Effect of altered human exposome on the skin and mucosal epithelial barrier integrity

ABSTRACT

Pollution in the world and exposure of humans and nature to toxic substances is continuously worsening at a rapid pace. In the last 60 years, human and domestic animal health has been challenged by continuous exposure to toxic substances and pollutants because of uncontrolled growth, modernization, and industrialization. More than 350,000 new chemicals have been introduced to our lives, mostly without any reasonable control of their health effects and toxicity. A plethora of studies show exposure to these harmful substances during this period with their implications on the skin and mucosal epithelial barrier and increasing prevalence of allergic and autoimmune diseases in the context of the “epithelial barrier hypothesis”. Exposure to these substances causes an epithelial injury with peri-epithelial inflammation, microbial dysbiosis and bacterial translocation to sub-epithelial areas, and immune response to dysbiotic bacteria. Here, we provide scientific evidence on the altered human exposome and its impact on epithelial barriers.

1. Introduction

The recently proposed epithelial barrier hypothesis suggests that disruption of the epithelial barrier due to exposure to harmful environmental agents along with genetic factors is responsible for up to two billion chronic, non-communicable diseases. The hypothesis attributes the rapid increase in allergic and autoimmune diseases in recent decades to industrialization, urbanization and the western lifestyle1–3 It is important in preserving the structural and functional integrity of the body by protecting the host from pathogen invasion and foreign substance infiltration. Maintaining the physiological epithelial barrier integrity is of utmost importance since its dysfunction is implicated with many chronic conditions such as allergic, autoimmune, and metabolic diseases.¹ Exposure to toxic/barrier damaging agents results in an impaired epithelial barrier in affected tissue. This epithelial barrier damage leads to a vicious cycle continuing with opportunistic pathogen colonization, translocation of microbiota to subepithelial tissues, immune response to the microbiome and colonized pathogens, microbial dysbiosis and chronic tissue inflammation which eventually leads to defective epithelial barrier healing (Figure 1).¹ In the context of the epithelial barrier hypothesis, the epithelial barrier impairment could cause local and systemic pathologies.¹ The local epithelial damage in affected tissues such as skin and mucosal sites leads to the development of allergic diseases.⁴ It should be noted that epithelial barrier impairment and microbial dysbiosis in affected tissues usually coincide. It is known that the gut epithelial barrier impairment and microbial dysbiosis are associated with systemic pathologies such as diabetes, obesity, rheumatoid arthritis, multiple sclerosis and ankylosing spondylitis, and even neurodegenerative and psychiatric diseases such as Parkinson’s disease, Alzheimer’s disease, autism spectrum disorders and chronic depression.¹

Figure 1.

The epithelial barrier hypothesis. The hypothesis attributes the rapid rise of allergic and autoimmune diseases to the increased exposure to hazardous substances, such as chemical sensitizers and air pollutants. The epithelial barrier impairment causes a vicious cycle of pathological events.

Human exposure, defined as the sum of the factors to which an individual is exposed during her lifetime, has changed alarmingly in recent years due to anthropogenic activities.^4,5 Today humans, domestic animals and wild animals are exposed to a wide range of hazardous environmental factors, such as particulate matter (PM), diesel exhaust particulates (DEP), ozone, industrial toxic gases, nanoparticles, nano (NP), and microplastics (MP), cigarette smoke, household cleaning agents, enzymes and emulsifiers in processed food and pesticides.^4,6–9 Exposure to these hazardous compounds, along with global warming and viral pandemics like COVID-19, is one of the greatest threats to humanity. Detergents used for laundry and dishwashing, household cleaners, cosmetics, conservatives and emulsifiers in packaged food, disinfectants and toothpastes represent complex mixtures that humans are confronted that apparently contain several toxic substances. In addition, several hundred thousands of new chemicals have been introduced to our lives during the last 60 years, without any meaningful toxicity control as a part of industrialization, urbanization, and modernization.^1,4 As an estimation, 350,000 chemicals are used in Europe.¹⁰ Global chemicals sales have been doubled during the last two decades and end up in the environment as a pollutant.¹⁰ By volume, three quarters of chemicals produced in Europe are hazardous.¹¹ The full extent of the effect of these environmental factors on our health remains to be elucidated, however, there is a plethora of studies demonstrating their damage to the epithelial barrier integrity that can culminate into chronic health problems.¹ Synergistic effect of these substances and how they would behave in inflammatory and affected tissues in certain diseases is an important aspect to be considered. It is crucial to improve our understanding of the underlying mechanisms affecting the integrity of the epithelial barrier at the skin and mucosal sites to develop novel treatments to restore its physiological function and to provide policymakers with science-based information to steer them in implementing new measures to reduce human exposure to these toxic agents. Herein, we provide a comprehensive overview of the impact of exogenous factors on respiratory, gastrointestinal, and skin barriers.

2. The change in the human exposome: The main threats to nature and human health

Anthropocene refers to the current geological epoch in which human activities significantly affect the Earth’s geology and ecosystems. Since the industrial revolution, the proposed beginning of anthropogenic influences, the human impact on the nature has become more evident and the consequences such as anthropogenic climate change, habitat destruction, and environmental pollution are now threatening the Earth’s ecosystem and human health.^1,6,12–20 According to current reports, population sizes of species in the nature have decreased by 60% between 1970 and 2014 and extinction rates are 100 to 1000 times higher than previous background rates.²¹

The term exposome describes all the environmental exposures individuals are facing during their lifetime.⁴ These factors can be divided into three categories: general external environment, specific external environment, and host-dependent internal environment.²² The general external environment includes a wider socioeconomic environment such as climate, urban-rural environment, and educational level. However, specific external environment includes more individual factors such as lifestyle, pollutant exposure, and infections. However, the host-dependent internal environment includes both biological effects of external exposure and biological responses such as metabolic factors, inflammation, and oxidative stress.^4,23,24 There have been alarming changes in the exposome in the last 70 years brought about by industrialization, urbanization, and modernization as exemplified by studies indicating human exposure to nearly 200,000–350,000 new chemicals.^4,5,10 Since the 1950s, the amount of plastic production has increased nearly 200 times, and it is estimated that the total amount of plastic produced worldwide by 2017 reached approximately 8.3 billion metric tons.^13,15,25 Today the human body is continuously exposed to a wide range of potentially harmful substances, such as PM, DEP, cigarette smoke, NP, MP, nanoparticles, ozone, nitric oxide (NO), nitrogen dioxide(NO₂), carbon monoxide (CO), sulfur dioxide(SO₂), household cleaners, laundry and dishwasher detergents, toothpaste, surfactants and emulsifiers in processed food, and pesticides (Figure 2). ¹ Annual global deaths from pollution-related diseases are estimated at 9 million, still more than COVID-19-related deaths, mostly in underdeveloped countries.^6,17

Figure 2.

