Inflammation and Cardiometabolic Diseases Induced by Persistent Organic Pollutants and Nutritional Interventions: Effects of Multi-Organ Interactions

Abstract

The development and outcome of inflammatory diseases are associated with genetic and lifestyle factors, which include chemical and nonchemical stressors. Persistent organic pollutants (POPs) are major groups of chemical stressors. For example, dioxin-like polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFASs), and polybrominated diphenyl ethers (PBDEs) are closely associated with the incidence of inflammatory diseases. The pathology of environmental chemical-mediated inflammatory diseases is complex and may involve disturbances in multiple organs, including the gut, liver, brain, vascular tissues, and immune systems. Recent studies suggested that diet-derived nutrients (e.g., phytochemicals, vitamins, unsaturated fatty acids, dietary fibers) could modulate environmental insults and affect disease development, progression, and outcome. In this article, mechanisms of environmental pollutant-induced inflammation and cardiometabolic diseases are reviewed, focusing on multi-organ interplays and highlighting recent advances in nutritional strategies to improve the outcome of cardiometabolic diseases associated with environmental exposures. In addition, advanced system biology approaches are discussed, which present unique opportunities to unveil the complex interactions among multiple organs and to fuel the development of precision intervention strategies in exposed individuals.

Graphical Abstract

1. Introduction

Inflammation triggers the early phases of many disease processes, and the increased production of inflammatory cytokines is associated with a higher risk of developing multiple disorders. For example, it has been established that inflammatory processes play a crucial role in the development and complications of cardiometabolic diseases (CMD) ¹, including cardiovascular disease (CVD), diabetes, and nonalcoholic fatty liver disease (NAFLD) ^{2, 3}. POPs are the most investigated organic environmental contaminants. POPs disturb the ecological balance and threaten the health of all organisms. Multiple epidemiological studies have reported the associations between exposure to persistent organic pollutants (POPs) and air pollutants (a mixture of POPs with gaseous pollutants, such as nitrogen dioxide, ozone, and sulfur dioxide) and an increased risk of CMD ^4–9. A common mechanism underlying most environmental pollutant-mediated disease risks is attributed to enhanced inflammation ^{10, 11}. Recent reports have linked the pathology of CMD with the involvement of multiple organ systems, including liver, heart, and gut ^12–15, and mounting evidence suggests that lipophilic and amphipathic POPs, such as dioxin-like polychlorinated biphenyls (PCBs) and per- and polyfluorinated substances (PFASs), promote CMD risks via gut microbiota dysbiosis and liver dysfunctions ^15–19. Emerging evidence supports a significant impact of POPs on immune functions ²⁰, gastrointestinal system ²¹, and pulmonary health ²². Organ interactions such as gut-lung axis ²³, gut-liver axis ²⁴, and gut-brain axis ²⁵ play important roles in environmental pollution-associated inflammatory disease progression. These reports highlight the complex network of interactions between host organs and the gut/microbiome. In addition, organ crosstalk has been established not only between two organs but among multiple organ systems, such as the cardiovascular, gastrointestinal, nervous, endocrine, metabolic, and immune systems ^{26, 27}. Thus, prevention or intervention strategies to counteract disease risks associated with exposure to environmental stressors should consider multiple organ interactions when aiming to reduce inflammation.

Consumption of healthy nutrients, i.e., foods rich in antioxidant and anti-inflammatory components, has been linked to CVD prevention for both healthy individuals and people at higher disease risk of CVD ^28–30. Studies indicated that phytochemical interventions, specifically those involving polyphenols and polysaccharides (dietary fiber), can reduce or prevent the development of inflammatory events induced by exposure to environmental pollutants ^31–35. This review highlights inflammatory disease mechanisms related to POPs (PCBs, PFASs, and PBDEs) exposure, and discusses the potential nutritional intervention approaches, with a focus on multi-organ systems interactions, thus, providing a scientific basis for the design of precision nutritional intervention strategies to prevent toxicity from environmental insults.

2. Search Strategy

We utilized the PubMed search to assess the topic-related literature. The specific methods are as follows: The PubMed database retrieval language is “persistent organic pollutant (Title/Abstract) AND inflammatory disease (Title/Abstract)”, “polychlorinated biphenyl (Title/Abstract) AND inflammatory disease (Title/Abstract)”, “PFAS (Title/Abstract) AND inflammatory disease (Title/Abstract)”, “intervention (Title/Abstract) OR nutrient (Title/Abstract) AND persistent organic pollutant (Title/Abstract)”, “intervention (Title/Abstract) OR nutrient (Title/Abstract) AND polychlorinated biphenyl (Title/Abstract)”, “intervention (Title/Abstract) OR nutrient (Title/Abstract) AND PFAS (Title/Abstract)”, and the publications date range from 2012 to 2023. We then filtered the literature based on the title, abstract, and full text of each paper, and a total number of 100 articles relevant to our topic were collected.

