profile of steatohepatitis and identified cytokeratin-18 as a more sensitive biomarker than aminotransferases. Experimental studies have elucidated the mechanisms underlying this progression. Vinyl chloride metabolites, at non-hepatotoxic doses, enhance inflammatory liver injury from secondary insults, such as endotoxins. They cause direct damage to mitochondria and lower the threshold for steatohepatitis, demonstrating the multiple-hit concept in which sensitizing exposure turns benign steatosis into active inflammation[5,20].

The other end of the spectrum was HCC, the exposomes of which contained both traditional and novel carcinogens. Aflatoxin B1 is an environmental hepatocarcinoma and dietary mycotoxin. Its albumin adduct biomarker has been prospectively associated with a higher risk of HCC and synergistic effects with hepatitis C virus infection and alcohol consumption. This is an infection-environment interaction and an exposure-exposure interaction[51]. Inorganic arsenic is a documented hepatocarcinogen that induces carcinogenesis via a combination of microbiological, inflammatory, genotoxic, and epigenetic pathways[25]. Recent investigations have suggested that high serum levels of perfluorooctane sulfonate are associated with a 4.5-fold increased risk of non-viral HCC in multiple ethnic groups. Metabolomic analysis has indicated that alterations in amino acid, glucose, and bile acid metabolism could act as intermediates in this relationship[32]. These findings provide a broader oncological perspective, considering the growing prevalence of early onset liver and biliary malignancies, which are partly related to multigenerational alterations in the exposome[8]. Direct evidence for the connection between environmental exposure and hepatocarcinogenesis in MASLD-related HCC is scarce, and the results should be interpreted cautiously. In contrast to a single exposure leading to continuous progression through all phases, different stages of the disease spectrum, including steatosis, steatohepatitis, fibrosis, and cancer, have been associated with separate exposures. Nonetheless, the overall implication is that environmental exposures may play a role in the ultimate outcomes that influence liver-related mortality.

ASSESSING THE HEPATIC EXPOSOME: BIOMONITORING, SUSCEPTIBILITY, AND MIXTURES

Implementing these insights necessitates the assessment of hepatic exposomes, an area in which the field is currently underdeveloped. Three primary challenges exist. The initial aspect was measurement. Biomonitoring estimates internal exposure by measuring the levels of chemicals or their metabolites in serum, urine, or tissue. However, a single exposure measurement may not be a good representation of lifetime exposure, particularly for non-persistent chemicals (e.g., phthalates and bisphenols) that are rapidly metabolized. Biomarker levels may also be modified by the disease they are trying to predict, as changes in renal clearance and body composition can confound cross-sectional relationships with PFAS[36]. The exposomics approach combines high-resolution biomonitoring with untargeted metabolomics of the liver and blood, allowing the assessment of biological reactions and not only exposure. When applied to human MASLD, this method identified contaminant-associated disruptions in bile acid and lipid metabolism, suggesting a potential hepatic exposome signature[6,10]. Methodologically, the field has transitioned from examining individual suspected chemicals to exosome-wide association studies. In these studies, numerous exposures were screened in an agnostic manner against health outcomes and subsequently ranked for mechanistic investigation. This approach demonstrates that the cumulative environmental contribution to liver disease risk surpasses that of the inherited polygenic risk[7]. Coordinated internal dosimetry measurements, consistent sampling to capture dynamic exposomes, and coupling to the molecular phenotype of the liver are required to unlock this potential.

The second difficulty is related to susceptibility. Host variables, with sex being one of the most prominent modifiers, profoundly shape hepatic response to exposure. Women are more susceptible to the steatogenic effects of PFAS and other persistent organic contaminants. This dimorphism has been ascribed to differences in hepatic lipid metabolism and the hormonal milieu, as revealed by meta-analyses and mechanistic models[9,10,12,14,45]. The life stage is a key component. The developmental window carries a large and persistent risk, as shown by prenatal exposure cohort data[30,31].