Our modernized lifestyle has dramatically altered the human exposome, the collection of exogenous factors that an individual is exposed to in its lifetime. Anthropogenic activities are responsible for the increased exposure to hazardous substances, such as particulate matter, diesel exhaust particulates, cigarette smoke, pesticides, emulsifiers in processed food, detergents, micro and nanoplastics, and traffic and industrial gas emissions.

Ambient and indoor air pollution

Air pollution is one of our era’s biggest menaces as it contributes to climate change and is a leading cause of respiratory diseases.²⁶ According to the World Health Organization’s (WHO) World Global Ambient Air Quality Database, 91% of the global population is exposed to poor air quality.^27,28 Ambient air pollution alone is responsible for an estimated 3.7 to 4.2 million annual deaths worldwide.⁶ Air pollution is a complex mixture of gaseous and particulate components. Gaseous components include NO, NO₂, SO₂, CO and ozone.²⁹ Air and aquatic PM originates from both natural and anthropogenic sources. Natural sources include dust, including desert dust, sea salt, and forest fires. In contrast, anthropogenic sources include traffic, power plants, factories, wood, and coal-burning emissions.³⁰ Studies suggest that air pollution aggravates cardiovascular and respiratory diseases and is associated with the development or progression of asthma, diabetes, reproductive, and various neurocognitive diseases.^31–33 PM is classified according to particle size (PM_0.1, PM_2.5, and PM₁₀). Epidemiological studies indicate that exposure to ambient PM pollution has increased over the past ten years coinciding with increased drug use, high fasting plasma glucose, and high body mass index.¹⁴ In the last 40 years, atmospheric black carbon concentration (which is a PM_2.5) generated as a by-product of incomplete combustion of fossil fuels, biofuels, and biomass, has shown a substantial increase of 1.57 times (from 0.70 μg/m³ in 1980 to 1.10 ± 0.22 μg/m³ in 2019) with an annual increase by 1.52% in China.³⁴ Moreover, it was reported that there was an independent association between short-term exposure to PM₁₀ and PM_2.5 and daily all-cause, cardiovascular, and respiratory mortality.³⁵ According to a meta-analysis, there is a positive and statistically significant link between the onset of asthma and exposure to black carbon, NO₂, PM_2.5 and PM₁₀, well-known traffic-related air pollution constituents.³⁶ Ambient air pollution, especially PM, is considered a neurotoxicant and impairs cognitive functions, learning abilities, and neurodevelopment. It is thought to be associated with depression, vascular dementia, and stroke. Along with urban PM, wildfire PM has also been associated with morbidity and mortality. An increased risk of hospitalization and emergency room visits for asthma, chronic obstructive pulmonary disease (COPD), and respiratory tract infection has been reported in individuals exposed to wildfire PM.¹⁹ Among other air pollutants, exposure to oxides of nitrogen affects the central nervous system and contributes to neurological disorders.³⁷ During COVID-19 restrictions, the atmospheric levels of air pollutants associated with traffic emissions including oxides of nitrogen, SO₂, and CO, and primary PM levels decreased due to the quarantine and lock-down measures imposed by the governments. In contrast, secondary PM levels remained unchanged or even increased during the same period.³⁸

Indoor pollution is a major problem, as pollution levels are often twice as high then outdoors and people spend 80–90% of their lives indoors.³⁹ Household air pollution is estimated to be responsible for 2.9–4.3 million deaths per year worldwide.² Thanks to social and economic development, household air pollution has declined in the last ten years.¹⁴ Although the risk exposure to tobacco use is declining, it is still responsible for more than 8 million deaths annually of which 1.2 million are from secondhand smoking,⁴⁰ mostly affecting low- and middle-income countries.^5,40

Micro- and nano- plastic pollution

The use of plastics has rapidly grown as these materials offer a low production cost and high stability and durability. However, plastic waste poses a threat to nature as most plastics are non-biodegradable. It is estimated that in 2015 globally 66–90 million metric tonnes of miss managed plastic waste are produced and every year 8 million tonnes of plastic waste are escaped to the oceans.^25,41 When plastic waste enters the environment, it breaks down into small fragments and particles such as MPs (1 mm to 5 mm) and NPs (1 nm to 1000 nm).^13,42 The degradation products can be detected in the air, water, and sediment.^13,16 It is reported that nano- and MPs are harmful to aquatic species, such as zooplankton, bivalves, and small fish.¹³ Moreover, NPs can penetrate living organisms and eventually enter the human food chain.^13,15 In addition, humans are exposed to airborne NPs through the airways and in contact with the skin.¹⁵

Processed foods: harmful additives in foods

The modern food industry provides a wealth of supply and diversity made possible by the incorporation of food additives, such as synthetic colorants, preservatives, stabilizers, surfactants, emulsifiers, and texturizers. There is mounting evidence suggesting that processed foods that contain food additives and advanced glycation endproducts (AGEs) due to heat processing disrupt the integrity of the epithelial barrier, a key pathological feature in the development of allergic and autoimmune diseases.^1,43 The consumption of processed food has been associated with all-cause mortality, obesity, metabolic syndrome and depression.⁴⁴ In addition, food contamination is possible by contact with dishware that has residues from cleaning products, such as detergents and anionic surfactants.^7,45,46