3. Persistent organic pollutants

3.1. Polychlorinated biphenyls (PCBs)

PCBs are POPs found in soil, air, and water. Fish and small organisms can absorb PCBs from the water and sediments in their habitat. PCBs accumulate in organisms through the food chain. Therefore, the major source of human exposure to PCBs is the dietary intake of contaminated food and water. In mammals, the liver is the most important tissue for the initial distribution of PCBs because it is highly perfused. Fatty tissue is the major storage compartment for PCBs, and adipose has the highest PCB tissue-to-blood partition coefficient due to the high lipophilicity of PCBs. For example, the human adipose/serum partition coefficient ranges from 50 to 370 ³⁶. The estimated half-lives of PCBs in different species range from 0.13 to 7.9 years depending on the degree of chlorination and the substitution pattern of the PCB congeners ³⁷. According to the information compiled by the Agency for Toxic Substances and Disease Registry (ATSDR, https://wwwn.cdc.gov/TSP/MRLS/mrlsListing.aspx), the minimal toxic dose (minimal risk levels, MRL) in humans for orally and chronically exposed PCBs (Aroclor 1254) is 20 ng/kg/day using immune toxicity endpoints. Dioxin-like PCBs likely modulate CVD and related pathologies by inducing oxidative stress, cellular dysfunction, and chronic inflammation in key cell types associated with atherosclerosis ³⁸. They have also been shown to initiate vascular endothelial cell dysfunction, induce key pro-atherogenic adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), increase monocyte attraction, and induce vascular permeability ^{38, 39}. PCBs could damage organ systems in which they are known to bioaccumulate, such as the liver and adipose tissues ^{12, 40}. At the transcriptional level, PCB126 activated the aryl hydrocarbon receptor (AhR) to produce an inflammatory response in preadipocytes ⁴¹. In a recent study, the exposure of insulin-resistant adipocytes to PCB126 in vitro led to impaired glucose uptake in myotubes, suggesting adipose-muscle communications ⁴². Animal experiments demonstrated that PCBs exposure led to inflammation in multiple organs, including the liver, adipose, gut, and vascular ^{40, 43, 44} (Figure 1).

Figure 1.

The involvement of multiple organ systems and interactions in PCB exposure induced toxicity (created with BioRender.com). AhR: aryl hydrocarbon receptor; FMO3: flavin-containing monooxygenase 3; HNF-1b: hepatocyte nuclear factor-1b; ICAM-1: intercellular cell adhesion molecule-1; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinase; NAFLD: nonalcoholic fatty liver disease; NF-κB: nuclear factor kappa-B; NLRP3: NOD-like receptor thermal protein domain associated protein 3; PAI-1: plasminogen activator inhibitor-1; PCB: polychlorinated biphenyl; ROS: reactive oxygen species; TMAO: trimethylamine oxide.

The liver is a major toxic organ for PCBs. It has been reported that PCBs altered normal hepatic nuclear receptor signaling and AhR function, disturbed hepatic metabolism, and promoted the production of inflammatory cytokines, all of these contribute to the development of NAFLD ⁴⁵. The role of a compromised liver in defining dioxin-like PCB126 toxicity on the peripheral vasculature and associated inflammatory diseases has been studied ^{40, 43}. In a mouse model of NAFLD, it was found that PCB126 exposure led to increased plasma inflammatory markers such as ICAM-1, plasminogen activator inhibitor-1 (PAI-1), and trimethylamine N-oxide (TMAO) ⁴⁰. In addition, redox stress-related metabolites were elevated in NAFLD mice exposed to PCB126 ⁴³. The data suggested that a compromised liver altered PCB-mediated toxicity, resulting in increased systemic inflammation ^{40, 43, 46}.

The interactions between the liver, gut, and vascular tissues contribute to the toxicity of PCBs. Certain metabolites (e.g., TMAO) formed by intimate crosstalk between gut microbiota and host liver enzymes could be causative mediators of pollutant-linked disease risks ^47–49. TMAO was positively associated with dioxin-like pollutant exposure in the Anniston and Alabama cohorts (residents who live close to a former PCB production site) ⁵⁰. An animal study revealed that PCB-induced upregulation of FMO3 led to increased circulating plasma levels of pro-atherogenic TMAO ⁵¹. TMAO was found to be associated with CMD by inducing foam cell formation, activating platelets, and promoting vascular inflammation ⁵². Other gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) and bile acids, might also be involved in cardiovascular health and disease ⁵³, especially after exposure to PCBs ⁵⁴. These data suggested that environmental exposures could lead to changes in gut microbial metabolites, which act as mediators of CVD.

The immune system plays an important role in PCB-mediated inflammation. For example, PCB126 promoted macrophage inflammation and polarized monocytes to an M1-like phenotype through AhR and nuclear factor kappa-B (NF-κB) pathways (Figure 1). As a result, inflammatory factors such as tumor necrosis factor alpha (TNFα) and Interleukin-1 beta (IL-1β), and oxidative stress-sensitive markers such as heme oxygenase 1 (HMOX1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were induced⁵⁵. In addition to the parent compound, the PCB metabolites could be stronger inducers of inflammatory markers. As a possible biotransformation product of PCBs, PCB29-pQ might be involved in the MAPK-NF-κB inflammatory pathway by activating the RIPK1/3-MLKL pathway through a reactive oxygen species (ROS)-dependent mechanism, thus promoting macrophage-derived foam cell necrosis and ultimately accelerating the release of inflammatory cytokines to form the necrotic core of plaques ⁵⁶. Furthermore, PCB29-pQ could promote macrophage/monocyte polarization to CD163⁺ macrophages, which would be a potential incentive to accelerate atherosclerosis through the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway ⁵⁷. Additionally, PCB29-pQ promoted the accumulation of lipids in macrophages via upregulation of lipid transporter CD36, activation of the endoplasmic reticulum stress response, and accompanied apoptosis and necrosis ⁵⁸. The mechanisms of other dioxin-like PCB (PCB118) and non-dioxin-like PCB (PCB153) induced inflammation are shown in Supplemental Table S1. Besides the direct effects of PCB on immune cells, the gut microbiota alterations may also contribute to changes in immune functions after PCB exposure. Environmental exposure to PCBs led to gut dysbiosis and increased gut permeability ⁵⁹, which could introduce toxicants, bioactive endogenous metabolites, and pathogens into the systemic circulation, causing immune alternations in the liver and other extrahepatic organs.