The third problem is mixing. Humans are exposed not to single chemicals in isolation, but to dynamic mixtures where chemicals might interact in an additive, synergistic, or antagonistic manner. The interaction of aflatoxin with alcohol and viral hepatitis and the diet-dependence of PCB toxicity highlight the need for investigating agents in context, as their study in isolation might lead to an overestimation of real-world dangers[17,51]. The confirmed hepatic accumulation of micro- and nanoplastics introduces additional complexity, as these particles function as both direct hepatotoxins and carriers of co-contaminants[38,39]. A recent experimental study demonstrated that the co-exposure of mice to polystyrene nanoplastics and the dietary carcinogen aflatoxin B1 resulted in increased hepatic fibrosis and inflammation compared to exposure to either agent alone. This effect is mediated by exacerbated gut dysbiosis and heightened activation of the toll-like receptor 4-nuclear factor-κB pathway[24]. Addressing the challenges of measurement, susceptibility, and mixtures is the primary methodological focus of environmental hepatology. The strength of human evidence currently exhibits significant variation across exposure classes, ranging from relatively robust findings for PFAS, aflatoxin, and vinyl chloride to preliminary data for micro- and nanoplastics, as summarized with representative population studies and evidence criteria in Figure 2.

CLINICAL AND PUBLIC HEALTH IMPLICATIONS

Reinterpreting MASLD as a condition influenced, in part, by the chemical environment has significant practical implications. Clinicians should expand their differential diagnoses to include steatohepatitis in lean patients or those with disproportionate metabolic risks. This consideration should extend to occupational and environmental exposures, as transaminase levels may remain normal despite significant toxicant-associated injury[50]. A comprehensive exposure history that includes occupation, residential proximity to industry or traffic, water sources, and consumer product usage is cost-free and can reveal modifiable contributors. In particular, children and teenagers need special attention as they are more vulnerable at important developmental stages. In addition, profiles of environmental pollutants and metabolites correlate with the histological severity of pediatric steatohepatitis[30,31,52]. Counseling could also include practical ways to reduce exposure, such as drinking filtered water, limiting food contact with plastic, and not cooking food in plastic containers. The danger of these measures is negligible even as the evidence base evolves. Some populations require special attention: Those working with industrial solvents, plastics, or metals; those living in areas with heavy traffic, industrial activity, or contaminated water; and pregnant women and young children, for whom exposure can have significant and long-lasting effects[31,50]. In these individuals, the discrepancy between normal aminotransferase levels and the substantial histological damage indicative of TASH suggests the need for increased dependence on imaging techniques to assess steatosis and fibrosis. Additionally, in research contexts, more sensitive markers of hepatocyte death, such as cytokeratin-18, have consistently demonstrated superior performance compared to transaminases as indicators of environment-related liver injury[31,50].

Environmental exposure significantly interacts with the modifiable behaviors that clinicians currently address. Cigarette smoke is a source of harmful metals and combustion products that contribute to the development and progression of NAFLD, fibrosis, and HCC. Hence, smoking cessation is a major strategy against hepatic exposure and cardiovascular risk[53]. Diet plays two roles. It is a route of entry for pollutants such as aflatoxins, bisphenols, and phthalates and provides the metabolic milieu that defines the adverse consequences of obesogens. Notably, certain pollutants exacerbate steatosis only in the presence of excess[16,17]. Counseling that combines exposure reduction with standard metabolic guidance simultaneously addresses diseases from two perspectives.

These wider implications pertain to public health. Owing to the pervasive and involuntary nature of dominant exposure, the most effective interventions must be upstream and regulatory rather than focused on individual actions[4]. A history of known hepatotoxic exposures, such as aflatoxin and vinyl chloride, illustrates that reducing exposure can lead to significant decreases in liver disease. This rationale also applies to current exposomes[50,51]. In this manner, a significant portion of the global MASLD burden may be preventable not only through individual behavior modification but also through improvements in water, air, and food packaging quality, as well as through the regulation of chemicals[1,6]. The implication is positive because environmental exposure is theoretically preventable, in contrast to inherited risks.