Anthropogenic climate change

Anthropogenic activities are responsible for global warming,^47–49 with a mean temperature increase of 0.2°C per decade.¹⁸ A recent study predicts global warming of 2.6°C (1.9°C to 3.7°C) by 2100, taking into account only the current energy policies and measures being developed by the countries participating in the Paris agreement. Nonetheless, the authors noted that warming can be limited to 1.9–2.0°C if all the conditional and unconditional pledges of the Paris agreement are met in full and on time.⁵⁰ The generation of large quantities of greenhouse gases has been a key driver of climate change, in particular carbon dioxide emissions. Moreover, deforestation cripples the Earth’s natural ability to remove atmospheric CO₂, further aggravating global warming and causing extreme weather events.^26,51 In the future, increases in morbidity and mortality are estimated due to climate change-related adverse effects such as heat-related illnesses, poor air quality, and undernutrition due to reduced food quality and security.¹⁸ It should be noted that the global risks from toxic pollution and climate change are highly correlated, with low- and middle-income countries being the most affected by both.¹⁷

3. Diseases associated with epithelial barrier impairment

The number of patients with chronic non-communicable diseases has been estimated to be less than 50 million in 1960s, which increased to almost 2 billion patients in 2020s. The first group of diseases is allergies, asthma, atopic dermatitis, colitis and celiac in which the affected skin and mucosa show inflammation.^52–58 The second group of diseases are autoimmune and metabolic diseases with the affected organ is distant from the damaged epithelial barriers.^59–64 The third group is chronic neuropsychiatric conditions with gut barrier leakiness and microbial dysbiosis in the gut.^65–68 The epithelial barrier is the primary constituent of the internal and external surfaces of the human body. Epithelial barriers in the gastrointestinal and respiratory tracts act as selective barriers that allow gas or nutrient translocation while maintaining a healthy microbiota and preventing pathogens from entering the host.^7,69,70 The mucosal barrier integrity is mainly maintained by tight junctions (TJ), adherens junctions, and desmosomes that seal off the paracellular space and prevents the diffusion of soluble mediators, proteins, or pathogens between apical and basolateral cell surfaces.^56,70 TJs seal the apical side of the neighboring epithelial cells and form the physical barrier even water cannot pass through, because of homodimeric covalent bonds. They are composed of transmembrane proteins, such as claudins, occludin, junctional adhesion molecules, and an intracellular protein called zonula occludens (ZO) and are the main regulators of the paracellular permeability.⁷⁰

The skin epithelium has a unique structure comprised of four layers: the stratum corneum, stratum granulosum, stratum spinosum, and the stratum basale.⁵² The stratum corneum is the outermost layer of the epidermis, which is composed of enucleated keratinocytes known as corneocytes. It is maintained by the intricate interaction of a complex lipid mixture in the extracellular space, the intracytoplasmic moisturizing factors, and the cornified envelope. Filaggrin (FLG) is an important structural protein of the cornified envelope, acts as a natural moisturizing factor and plays a role in the alignment of keratin filaments.^71–73 TJs are mainly located in the stratum granulosum of the epidermis and regulate cell permeability.

In addition to the physical barrier function, the epithelial barrier also exhibits antimicrobial activity against exogenous insults as it can secrete antimicrobial peptides, proteases, and antioxidants.⁷⁴ Membrane-bound and cytosolic pattern recognition receptors in epithelial cells recognize various pathogen components and activate downstream signaling, promoting the release of pro-inflammatory cytokines/chemokines and attracting and activating cells from the innate and adaptive immune system.^74,75

Maintaining a healthy epithelial barrier is considered a crucial first step in preventing many chronic inflammatory conditions. An extended “epithelial barrier hypothesis” has been recently proposed that attributes epithelial barrier dysfunction to the development of allergic, autoimmune, and metabolic diseases.^1,76 Disruption of epithelial barrier homeostasis leads to subsequent pathophysiological events such as microbial dysbiosis, colonization of opportunistic pathogens, translocation of microbiota, inflammation and immune response to commensals and colonizing opportunistic pathogens, and eventually, the defective barrier healing capacity of the epithelium (Figure 3). In the context of the epithelial barrier hypothesis, damage to the epithelial barrier integrity is due to genetic factors in a small fraction of patients but is mainly attributed to exposure to environmental insults introduced during industrialization, modernization, and westernization. Further research on the effect of environmental factors on our health is warranted as the humans are in continuous contact with these barrier-damaging agents at unprecedented concentrations.¹ The epithelial barrier is responsible for maintaining microbiota homeostasis. A healthy microbiome limits pathogenic microorganism colonization over epithelial surfaces and provides barrier strengthening substances such as short-chain fatty acids and tryptophan metabolites.^77,78 Other microbiome related products such as bile acid, conjugated fatty acids, polyamines, and polyphenolic derivatives have many regulatory functions essential for maintaining the integrity of the intestinal epithelial barrier.⁷⁹ The link between dysbiosis and diseases characterized by an impaired epithelial barrier is well documented.^1,80–88 Although they are often found together, it is unclear which one occurs first. Nevertheless, an impaired epithelial barrier eventually leads to microbial translocation to subepithelial tissues and inflammation (Figure 4).¹

Figure 3.

Epithelial barrier damaging factor cause series of pathological events. The external barrier damaging stimuli impair the epithelial barrier, increasing its permeability and facilitating the entry of foreign substances and microbial translocation to interepithelial and subepithelial regions. A cascade of events follows including continuous immune responses against allergens and the development of tissue microinflammation, which have been implicated in the development of various diseases due to a vicious cycle of a leaky barrier and chronic inflammation.

Figure 4.

The microbiome has an important role in epithelial barrier physiology. Generally, a diverse microbiome is associated with a healthy epithelial barrier. Microbiota metabolites with immunosuppressive activities, such as short-chain fatty acids and tryptophan, play a key role in maintaining the barrier function. Dysbiosis has been linked to allergic and autoimmune diseases characterized by an impaired epithelial barrier. Loss of microbial diversity can lead to an impaired barrier and vice versa.