MicroRNAs (miRNAs) are a class of small oligonucleotides that interact with messenger RNA. PCB-induced oxidative stress and production of pro-inflammatory cytokines could be regulated by miRNAs. For example, it was found that co-exposure to TCDD and PCB could increase the mRNA level of ICAM-1 which was regulated by miR-130a-3p ⁶⁰. Aroclor 1260 increased miR-21, miR-31, miR-126, miR-221 and miR-222 expression levels ⁶¹. miR-21 was reported to increase fibrosis and cardiac hypertrophy ⁶², while miR-31, miR-126, miR-221, and miR-222 modulated inflammation ⁶³. A significant increase in miR-192–5p was observed in PCB126 and/or Aroclor1260 exposed mouse livers ⁶⁴. In addition, an epidemiology study revealed that circulating miR-192–5p was a hepatotoxicity biomarker from PCB exposures ⁶⁵. miR-192–5p could promote the activation of M1 macrophages and increase the expression of iNOS, IL-6, and TNF-α via Rictor/Akt/FoxO1 signaling pathway ⁶⁶, which might contribute to PCB-induced toxicity. It was reported that circulating miRNAs could be secreted from different organs, including the liver, adipose, muscle, and the cardiovascular system ⁶⁷. Therefore, miRNAs might serve as messengers that facilitate communication between secreted cells/tissues with receptor cells/tissues, thereby potentially having important roles in organ crosstalk.

As multiple organs are involved in PCB toxicity, it is interesting to know the rankings of the effects on different organs. Oral ingestion of contaminated food and water is one of the major routes of PCB exposure. Therefore, the gut and microbiome represent the first defensive barrier towards PCBs. The liver is a critical organ for PCB metabolism, and the fat is the major storage compartment for PCBs, suggesting these organs are more likely to be exposed to higher concentrations of PCBs than other tissues. Increasing evidence suggests that the gut microbiome mediates liver functions and plays an important role in the progression of toxicant-induced liver diseases. In addition, the liver regulates the metabolism and innate immunity in other organs, therefore alterations in liver functions can also impact the metabolic signaling and immunity of other host organs ²⁶. It was reported that PCBs induced adipose tissue dysfunction, including abnormal lipid accumulation ⁶⁸, altered adipokine and cytokine secretion ^{40, 41}, i.e., adiponectin, IL-6, MCP-1, and TNF-α, which in turn affected muscle metabolism ⁴². These effects could be consequences of adipocyte AhR activation⁶⁹. Therefore, it seems plausible that exposure to PCBs may affect the gut microbiome function and structure, accompanied by liver and adipose dysfunction and then the effects could be extended to distal organs and the physiological health of the host. To provide a quantitative estimation of which organ is affected first and most seriously, the toxicokinetics needs to be taken into consideration.

3.2. Polyfluoro- and perfluoroalkyl substances (PFASs)

PFASs are widely used in industrial processes and consumer products. These compounds are found to be ubiquitous in environmental media because of their innate chemical stability. Widespread human exposure to PFASs via drinking water and contaminated food, along with their long biological half-lives have led to measurable PFASs in many populations worldwide. PFASs are highly efficiently absorbed in animals and humans ⁷⁰. The vast majority of PFASs entering the body are absorbed in the gastrointestinal tract and then distributed to various tissues. A large percentage of PFASs is retained in serum, liver, and kidney, and some can also accumulate in the intestine ⁷¹. The estimated half-lives of PFAS range from 0.63 y (perfluoropolyether) to 18.5 y (6:2 chlorinated polyfluorinated ether sulfonate) in humans ^{72, 73}.

The health effects of PFASs exposure have become a global concern. Emerging evidence suggested that exposure to PFASs was associated with inflammatory diseases, including metabolic dysfunctions (i.e., CVD, NAFLD, and chronic kidney diseases) and immune-related health conditions (i.e., allergic diseases, infection, and vaccine response) ^{74, 75}. The liver is a well-established toxic target organ for many PFASs. With hepatocellular hypertrophy being used as the toxicology endpoint, it was found that the shapes of the dose-response curves were similar for short- and long-chain perfluoroalkyl carboxylic acids (PFCAs) and perfluorobutanesulfonic acid (PFBS) (slopes ranged from 12.0 to 18.0) ⁷⁶. However, different dose-response curves were observed for perfluorooctane sulfonate (PFOS) and perfluorohexanesulfonic acid (PFHxS), with slope values being 4.1 and 4.6 respectively. The results suggested that liver toxicity among PFASs was different. According to ATSDR, the MRL of orally exposed PFASs (PFOA, PFOS, PFNA, and PFHxS) is 2–20 ng/kg/day in humans by using developmental and endocrine toxicity endpoints. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005–2012, Omoike et al. found that increased exposure to PFASs resulted in increased serum concentrations of markers associated with chronic inflammation and oxidative stress, including lymphocyte count, serum iron, albumin, and bilirubin ⁷⁷. Meneguzzi et al. reviewed epidemiological studies exploring the relationship between PFASs exposure and thromboembolic cardiovascular disease and found that changes in plasma membrane fluidity and calcium signaling were observed with PFASs exposure, along with platelet activation hypersensitivity ⁷⁸. Animal and cell culture experiments demonstrated that PFASs exposure resulted in oxidative effects in cells and tissues, leading to inflammation in organs including the liver, gut, brain, and immune system (Figure 2).