CHALLENGES AND LIMITATIONS

This field has encountered significant and recognized limitations. Much of the human evidence is cross-sectional and observational, making it susceptible to reverse causation, because a diseased liver may influence the handling and serum levels of the chemicals being examined. There is also the possibility of residual confounding owing to factors such as nutrition, socioeconomic position, and co-exposure[36]. The research contains internal inconsistencies: Meta-analyses show substantial connections for some endocrine disruptors but null or inverse effects for others. In addition, sensitivity analyses are typically unstable and show real variations in populations, exposure ranges, and outcome criteria[9,45]. Persistent chemicals accumulate in biological systems for long periods, but non-persistent compounds fluctuate over time, posing different measurement issues. Consequently, single biomarker measurements do not adequately reflect the lifetime exposure. The detection of microplastics in the human liver is notable; however, it currently indicates the presence of microplastics rather than establishing causation. It remains unclear Whether the accumulation leads to fibrosis or is a consequence of it[38,39]. Much of the mechanistic research has originated from rodent models or single-chemical high-dose designs, which may not accurately represent chronic low-level human mixture exposure. Moreover, experimental models are often different in several contemporaneous variables, such as co-exposure, food, and illness state, making it difficult to attribute the observed liver effects to the exposure of interest alone. This requires regulated designs that isolate specific factors. Publications and freedom of analysis can create positive relationships. Ultimately, the literature exhibits methodological heterogeneity, and this review is narrative rather than systematic. Consequently, the evidence presented should be interpreted as a synthesis of direction and plausibility, rather than a pooled effect size. The main challenges and corresponding approaches required to address them are summarized in Table 2.

Table 2 Key challenges and proposed solutions for advancing the hepatic exposome in clinical hepatology.

Challenge	Description	Proposed solution/future direction
Exposure measurement	Single biomarkers poorly capture lifetime exposure; non-persistent chemicals fluctuate, persistent ones bioaccumulate	Serial biomonitoring within prospective cohorts; couple to untargeted exposomics-metabolomics to read biological response
Reverse causation and confounding	Diseased liver alters chemical handling and serum levels; diet and socioeconomics co-vary	Prospective designs establishing temporality; pre-diagnostic biospecimens; careful covariate control
Inconsistent and heterogeneous evidence	Meta-analyses show robust associations for some chemicals but null/inverse for others; unstable sensitivity analyses	Harmonized exposure and outcome definitions; individual-participant-data pooling; transparent reporting
Chemical mixtures	Humans are exposed to dynamic combinations with additive, synergistic, or antagonistic effects	Mixture-aware statistical methods; nutrient-toxicant and exposure-exposure interaction studies
Susceptibility and sex differences	Hepatic response is host-dependent; women and early-life windows show heightened risk	Sex-stratified analyses adequately powered; life-course and developmental cohort designs
Causal inference	Much evidence is observational and mechanistic data often single-chemical/high-dose	Human liver organoids and microphysiological models; Mendelian-randomization-style and quasi-experimental approaches
Clinical translation	No validated tools to detect or stratify exposome-associated liver injury	Develop and validate a hepatic exposome biomarker panel of exposure and effect; integrate exposure history into care
Prevention and regulation	Exposures are largely involuntary and ubiquitous	Upstream regulatory action on water, air, and food packaging; surveillance of regrettable substitution

FUTURE DIRECTIONS

Progress necessitates approaches that match the intricacy of the exposome. Prospective birth and adult cohorts with serial biospecimen banking are essential for establishing temporality and capturing exposure during sensitive windows. These cohorts should be integrated with the exposomics-metabolomics framework to measure biological responses, rather than exposures[6,10]. Prenatal-mixture and persistent-pollutant-mixture investigations suggest that analytical methodologies for mixtures, rather than individual chemicals, are needed. In addition, study designs should be appropriately powered to discover sex-specific effects that traditional analyses may miss[31,45]. Environmental risk factors can be distinguished from hereditary variables by integrating exposomic and epigenomic data to identify susceptible subgroups. This view is supported by data that show that environmental exposure is more important than polygenic risk in the context of hepatic diseases[7]. Human-relevant experimental systems, including liver organoids and microphysiological models, provide ethically and mechanistically informative links between population associations and causal biology[18]. Ultimately, the objective was to develop a clinically applicable hepatic exposome panel comprising a validated collection of biomarkers for exposure and effect that can stratify risk, inform counseling, and function as endpoints for assessing regulatory interventions.