Disruption of the epithelial barrier contributes to the pathogenesis or development of chronic lung, skin and intestinal diseases characterized by epithelial barrier impairment in affected tissues. In addition, culminating evidence shows gut barrier defects in various autoimmune diseases affecting tissues other than gut, metabolic and neuropsychiatric diseases (Table 1).

Table 1.

Diseases associated with epithelial barrier impairment.

Diseases with epithelial barrier impairment in affected tissues
Asthma Allergic rhinitis Chronic rhinosinusitis Atopic dermatitis Inflammatory bowel disease Celiac disease Eosinophilic oesophagitis
Autoimmune and metabolic diseases linked with gut epithelial barrier defect
Rheumatoid arthritis Ankylosing spondylitis Multiple sclerosis Type 1 and 2 Diabetes Obesity Nonalcoholic steatohepatitis
Neuropsychiatric disease linked with gut epithelial barrier defect
Autism spectrum disorders Parkinson disease Alzheimer disease Stress-related psychiatric Disorders Chronic depression

Diseases with epithelial barrier impairment in affected tissues

It is well established that epithelial barrier impairment is involved in the pathogenesis of chronic respiratory diseases such as asthma, allergic rhinitis (AR) and chronic rhinosinusitis. The barrier function of the epithelium is impaired through decreased TJ molecule expression in asthmatic patients. Decreased expression of E-cadherin, β- catenin, occludin, and ZO-1^89–91 was observed in the airway epithelium of asthma patients all of which cause epithelial barrier leakiness induced by T helper (Th)-2 cells, interleukin (IL)-4, and IL-13.^92,93 Downregulation of ZO-1 and claudin-18 were demonstrated in eosinophilic, mixed, and neutrophilic experimental mouse models of asthma.⁹⁴ Moreover, lower occludin and ZO-1 expressions in patients with house dust mite-induced AR⁵⁶ and decreased expression of claudins was observed in the nasal mucosa epithelium of AR patients which was accompanied by an impaired barrier function.⁹⁵ Soyka et al. showed that primary epithelial cell cultures from patients with chronic rhinosinusitis with nasal polyps had an impaired epithelial barrier evidenced by low transepithelial resistance, as well as decreased occludin and claudin-4 expressions.⁵⁵

Skin barrier deficiency in atopic dermatitis (AD) is related to loss of functions mutations in the FLG gene,⁹⁶ and the reduced expression of FLG2 has been demonstrated in the epidermis of AD patients.⁹⁷ The FLG mutations were also found in AD patients with eosinophilic asthma.⁹⁸ Skin biopsies of allergic contact dermatitis patients in the presence of p-phenylenediamine showed reduced expression of claudin-1, claudin-8, claudin-11, occludin, FLG1, FLG2, and loricrin.⁹⁹ The compromised epidermal barrier activates a local and systemic type 2-predominant response, characterized by elevated levels of IL-4, IL-5, IL-13, and IgE.^100,101

The intestinal epithelium is crucial in maintaining intestinal homeostasis. Impairment of the epithelial barrier results in elevated intestinal permeability and promotes a leaky barrier resulting in abnormal interactions between intestinal epithelial cells and immune cells residing in the lamina propria. Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, have been linked to a disrupted intestinal epithelium.¹⁰² In Crohn’s disease, the epithelial barrier function is impaired due to the altered TJ structure. Upregulation of claudin-2 and downregulation and redistribution of claudin-5 and claudin-8 were associated with impaired intestinal barrier function in mild to moderately active Crohn’s disease.¹⁰³ An impaired barrier function is also implicated in the pathogenesis of the Celiac disease, characterized by a decreased expression and redistribution of occludins, claudins, and junctional adhesion molecules.¹⁰⁴ Pro-inflammatory responses relating to a complex network of cytokines further aggravate barrier dysfunction in patients with inflammatory bowel disease.¹⁰⁵ Gluten ingestion can trigger celiac disease as one of its proteins, gliadin, induces the release of zonulin, a protein involved in opening the TJ.¹⁰⁶ In addition to the barrier impairment regarding intestinal epithelium, there are also other gastrointestinal tract-related barrier disorders as exemplified in eosinophilic esophagitis, an atopic disease involving the esophagus.^107,108 The dysregulation of transcription factor hypoxia-inducible factor-1α impairs claudin-1 expression resulting in dysfunction of the stratified squamous esophageal epithelial barrier in eosinophilic esophagitis patients.¹⁰⁹

Autoimmune and metabolic diseases linked with gut barrier defect

Impairment of the intestinal barrier is associated with various autoimmune and metabolic diseases. Elevated serum zonulin levels are accompanied by a leaky intestinal barrier, microbial dysbiosis, and inflammation as exemplified in ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes.^{62,63,110,111} Zonulin induces a decrease in occludin and cadherin expression in the gut vascular barrier of ankylosing spondylitis patients, accompanied by downregulated claudin, occludin, and ZO-1 expression modulated by ileal bacteria.⁶³ Barrier disruption through zonulin upregulation appears to precede the onset of type 1 diabetes¹¹¹ and arthritis.⁶² The development of insulin resistance in type 2 diabetes has been linked to gut microbial dysbiosis and the impairment of the intestinal barrier.^112,113 In addition hyperglycemia causes increased intestinal barrier permeability in mouse models of obesity and diabetes through a GLUT2-dependent decrease of tight and adherence junction integrity.¹¹⁴ Obesity is associated with higher gastroduodenal permeability (but not small intestine and colonic) with a pro-inflammatory systemic and intestinal profile.¹¹⁵ Impaired intestinal barrier function has a critical role in the pathogenesis of gut-liver-associated diseases, including fatty liver disease and cirrhosis.^116–118 Immunohistochemical analysis in duodenal biopsy specimens showed lower ZO-1 staining compared to healthy subjects and a significant increase of small intestinal bacterial overgrowth in nonalcoholic liver disease.¹¹⁶ In a mouse model of alcoholic steatohepatitis, disruption of intestinal TJ was associated with enhanced intestinal endocytosis of occludin.¹¹⁹