Figure 2.

The involvement of multiple organ systems and interactions in PFAS exposure induced toxicity (created with Figdraw.com). BBB: blood-brain barrier; GBB: gut-blood barrier; LTC4: leukotriene C4; LPS: lipopolysaccharide; PFAS: polyfluoro- and perfluoroalkyl substances; PGD2: prostaglandin D2.

Gut-liver interactions play an important role in PFAS toxicity ¹⁹. Mouse studies suggested that PFOS disturbed liver metabolism at transcription and metabolome levels, which overlapped with increases in Bacteroidetes, Clostridium, and Streptococcus, and decreases in Firmicutes, Flavonifractor, Alistipes, and Enterococcus ^{17, 18, 35}. Suppression of gut microbiota using antibiotics and supplementation of bacteria by fecal cell transplant (L. reuteri, E. faecalis, and Akk. muciniphila) attenuated the adverse liver effects induced by PFOS, suggesting that PFOS-induced liver injury is mediated through remodeling of the gut microbiota ¹⁷. Furthermore, the correlation between the gut microbiome and alterations in the hepatic PPAR pathway (lpl, slc27a2a, and Acox3) after PFAS exposure suggested a probable interaction between changes in the gut microbiota and hepatic lipid metabolism.⁷⁹. Several new PFASs have also been shown to induce dysbiosis, which has been linked to a series of intestinal and liver diseases. For example, exposure to 6:2 chlorinated polyfluoroalkyl ether sulfonate ⁸⁰, hexafluoropropylene oxide dimer acid (HFPO-DA) ⁸¹, and sodium ρ-perfluorous nonenoxybenzene sulfonate (OBS) ⁸² could cause inflammation in the gut, destruction of tight junction structure, reduced intestinal mucus secretion, and hepatic metabolism disorder.

PFAS exposure has been implicated in neurotoxicity in humans ⁸³, and recent studies suggested that the gut-brain axis was an important link in PFAS-induced neurotoxicity ^{84, 85}. For example, PFOA exposure led to cognitive deficits in mice and caused inflammation in the gut and brain by increasing lipopolysaccharide (LPS), TNFα, IL-1β, and cyclooxygenase-2, while fecal microbiota transplantation mitigated these symptoms ⁸⁵. These effects could be related to PFOA-induced alterations in gut microbial composition and functions. The levels of Bifidobacterium-psudolongum and Bifidobacterium-bifidum, the gut bacteria that sustain mucosa thickness and barrier integrity, decreased after PFOA exposure in mice. In addition, acetic acid, propionic acid, and butyric acid, the SCFAs that suppress colonic inflammation by activating GPR43 and GPR109a were decreased. These effects led to impaired barrier integrity which resulted in higher LPS invasion into the systemic circulation and induced inflammation in the brain as demonstrated by the increased levels of LPS, TLR4, NF-κB, and IBA-1 in the brain. Similarly, perfluoroalkyl phosphonic acids (PFPiAs), significantly increased the abundance of Gram-negative bacteria in zebrafish ⁸⁴, which led to increased levels of LPS and inflammation in the gut and brain. The LPS was delivered to the brain through the gut–brain axis, damaged the blood–brain barrier (BBB), and caused mitochondrial damage as well as apoptosis in the brain. This mechanism was verified by the fact that antibiotics reduced the LPS levels in the gut and brain, accompanied by reduced inflammatory responses.

Emerging evidence suggests that PFAS exposure in humans is associated with immune-related health conditions, including allergic diseases, infection, and vaccine response ⁷⁵. Cardio-metabolic disorders are typically associated with increased inflammation. However, PFAS are already known to be immuno-suppressive, reflected by the inverse relationship between PFAS exposure levels and TNFα in humans ⁸⁶. PFAS affects multiple aspects of the immune system, including modulation of nuclear receptors (e.g., NF-κB, PPARs), Ca²⁺-signaling, as well as modulation of oxidative stress ⁸⁷. Moreover, PFAS exposures are associated with altered lipid levels by upregulating gene expressions in lipid metabolism, e.g., CD36 ⁸⁸, which might contribute to immune cell dysfunctions and cardio-metabolic disorders ⁸⁹. It has become increasingly understood that immune cells could sense environmental signals and promote multi-organ interplays ⁹⁰. PFOS and PFOA are the most commonly studied PFASs in relation to immunotoxicity. They altered the expression of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) in macrophages ⁹¹, upregulated cytokine production (IL-4 and IL-13) in Th2 cells ⁹², and activated inflammatory responses in mast cells by increasing the production of inflammatory eicosanoids, leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) ⁹³. Inflammasome, a high-molecular-weight complex present in the cytosol of stimulated immune cells that mediates the activation of inflammatory caspases, was identified as the key factor regulating PFAS recognition in the cells and triggering cellular inflammatory responses in organs ^{94, 95}. PFOA exposure increased NLRP3 inflammasome aggregation in mice liver, and autophagy was found to be associated with PFOA-induced NLRP3 activation, highlighting the mechanisms used by PFOA to trigger cellular inflammatory responses ⁹⁵. PFOS could induce AIM2 inflammasome dependent IL-1β production in macrophages. This mechanism was further verified using Aim2-deficient mice, which were protected from PFOS-induced multiple tissue inflammation and damage, including liver, lung, and kidney, proving the important role of the immune system and AIM2 inflammasome in multi-organ toxicity after PFOS exposure ⁹⁴. Mechanistically, this process was mediated by PFOS-induced mitochondrial dysfunction and mitochondrial DNA release (Supplemental Table S2). Together, these studies indicated that the immune cells could regulate multi-organ inflammation after sensing environmental insults. Nevertheless, we still need a better understanding of the toxicity mechanisms of environmental exposure underlying immune system-organ interactions.