Therapeutic outcomes were also observed. Pharmaceutical interventions are possible for several pathways of environmental chemical-induced liver damage, providing the potential to ameliorate exposome-related disorders while concurrently decreasing exposure. Pharmacological targets include the FXR-bile acid axis, which is damaged by bisphenols and metals. The FXR agonist obeticholic acid improved hepatic fibrosis in a phase 3 REGENERATE trial for steatohepatitis[54]. Obeticholic acid is not licensed for metabolic dysfunction-associated steatohepatitis, and development for this application was discontinued due to regulatory concerns regarding the benefit-risk balance. This experience reduces expectations for this particular drug, but the FXR axis remains a valid therapeutic target and is currently being investigated using next-generation agonists[55]. The NLRP3 inflammasome is triggered by chemical and metabolic stresses, and its inhibition has been shown to attenuate inflammation and fibrosis in animal models[21]. Additionally, the gut-liver axis, influenced by various pollutants, may be altered using microbiota-targeted approaches[23]. Targeting these shared nodes will not replace the need to reduce exposure; however, it provides an additional approach for mitigating hepatic injury in individuals who have already been exposed.

NOVELTY OF THE STUDY

To our knowledge, this review is one of the first to integrate various aspects of environmental hepatology into a cohesive, clinically focused examination of the hepatic exposomes in MASLD. This novelty is attributed to five distinct contributions. First, it integrates structurally unrelated exposure classes, including per- and PFAS, micro- and nanoplastics, endocrine-disrupting plasticizers, persistent organic pollutants, toxic metals, and air pollution, within a single mechanistic framework of convergent hepatic injury, rather than addressing each contaminant in isolation. Second, it evaluates the strength of human evidence clearly and consistently across the abstract, main text, and specific figure, differentiating exposures with relatively strong human data from those such as micro- and nanoplastics, which are biologically plausible yet unproven, while also distinguishing between association and causation. Third, it distinguishes host-susceptibility factors, specifically sex and life stage, from exposure-related modifiers, including mixture composition, dose, and timing, emphasizing sex-specific and developmental susceptibility as central organizing principles rather than mere afterthoughts. Fourth, it reconceptualizes progression not as a singular continuous exposure-driven course, but as specific associations between particular exposures and distinct liver outcomes. Fifth, it translates these insights into specific clinical and public health actions, including targeted exposure history, increased reliance on imaging, cytokeratin-18 when transaminases are normal, and the development of a validated hepatic exposome biomarker panel to aid in risk stratification and prevention.

CONCLUSION

The traditional view of MASLD as a condition resulting from overnutrition and metabolic syndrome is accurate, but incomplete. A growing body of evidence suggests that the chemical environment, specifically the hepatic exposome, is a plausible and modifiable contributor to steatotic liver disease, encompassing the progression from steatosis to steatohepatitis and fibrosis and potentially contributing to hepatocarcinogenesis. Per- and PFAS, micro- and nanoplastics, phthalates, bisphenols, persistent organic pollutants, toxic metals, and air pollution are structurally distinct but collectively impact biological systems through mechanisms such as nuclear receptor disruption, mitochondrial and oxidative damage, inflammasome activation, stellate-cell fibrogenesis, disruption of the gut-bile acid axis, and developmental reprogramming. The evidence strength varied significantly among these exposures, being relatively strong for per- and PFAS and classical hepatotoxicants, while remaining preliminary for micro- and nanoplastics. Most human data are associated rather than causal. Recognizing these exposures is clinically significant as they may be associated with considerable liver injury despite normal transaminase levels and low metabolic risk. Furthermore, unlike genetic factors, this recognition is crucial for prevention, as exposure can be modified. Integrating environmental hepatology at the core of our understanding, stratification, and prevention of steatotic liver disease represents a significant opportunity for this field.