Neuropsychiatric disease linked with gut barrier defect

Recent studies revealed that there are numerous neuropsychiatric diseases associated with an impaired gut barrier. Alzheimer’s disease is associated with intestinal inflammation, barrier deficiency, and microbial dysbiosis.^66,67 Similarly, barrier impairment was found in intestinal biopsy samples from people with Parkinson’s disease along with elevated zonulin concentrations in the blood and feces.^66,120 An amyotrophic lateral sclerosis mouse model shows a disrupted gut TJ structure and increased permeability, as well as decreased ZO-1 and E-cadherin expression levels.¹²¹ Patients with autism spectrum disorder shows an altered gut permeability through the decreased expression of barrier-forming TJ components.⁶⁵ Acute stress has been shown to disrupt the intestinal barrier in animal models.⁶⁸ Kelly et al. showed that depression is associated with decreased gut microbiota richness and diversity. Moreover, the behavioral and physiological characteristics of depression can be induced in microbiota-depleted rats with fecal microbiota transplantation from depressed individuals.¹²² Microbial dysbiosis, bacterial translocation in the gut, and an inflammatory response to commensals are common in patients with chronic depression.¹²³

4. Epithelial barrier damaging environmental factors

Air pollution and related substances

Air pollution a complex mixture of hazardous gases and PM has detrimental effects on mucosal and skin epithelial barriers. Ambient air pollution accounts for health problems such as COPD, asthma, AR, bronchiolitis, cardiovascular disorders, reproductive and central nervous system malfunction, and lung cancer.^26,124 Exposure to air pollutants, such as PM, DEP, ozone and NO₂, induces the generation of reactive oxygen species (ROS) and impairs the epithelial barrier function in human epithelial cells (Table 2).^{29,30,125–131} The human microbiome and its immunomodulatory potential are negatively impacted by an increased exposure to the natural environment.¹³² Cavaleiro Rufo et al. found that at the age of seven, living close to a rural area has a preventive effect on the development of allergy disorders and asthma.¹³³ The symbiotic relationship between the microbiota in the airways and the host is crucial for maintaining airway immune homeostasis.¹³⁴Air pollutants can also alter the innate immune cells in airways, causing asthma symptoms to worsen.¹³⁵ Recent studies demonstrate the importance of Toll-like receptor (TLR) and nucleotide-binding oligomerization domain-like receptor signaling in air pollutant-induced responses in the lung.¹³⁶

Table 2.

In vitro and in vivo models of the respiratory epithelial barrier disruption triggered by air pollution-related substances.

Substance	Evidence	Reference(s)
Particulate matter	PM2.5 exposure in a BEAS-2B cell line increased apoptosis, decreased viability, and decreased ZO-1 and e-cadherin mRNA expression.125	125
	PM2.5 exposure cause ROS activation and apoptosis.138,140	138,140
	PM2.5 and urban PM disrupt TJ molecules of the human nasal epithelium and exacerbate AR.141–143	141–143
	PM10 induces epithelial barrier damage in a primary rat alveolar epithelial cell culture.147	147
Micro- and nano-plastics	Polystyrene micro and nanoparticle exposure induce cytotoxicity, apoptosis, and autophagy in human bronchial and alveolar cell culture models.131,200	131,200
	Polystyrene micro and nanoparticle exposure damage the bronchial epithelial barrier by reducing ZO-1 mRNA expression.	131,200
DEP	DEP induce epithelial barrier damage in human bronchial epithelial cell line.154,155	154,155
	DEP increase IL-33, IL-25, and TSLP cytokine production with Th-2 activation in allergic severe asthma patients.	151–153
Ozone	Ozone exposure causes respiratory barrier injury in mouse models.126,159	126,159

IL: Interleukin; PM: Particulate matter; Th: T helper; TJ: Tight junction; TSLP: Thymic stromal lymphopoietin; ZO: Zonula occludens

Particulate matter

PMs generated from anthropogenic sources have a higher oxidative potential, especially secondary organic aerosols from residential biomass burning and vehicular non-exhaust emissions.¹³⁷ As one of the main components of air pollution, PM_2.5 is known to induce apoptosis, airway barrier dysfunction, breaking of inhalational tolerance, and sensitization to allergic antigens.^125,138 Moreover, PM can pass through the epithelial barrier and accumulate in the endothelium.¹³⁹ PM_2.5 exposure has been demonstrated to have deleterious effects on the lung function of mice, including decreased total lung capacity, residual volume, and vital capacity.¹⁴⁰ Exposure to PM_2.5 is implicated in apoptosis, decreased TJ protein expression, and airway inflammation by NF-κB and MAPK activation,⁹⁴ and exacerbates asthma in an OVA-induced mouse model of allergic asthma.^125,141 Recent evidence indicates that PMs of various sizes, including urban PM (5.85 μm and 10.5 μm) and PM_2.5 disrupt TJ barriers of the human nasal epithelium and exacerbate AR, suggesting an increased risk of rhinitis and rhinosinusitis in areas with high PM pollution.^69,142–144 PM_2.5 and black carbon exposure, was associated with the development of asthma in childhood.¹⁴⁵ Exposure to PMs from biomass fuels has been reported as a major risk factor for COPD development,¹⁴⁶ and epithelial barrier damage.¹⁴⁷ A recent study has shown that exposure to PM₁₀ and DEP causes occludin dissociation from ZO-1, resulting in an impaired alveolar epithelial barrier.¹⁴⁸ Exposure to traffic-related air pollutants, oxides of nitrogen, and PM is associated with increased odds of incident eczema and is more pronounced with nonatopic eczema in elderly women.¹⁴⁹ Prenatal exposure to PM_2.5 during weeks 7 to 17 of pregnancy was significantly associated with an increased risk of childhood eczema by 6 years of age. The risk was increased in children who were not breastfed or exposed to prenatal environmental tobacco smoke.¹⁵⁰