3.3. Polybrominated diphenyl ethers (PBDEs)

Polybrominated diphenyl ethers (PBDEs) are widely used as flame-retardant additives in consumer and household products. PBDEs have become a global environmental organic pollutant due to the properties of persistence and bioaccumulation ⁹⁶. Exposure to these chemicals has been associated with hepatotoxicity, developmental neurotoxicity, metabolic dysfunctions, and reproductive disorders ^{97, 98}. According to ATSDR, the MRL for PBDE is 3 ng/kg/day for oral administration in humans using development and endocrine toxicities endpoints (https://wwwn.cdc.gov/TSP/MRLS/mrlsListing.aspx). BDE-209 is one of the most predominant PBDE ⁹⁶. It was reported that BDE-209 enhances oxLDL-induced macrophage foam cell formation by increasing Toll-like receptor 4 (TLR4)-dependent lipid uptake in macrophages ⁹⁹. The effect and potential molecular mechanism of BDE-209 adhesion between THP-1 monocytes and human aortic endothelial cells (HAECs) were investigated. It was found that BDE-209 potentiated ICAM-1 expression and increased adhesion by downregulating miR-141 ¹⁰⁰. BDE-209 induced oxidative stress and inflammation and ultimately led to endothelial dysfunction and cardiovascular injury in rats ¹⁰¹. In addition, PBDEs impacted host metabolism in an intestinal microbiome-dependent manner in mice, indicating that gut dysbiosis may contribute to PBDE-mediated metabolic disturbance ¹⁰² (Supplemental Table S3).

4. Nutritional intervention of environmental pollutant-mediated inflammatory diseases

Nutritional interventions have been considered as an effective strategy to reduce the risk of inflammatory diseases ^{103, 104}. Flavonoids are a large group of phenolic compounds present in foods of plant origin and have a broad range of health-beneficial effects, including antioxidation and anti-inflammation¹⁰⁵. Growing evidence suggests that flavonoids contribute to the prevention or reduction of the damage caused by certain environmental pollutants (Table 1–3). The gut microbiota plays an important role in overall host health, and disruptions in microbiota homeostasis by environmental exposures have been implicated in developing inflammatory diseases ¹⁰⁶. Therefore, utilization of dietary interventions to mitigate the negative effects of environmental exposures on gut microbiota could be a feasible approach to reduce inflammatory disease risks associated with pollutant exposure. Dietary fibers are a diverse set of carbohydrate polymers. Numerous studies have reported that diets that are high in fiber play a protective role in the occurrence of inflammatory diseases. The mechanisms behind the protective effects of high-fiber diets included modulation of lipid metabolism ^{107, 108}, alterations in the intestinal microbiome structure and metabolism ¹⁰⁹, and immunomodulation effects ¹¹⁰. Growing evidence highlighted the importance of dietary fibers in influencing health maintenance and disease development after environmental exposures ^{34, 35, 111}, indicating the great potential of using dietary fiber in the intervention of environmental diseases.

Table 1.

Mechanisms of nutritional intervention against PCB-mediated toxicity

Environmental Chemicals (Dose, route, duration)	Nutrients (Dose, route, duration)	Subjects	Disease endpoint	Mechanisms	Reference
PCB126 (5 μmol/kg mouse, gavage, in weeks 10, 11, and 12)	Green tea extract (1%GTE-supplemented diet, oral, 12 weeks)	C57BL/6 mice	Liver injury. Reduce the expression of key markers of inflammation (MCP-1 and CCL3)	Upregulate a battery of antioxidant enzymes; upregulate genes transcriptionally controlled by AhR and Nrf2 proteins	33
PCB126 (1.5 mg/kg, gavage, twice a week for two weeks)	Inulin (250 mg/kg/day fiber, given drinking water containing inulin, throughout the PCB126	male C57BL/6 J mice	Liver inflammation and fibrosis. Inulin treatment decreases the hepatic mRNA levels of TNFα, Ccl2, Ccl3, CoL1a1, and Sirius red staining	Affect the structure of gut microbiome. Inhibit PCB126-induced reduction of intestinal ZO-1 expression and reduce the release of inflammatory cytokines	111
PCB126 (1 μmol/kg, oral gavage, at weeks 2 and 4)	A high cholesterol diet with 8% inulin, 12 weeks	male Ldlr−/− mice	Atherosclerosis. Inulin decreases aortic root lesion area in Ldlr−/− mice	Production of protective metabolites, decrease in atherogenic lipoproteins and cholesterol	34
POPs (diet containing a mixture of POPs, including PCB, PBDE, dioxin, and DDT weeks 0 to 10)	Cranberry extract (200 mg/kg, from week 10 to week 16)	male C57BL/6J mice	Harmful effects of the weight loss process. Cranberry extract treatment leads to lower fasting glycemia and improved glucose tolerance	Improve glucose homeostasis, target the gut microbiota, and increase the relative abundance of Parvibacter	125
POPs (PCBs and organochlorine pesticides)	Vitamin C (1000 mg/day Vitamin C, oral, 2 months)	15 healthy California women	Blood concentrations of POPs	Reduce body burdens of POPs	113

Table 3.