Diesel exhaust particles

DEPs, traffic-related air pollutants, are regarded as environmental factors that exacerbate allergic diseases. Studies demonstrated that DEP promotes Th2 cell responses and mediates up-regulation of IL-33, IL-25 and thymic stromal lymphopoietin with increased IgE and Th-2 activation, potentially linking environmental pollution and severe allergic asthma.^151–153 Van den Broucke et al. reported DEP causes bronchial epithelial barrier impairment without directly or indirectly activating human mast cells in vitro.¹⁵⁴ The effect of DEP exposure on the airway epithelial barrier junctions and its function was demonstrated using in vitro and in vivo models. Exposure to DEP may produce long-term alterations in airway epithelial barrier function.^142,155,156 DEP exposure resulted in a significant concentration-dependent decrease in barrier integrity as well as decreased tricellulin mRNA expression in a bronchial epithelial cell line culture.¹⁵⁵

Epicutaneous exposure to DEP or DMBA (7,12-dimethylbenz[a]anthracene) leads to an AD-like phenotype by activation of the aryl hydrocarbon receptor (AhR) transcription factor in a transgenic mouse model that expresses a constitutively active AhR.¹⁵⁷

Air pollution related hazardous gases

Ozone and oxides of nitrogen such as NO and NO₂ induce the generation of ROS and reactive nitrogen species and impair the epithelial barrier function in human epithelial cells.^{126,128,158,159} In asthmatic patients presenting to more than one emergency department for asthma, ambient NO₂ concentrations have been shown to be associated with death from all causes.¹⁶⁰ And a study estimated that NO₂ pollution is responsible for 4 million new pediatric asthma cases per year.¹⁶¹ A population-based prospective study demonstrated that NO₂ is associated with an increased risk of atopic eczema in male adults.¹⁶² In a mouse model SO₂ exposure via inhalation caused increased airway epithelial permeability without histological changes.¹⁶³

Ozone, a major air pollutant, is highly toxic to the human respiratory system. Its exposure can cause airway hyperreactivity, airway inflammation, and epithelial barrier disruption by inducing ROS production and it is thought to have an important role in the pathogenesis of chronic respiratory diseases such as asthma and COPD.^128,130,164 Moreover, studies revealed that ozone exposure causes lung epithelial barrier injury in mouse models and primary normal human bronchial epithelial cells (NHBECs) cultures.^126,159,165 Although further studies are warranted, there is early evidence suggesting that exposure to ozone increases lung epithelial barrier permeability in healthy subjects.^166,167 A recent study demonstrated that the co-exposure of ozone and carbon black (which is different from black carbon) causes lung function decline along with increased inflammation (high epithelial alarmin, IL-1β, IL-6, IL-13, Muc5b secretion) and bronchiolar epithelial necrosis.¹⁶⁸ Malondialdehyde collected from nasal fluid was proposed as a biomarker of the oxidative stress attributed to PM_2.5 and ozone exposures and can be used to monitor asthma status in relation to air pollution.¹⁶⁹

Volatile organic compounds

Volatile organic compounds (VOCs) are carbon-based molecules with a low boiling point and so readily vaporize at room temperature. Some of these volatile substances are cytotoxic and/or carcinogenic solvents such as benzene, toluene, and formaldehyde, present in cleaning products, wallpaper, paints, and plastics.^170,171 Certain VOCs can react with NO₂ to form ozone under UV light from the sun.¹²⁷ Using an airborne formaldehyde provocation test, Kim et al. demonstrated that topical stimulation of the skin with formaldehyde gas for 1 hour aggravated transepidermal water loss and increased skin pH in both healthy and AD children. The observed skin barrier impairment was more prominent in the AD group compared to controls and was further disrupted with an additional 1 h of continuous exposure in a time-dependent manner at a constant dose.¹⁷²

Anthropogenic climate change

Greenhouse gas emissions, especially CO₂, have rapidly increased during the last 60 years due to anthropogenic effects resulting in global warming of the Earth’s atmosphere¹⁷³ There is mounting scientific evidence linking climate change to the emergence and exacerbation of AR, asthma, and other chronic respiratory disorders.¹⁷⁴ Climate change alters vegetation distribution patterns and aggravates the intensity and frequency of extreme weather events.^174,175

The elevated CO₂ and NO₂ levels in the atmosphere enhance the allergenicity of some plants by increasing the rate of photosynthesis, pollen production and prolong the pollen season.¹⁷⁶ The higher pollen concentrations can increase respiratory symptoms during the first year of life.¹⁷⁷ Floods provide ideal conditions for mold growth further aggravating allergic diseases. Global warming is intensifying the severity of thunderstorms that can trigger severe asthma attacks. Notably, the Melbourne asthma outbreak in 1992 coincided with a severe thunderstorm with a surge in hospital admissions. Hydration of the pollen grains fragments it into an aerosol carrying the allergen of sufficiently small size to easily enter the lungs and aggravate respiratory allergies and asthma.^178–181

Global warming and climate change have caused an increase in the extension and severity of desert dust storms, which can travel several thousand kilometers and affect the northern lands of the Saharan Desert and Arabian Peninsula. Desert dust causes an increase in mortality and morbidity due to airway diseases such as lower respiratory tract infection, COPD and asthma.^182,183 Itazawa et al. showed that inhaling transborder desert dust raised the risk of developing nasal, ocular, and respiratory symptoms in infants.¹⁸⁴ Desert dust can locally-increase PM₁₀ levels, and together with long-term changes in maximum temperature, they impact morbidity and mortality due to respiratory diseases.¹⁸²