Mechanisms of nutritional intervention against BDE-209 mediated toxicity

Environmental Chemicals (Dose, route, duration)	Nutrients (Dose, route, duration)	Subjects	Disease endpoint	Mechanisms	Reference
BDE-209 (5 μmol/L, media, 12 h)	Luteolin (5, 50, 100 μmol/L, media, 24 h)	Caco-2 cells	Intestinal barrier damage. Luteolin increases the expression of tight junction proteins (ZO-1, occludin, and claudin-1)	Reduce the level of reactive oxygen species, inhibit the secretion of proinflammatory cytokines, inhibit the ERK and NF-κB/MLCK signaling pathways, and activate the Nrf2/ARE signaling pathways	137
BDE-47 (150 mg/kg/day, oral gavage, 12 w)	Troxerutin (150 mg/kg/day, oral gavage, 12 w)	male ICR mice	Liver index, serum ALT level, F4/80 (Kupffer cell marker) and IL-1β	Attenuate oxidative stress-mediated NAD+-depletion, restore SirT1 expression and activity	138

In addition to the effects on toxicodynamics, nutritional intervention could affect the toxicokinetic processes of environmental pollutants. For example, antioxidant vitamins, such as vitamin C, can remove the free radicals inside or outside cells and keep the stability of the redox system in the body. It has been reported that vitamin C exerts hepatoprotective effects against chemical-induced liver injuries in mice ¹¹². A pilot study reported that vitamin C intervention might lower the levels of POPs, including organochlorine pesticides and PCBs, in the blood of healthy women ¹¹³. This was proposed to be related to the accelerated hydroxylation metabolism of POPs by vitamin C, which could reduce the duration of the toxic effects of POPs in vivo. However, only 15 female subjects were included in this pilot study, and follow-up investigations should include more subjects to confirm the intervention effects of vitamin C. Fiber-rich food intake has been associated with lower environmental pollutant levels in humans, including PFAS ¹¹⁴, acrylamide¹¹⁵, and isopentanaldehyde ¹¹⁶. Although the mechanism of high dietary fiber intake on decreased pollutant exposure in humans remains unknown, it was postulated that dietary fiber reduced the absorption of pollutants and increased their excretion into feces. In an animal study, lower PFOS accumulation in livers was observed in mice fed with soluble fiber-supplemented diets compared with the control diet. This could be because soluble fibers can potentially reduce the reabsorption of PFOS by regulating apical sodium-dependent bile acid transporters, Na⁺ taurocholate cotransport polypeptides, and organic anion transporting polypeptide transporters, and thus increase PFOS excretion in feces ³⁵.

Recently, there has been an increasing interest in probiotics intervention with high xenobiotics binding capacity ¹¹⁷. For example, lactic acid bacteria (LAB), including Lactobacillus plantarum ¹¹⁸ and Lactobacillus rhamnosus ¹¹⁹ have been discovered to accelerate the removal of heavy metal (cadmium ^{118, 119}), POPs (phthalates ¹²⁰), and bisphenol A ¹²¹. Additionally, a pilot study suggested that L. rhamnosus GR-1 supplemented yogurt protected against the increased mercury and arsenic levels in the blood of pregnant women ¹²². Furthermore, it was found that a probiotic mixture (Saccharomyces boulardii + Lactobacillus rhamnosus + Lactobacillus planarum LP 6595+ Lactobacillus planarum HEAL9) ameliorated systemic inflammation caused by phthalates and bisphenol A mixture in Wistar rats ¹²³. Thus, probiotic cultures are expected to become important among the other protective agents, such as antioxidants, vitamins, and dietary fibers, to reduce environmental toxicity ^{117, 124} by affecting both toxicokinetic (accelerate excretion and reduce body burden) and toxicodynamic (decrease inflammation) processes induced by pollutants. A summary diagram of the mechanisms of nutritional intervention against environmental chemical-mediated diseases is shown in Figure 3.

Figure 3.

Mechanisms of nutritional intervention against environmental chemical-mediated inflammatory diseases via multi-organ interactions (created with BioRender.com). Polyphenols mainly affect the toxicodynamic processes of environmental pollutants (antioxidant and anti-inflammation). However, vitamin C, probiotics, and dietary fibers affect both toxicodynamic and toxicokinetic processes associated with exposure to POPs. AhR: aryl hydrocarbon receptor; BDNF: brain-derived neurotrophic factor; CREB: cAMP-response element binding; DP: degree of polymerization; GPCR: G protein-coupled receptor; HDAC: histone deacetylase; HSC: hepatic stellate cells; Nrf2: nuclear factor erythroid-related factor 2; POPs: persistent organic pollutants; ROS: reactive oxygen species; SOD: superoxide dismutase; TD: toxicodynamics; TK: toxicokinetics.