Cigarette smoke and e-cigarettes

Inhalation of cigarette smoke disrupts the airway epithelial barrier and may contribute to the pathogenesis of chronic lung diseases such as asthma, AR and COPD.^185–187 Toxic agents in cigarette smoke disrupt the epithelial barrier function by inducing oxidative stress in the airway epithelium.¹⁸⁶ Lung tissue sections of patients with COPD and NHBECs from healthy subjects were used to demonstrate that repeated cigarette smoke exposure reduces E-cadherin and ß-catenin expression and impacts the tension of epithelial cells by increasing actin polymer levels to further destabilize cell adhesion.¹⁸⁸ Tatsuta et al. also observed airway epithelial barrier dysfunction and enhanced permeability in Calu-3 cells treated with cigarette smoke extract in a concentration-dependent manner.¹⁸⁵ Furthermore, cigarette smoke exposure elevated the number of inflammatory dendritic cells in the lung and compromised epithelial barrier integrity, both of which were aggravated by H1N1 infection.¹⁸⁹ A cross-sectional study of house dust mite-sensitized AR patients demonstrated that living in urban areas and exposure to secondhand smoke was associated with a defective nasal epithelial barrier attributed to a reduced expression of occludin and claudin-7.¹⁸⁷

Electronic cigarettes (e-cigarettes) have a nicotine delivery system and have become increasingly popular during the last decade. The aerosol generated when smoking e-cigarettes varies in composition and mainly consists of propylene glycol (PG) and vegetable glycerin (VG) as solvents, nicotine, and optional flavoring,¹⁹⁰ all of which are potentially toxic substances.¹⁹⁰ The adverse effect of repeated inhalation of these products on the airways has been evaluated in preclinical models. E-cigarette exposure impairs the airway epithelium, including abnormal mucus composition and epithelial barrier function, and alters the cytokine profile of lung macrophages.¹⁹¹ Short-term daily exposure to e-cigarette vapor weakened the human airway epithelial barrier function as demonstrated in air-liquid interface cultures of primary NHBECs, increasing its permeability and facilitating the passage of external stimuli.¹⁹² In vitro experiments where PG/VG was vaped onto the apical surface of HBECs demonstrated a reduction in glucose transport by these e-cigarette vapors.¹⁹³

Micro- and nano-plastics

There are three potential routes by which MPs and NPs can enter our body, namely inhalation, ingestion, and skin contact. The potential health hazards of inhalation and ingestion of MPs and NPs are attracting attention as they are increasingly detected in the air and food products, entering both our respiratory and digestive systems, respectively. MPs are present in possibly every food, as demonstrated in honey, milk, beer, fish, table salt, drinking water, and air.^15,42,194 Current safety hazard assessments of MPs and NPs on human health mostly pertain to gut and lung toxicity through mechanisms that involve oxidative stress, inflammatory reactions, and metabolic disorders.¹⁹⁵

Atmospheric micro- and nano-plastic pollution is now a global health concern affecting both urban and suburban areas. Moreover, significant amounts of MPs have been detected in remote regions, suggesting the capability of atmospheric MPs to travel long distances.^13,196 Indoor MP and NP pollution are significantly higher compared to outdoor levels, and so its effect on health warrants further investigation.¹⁹⁶ Humans are continuously inhaling toxic MPs and NPs present in polluted air throughout their lives.^42,196

Inhaled MPs and NPs are known to induce inflammation, oxidative stress, and cytotoxicity. In addition, these particles can translocate to subepithelial tissues passing through the epithelial barriers.^13,197 The toxicity is dependent on the particle size, density, surface area, and its microenvironment such as pH, ionic strength, clearance capacity of the mucosa, and the amount of secreted mucin.^197,198 Both MPs and NPs can reach the alveolar surface of the lungs, but additionally, NPs can enter the bloodstream by crossing the alveolar-capillary barrier.¹⁹⁷ It has been shown that polystyrene NPs down to 50 nm can reach the lung parenchyma and lung draining lymph nodes of mice after intranasal administration.¹⁹⁹ Additionally, polystyrene micro-and nanoparticle exposure is known to cause cytotoxicity, apoptosis, and autophagy in human bronchial and alveolar epithelial cell lines via endoplasmic reticulum stress caused by misfolded protein aggregation and mitochondrial disruption. Polystyrene particles also induce ROS and proinflammatory cytokine production such as IL-6 and IL-8.^13,131,200 Moreover, polystyrene MPs and NPs damage the bronchial epithelial barrier by decreasing ZO-1 expression in a dose-dependent manner.^131,200 All of the adverse events discussed above can disrupt the epithelial barrier integrity.

In vivo studies have demonstrated an inflammatory response to MPs, contributing to intestinal leakage and immunotoxicity.²⁰¹ Jin et al. reported that polystyrene MPs accumulate in the gut and lead to intestinal barrier dysfunction, gut microbiota dysbiosis, and bile acid metabolism disorder in mice.²⁰² Recently, Lee et al. reported loose glands in the colon and duodenum, visible swelling in the lamina propria, lymphocyte and plasma cell infiltration, and other inflammatory events in mice after being exposed to polyethylene MPs for five weeks. In addition, MPs decreased the percentage of CD4+ regulatory T and Th17 cells. Their results also indicated that a high concentration of MPs induced small intestinal inflammation through TLR4 signaling.²⁰³ A recent meta-regression study revealed that exposure duration, concentration, and irregular morphology are the major factors determining the cytotoxicity of MPs.²⁰⁴ Recently, Domenech et al. showed that although micro and nano polystyrene particles can enter and cross the intestinal barrier.²⁰⁵ Forte et al. suggested that the polystyrene NPs accumulated in the cytoplasm of human gastric adenocarcinoma cells and upregulated IL-6 and IL-8 genes involved in gastric pathologies.²⁰⁶ Mahler et al. used in vitro and in vivo intestinal loop models of the epithelium and reported that acute oral exposure to polystyrene NPs could interfere with iron transport. Chronic exposure can cause remodeling of the intestinal villi.²⁰⁷