4.1. Nutritional intervention of PCB exposure-mediated diseases

Polyphenols could protect against the toxicity of dioxin-like PCBs due to their antioxidation properties. For example, PCB-exposed mice kept on a green tea-supplement diet exhibited an overall decrease in oxidative stress primarily due to the upregulation of a battery of antioxidant enzymes and upregulation of genes transcription controlled by AhR and Nrf2 proteins ³³.

Since the primary route of exposure to dioxin-like PCBs is ingestion, and gut microbiome disturbance has been observed in animals exposed to PCBs, interventions are thus tailored to this observation. It was demonstrated that cranberry extract reduced the harmful effects of POPs (a mixture of PCB, PBDE, dioxin, and DDT and metabolites) exposure by targeting the gut microbiome and causing the increased abundance of Parvibacter, a genus involved in xenobiotic metabolism ¹²⁵. The work with prebiotic fibers showed that consumption of the dietary fiber inulin could reduce dioxin-like PCB-mediated hepatotoxicity and gut dysbiosis in hyperlipidemic LDLR-deficient mice ³⁴. In another study, it was found that inulin treatment ameliorated both inflammation and fibrosis in the liver of PCB126-exposed mice ¹¹¹. Interestingly, Hoffman et. al found inulin consumption decreased PCB126-induced hepatic lipid accumulation ³⁴; however, in the study reported by Su et.al, inulin treatment did not change the hepatic lipid accumulation in PCB126-exposed mice ¹¹¹. This discrepancy might be related to the dose of inulin. In the first fiber intervention study, the mice were fed with an 8% inulin-supplemented diet (inulin is the sole dietary fiber source) for 12 weeks (approximately 20 g/kg/day), while in the second study, mice were treated with drinking water containing inulin (equivalent to 250 mg/kg/day). Laboratory mice are usually fed with a standardized chow diet that typically contains 5% of fiber. Therefore, the 8% fiber-supplemented diet reported by Hoffman et al. represented an approximate 60% increase in fiber contents compared with the standard chow. For humans, it was suggested that dietary fiber intake should be increased by about 50% compared to current intake ¹²⁶, which is 16–24 g/day and 16.2 g/day in European countries and the US, respectively ^{127, 128}. Therefore, the diets used in the animal study reported by Hoffman et. al represented the increase in dietary fiber intake recommended for humans. Nutritional intervention strategies against PCB-mediated toxicity are listed in Table 1.

4.2. Nutritional intervention of PFAS exposure-mediated diseases

The toxicity of PFASs could be attenuated by dietary fibers and polyphenols. It has been demonstrated that quercetin could ameliorate liver injury induced by PFOA exposure by reducing oxidative stress and inflammation ¹²⁹. In addition, liver injury in mice treated with PFOS was reduced by naringin. The mechanisms were associated with the regulation of oxidation stress, inflammation, and apoptosis pathways ¹³⁰. Steatosis and liver inflammation were observed in mice exposed to PFOS for 21 days, and concurrent administration of grape seed proanthocyanidin extract (GSPE) reduced PFOS-induced liver toxicity by normalizing lipid metabolism, oxidative stress, and inflammatory responses ¹³¹. Eke et al. reported that curcumin (diferuloylmethane), a natural compound present in the rhizome of the turmeric plant (Curcuma longa), protected against PFOS-induced genotoxic/apoptotic effects and the DNA damage in liver tissues of Wistar albino rats ¹³². In addition, Su et al. found that vitamin C protected against PFOS-induced liver damage in mice through suppressing inflammatory reactions and endoplasmic reticulum stress ¹³³. Dietary interventions targeting the gut microbiome showed that soluble dietary fiber (inulin or pectin) fed mice were less susceptible to PFOS-induced liver metabolism disruption, hepatic lipid accumulation, and transcriptional changes ³⁵. Nutritional intervention strategies against PFAS-mediated toxicity are presented in Table 2.

Table 2.

Mechanisms of nutritional intervention against PFAS-mediated toxicity

Environmental Chemicals (Dose, route, duration)	Nutrients (Dose, route, duration)	Subjects	Disease endpoint	Mechanisms	Reference
PFOA (10 mg/kg/day, i.g., 14 d)	Quercetin (75 mg/kg/day, i.g., 14 d)	Male Kunming mice	Liver injury. AST, ALT, lactate dehydrogenase, and total bile acids	Reduce oxidative stress and inflammation	129
PFOS (10 mg/kg/day, i.g., 3 w)	Naringin (100 mg/kg/day, i.g., 3 w)	Male mice	Liver injury. Naringin supplementation led to the resumption of elevated serum hepatic enzyme activities in PFOS-exposed mice	Relate to the regulation of oxidation, inflammation, and apoptosis pathways	130
PFOS (10 mg/kg/day, i.g., 21 d)	Grape seed proanthocyanidin extract (150 mg/kg/day, i.g., 21 d)	Male Kunming Mice	Steatohepatitis. Grape seed proanthocyanidin extract restores decreased serum liver enzyme activity and histological abnormalities in PFOS-exposed mice	Regulate lipid metabolism, oxidative stress, and inflammatory responses	131
PFOS (3 ug/kg/day, by drinking water, 7 w)	soluble fibers (inulin or pectin) (8% insulin or pectin, diet, 7 w)	Male C57BL/6J mice	Inulin supplementation ameliorates PFOS-induced metabolic disturbance in liver	Affect microbe-liver metabolism and interactions	35
PFOS (10 mg/kg/day, i.g., 21 d)	Vitamin C (100/200 mg/kg/day, i.g., 21 d)	Male ICR mice	Liver steatosis. VC treatment decreases serum levels of ALT and AST	Suppress hepatocellular inflammatory reaction and ER stress	133
PFOS (0.6/1.25/ 2.5 mg/kg, gavage, 4 w)	Curcumin (80 mg/kg, gavage, 30 d at 48 h intervals)	Wistar rat	DNA damage in the liver. Curcumin supplementation reduces liver DNA damage	Decrease the expression levels of caspase 3 and 8	132

The dose of those phytochemicals (quercetin, naringin, proanthocyanidin, and curcumin) ranges from 75–150 mg/kg/day in animal intervention studies (Table 2). Although the average human daily intake of those phytochemicals from food is relatively low (e.g., daily intake of quercetin is estimated to be 10–100 mg), higher intakes can be achieved using selected nutraceuticals ¹³⁴. After oral administration, glycosides (quercetin, naringin) are mostly hydrolyzed and absorbed from the intestines as deconjugated aglycones, which could be further metabolized in the liver. It has been demonstrated that the metabolism of glycosides was different between rodents and humans ¹³⁵. Therefore, species differences in metabolism should be taken into consideration when translating rodent studies to human intervention strategies.

4.3. Nutritional intervention of PBDE exposure-mediated diseases

The toxicity of PBDE could be attenuated by polyphenols. Luteolin is a natural flavonoid compound in different fruits and vegetables ¹³⁶. It was reported that in Caco2 cells exposed to BDE-209 (a major congener of PBDE), luteolin reduced the level of reactive oxygen species, inhibited the secretion of proinflammatory cytokines, and played a protective role in the intestinal barrier (increased tight junction proteins ZO-1, occludin, and claudin-1) ¹³⁷. In another study, it was demonstrated that troxerutin, a trihydroxyethylated derivative of the natural bioflavonoid rutin, protected against BDE-47 induced liver inflammation by attenuating oxidative stress-mediated NAD⁺ depletion ¹³⁸. These studies indicated that natural compounds had important protective effects and could potentially be used as dietary supplements against the toxicity of PBDEs (Table 3).

5. System biology approaches to explore multi-organ toxicity and precision intervention

Accumulating evidence suggests that the gut microbiome-tissue crosstalk is a major player in POPs-associated diseases. Dietary supplementation with prebiotics/probiotics appears to be a promising intervention for reducing the damage caused by pollutants and restoring the balanced structure of the gut microbial community. Further investigations on gut microbiome-host interactions are warranted by using system biology techniques such as metabolomics, metagenomics, metatranscriptomics, and stable isotope probing ^139–142. Metabolomics enables holistic and systematic analyses of metabolites in a biological system. Integrative analysis of metabolomics, proteomics, and transcriptomics is a very appealing technology to investigate toxicity and precision nutritional effects that can provide an in-depth understanding of the etiology of functional dysbiosis and multi-organ interactions. Metagenomics and metatranscriptomics provide taxonomical and functional profiles of microbiomes ¹⁴³, which in combined with metabolomic analysis could produce a more comprehensive picture of the etiology of dysbiosis and gut microbiome-tissue axis. As systems biology extends its application from bulk assays to more precise identifications of cells perturbed by toxicants, single cell techniques represent a valuable tool for understanding cell specific alterations in response to toxicant insults as well as the diversity and spatial changes within microorganism communities ^{144, 145}, which would be anticipated to provide new insights on the mechanism of organ crosstalk at the dimension of intra- and inter-cellular responses. It should be noted that the effects of multi-organ toxicity and nutritional intervention may vary from person to person, depending on factors such as the baseline gut microbiome and intrinsic host factor. Therefore, precision/personalized intervention regimens should be considered.

The latest development of multiorgan-on-a-chip, a 3D engineered biological model implemented in microfluidic platforms, is a microphysiological system capable of modeling organ-level responses. Compared with the traditional single organ-on-a-chip, the multiorgan model allows investigations of cross-organ communications ¹⁴⁶. For example, a liver/lung-on-a-chip was developed and applied to investigate the liver-lung interactions in the toxicity of aflatoxin B1 ¹⁴⁷. It was found that both tissues remained viable and functional for 28 days when cocultured in the chip, and detoxification of aflatoxin B1 by the liver protected against its lung toxicity. Multiorgan-on-a-chip technology offers new opportunities in system toxicity and precision nutrition studies while supporting the implementation of the 3Rs of animal research (replacement, reduction, and refinement).

6. Conclusions

The toxicity of POPs is linked to the multi-organ interplays involving the liver, gut, brain, vascular, and immune system, which lead to inflammation and cardiometabolic diseases. Consumption of food rich in anti-inflammatory phytochemicals, dietary fibers, and vitamins may be a feasible way to counteract POP toxicity by acting on multi-organ interactions and preventing inflammatory diseases. Future research should consider the investigation of lesser studied nutrient mixtures rather than single compounds. By integrating data from a single cell- to ecosystem-level processes, from single- to multiple-organ systems, together with omics analyses, a more comprehensive understanding of the multi-organ interactions can be generated, and meaningful insights into the mechanisms of toxicity will be provided, which will accelerate the development of precision intervention strategies.

Highlights.

• Organ interactions play important roles in POPs-induced inflammatory diseases.

• A complex network of interactions exists between host organs and gut/microbiome.

• Nutritional intervention strategies should consider multiple organ interactions.