Nanoparticles

Nanoparticles are considered particle matter with a diameter less than 1000 nm. With unique physical and chemical properties, nanoparticles can be tailored to a wide range of applications, including as additives in food products and in the pharmaceutical industry as drug delivery systems.²⁰⁸ There are increasing concerns about the toxicity of nanoparticles on the epithelial barrier as they can activate an inflammatory response in a dose-dependent manner. The generation of damage-associated molecular patterns induces a cascade of events that disrupts the gut microbiota homeostasis. Examples of potentially hazardous nanoparticles include titanium dioxide (TiO₂), zinc oxide (ZnO), silica dioxide (SiO₂), iron oxide (Fe₃O₄), silver (Ag), and cationic liposomes. Several studies have demonstrated disruption of the barrier integrity and an increase in cell leakage in Caco-2 cells following administration with TiO₂ and SiO₂.^{198,208–210} Their respiratory epithelial damaging effects were demonstrated in in vitro and in vivo studies. TiO₂ nanoparticles disrupt the barrier integrity of NHBECs²¹¹ and exacerbate respiratory syncytial virus induced airway barrier damage in a mouse model.²¹² In an in vitro model of the intestine using co-cultured Caco-2/THP-1 cells, Kampfer et al. demonstrated the increased vulnerability of the epithelial barrier integrity toward Ag nanoparticles when exposed in its inflammatory state.²¹³ In addition, Ag nanoparticles cause alterations on intestinal epithelial barrier permeability genes on ileal tissue explants.²¹⁴

Carbon nanomaterials (CNMs) are used in agriculture to activate seed germination, growth, and fruit production. However, the potential toxicity of ingested CNMs on animals and humans raises concerns.²¹⁵ Several in vivo studies have demonstrated adverse effects linked to the ingestion of CNMs.^216,217 Lahiani et al. reported the cytotoxicity of multi-walled carbon nanotubes (CNT) at a high concentration of 10 µg/mL impaired intestinal epithelial integrity and altered the gene expression pattern in an in vitro model of T-84 human intestinal epithelial cells. However, no significant toxicity was observed when the T-84 human intestinal epithelial cells were exposed to extracts from fruits containing CNTs or pure CNT at the same concentration.²¹⁵

Pesticides

Pesticides refer to all compounds (insecticides, herbicides, and fungicides) that are applied to destroy pests.²¹⁸ Synthetic organic pesticides, one of the most commonly used pesticide types, are chemically classified as organochlorine, organophosphate, carbamate and pyrethroid pesticides.²¹⁸ Although organochlorine pesticides are banned due to their high toxicity, slow degradation and bioaccumulation properties in most developed countries they are still widely used worldwide.^219,220 Half the lifetime of various organochlorines can be reached 15 years and it is still can be detected in environment.^218,221 Pesticides especially organochlorines can contaminate soil, water, and foods such as meat, fish, poultry, and dairy products. Humans are exposed to pesticides mostly by eating contaminated food, inhalation and skin absorption, and various studies show that pesticides especially organochlorines can be detected in different human tissues, mostly in tissues with high lipid content.^222–226 Many pesticides from different chemical groups cause ROS activation on various human cell types such as human intestinal cell line, Caco-2, immortalized keratinocyte cell line, HaCaT, and human liver cancer cell line, HepG2.^227–229 Organochlorine pesticides have cancerogenic and neurotoxic effects on humans. Their exposure is associated with blood pressure disorders, and endocrine, reproductive, liver and immune disfunction.^219,230 Organochlorine pesticides such as dieldrin, endosulfan, heptachlor and lindane cause ROS activation in the HaCaT cell line, in addition, endosulfan and heptachlor have cytotoxic effects.²²⁸ A group of pesticides previously shown as food contaminants such as deltamethrin (pyrethroid pesticide), lambda-cyhalothrin (pyrethroid pesticide), fenitrothion (an organophosphate pesticide), fipronil (phenylpyrazole pesticide) and teflubenzuron has cytotoxic effects on Caco-2 cells. In addition, fenitrothion and teflubenzuron exposure cause increased epithelial barrier permeability on Caco-2 cells.²²⁹ Neonicotinoid insecticides which is another group of pesticides being used on large scales have been found to contaminate fruits and vegetables.²³¹ A recent study demonstrated that a neonicotinoid pesticide imidacloprid exposure impairs intestinal epithelial barrier integrity both in vitro in Caco-2 cells and in vivo on a rat oral toxicity model. Exposure to imidacloprid in Caco-2 cells resulted in decreased expression of occludin, claudin-1 and ZO-1.²³²

Detergents and household cleaners

Bleach, ammonia-containing detergents, and other substances present in disinfectants (e.g., chloramine-T, quaternary ammonium compounds, and ethanolamine), irritate the lungs and can exacerbate asthma, rhinitis, or respiratory symptoms.^233–235 An epidemiological study demonstrated that occupational exposure to disinfectants, including formaldehyde, glutaraldehyde, enzymatic cleaners, hypochlorite bleach, and hydrogen peroxide, was related to an increased risk of poor control of asthma in nurses.²³⁶

Inhalation of irritants can induce lung permeability and remodeling of the airway epithelium by promoting a pro-inflammatory response, oxidative stress, and neurogenic inflammation due to exposed nerve endings.^236–238 Inhalation of chlorine vapors from sodium hypochlorite solutions irritates the airway and contributes to respiratory symptoms, asthma, and chronic bronchitis.²³⁴ Acute chlorine gas exposure in mice resulted in severe injury of the bronchial epithelium.²³⁹ In an ovalbumin-induced mouse model of allergic asthma, OVA-sensitized/challenged mice subjected to a low dose of chlorine vapors exhibited enhanced airway hyperresponsiveness and eosinophilic inflammation with the presence of Th2 cells, an increase in innate lymphoid cell (ILC)-2s and ILC-3s, and CD11c^int monocyte-derived macrophages, compared to controls.²⁴⁰

Laundry detergents contain phosphates, surfactants, and various enzymes (proteases, lipases, amylases, cellulase).²⁴¹ Cellulase, lipase, and amylase, derived from Bacillus licheniformis, are considered as potent allergens as proteases. The addition of surfactants and enzymes to detergents dates back to the 1960s. They are widely used in detergent washing powders and are suspected to cause occupational asthma in the detergent industry.^242,243 Even at low concentrations, laundry detergents and rinse residue are cytotoxic in a dose-dependent manner and directly impair TJ barrier integrity of NHBECs while upregulating lipid metabolism and apoptosis-related genes.²⁴⁴

Identifying biomarkers of occupational asthma associated with exposure to cleaning products is warranted to monitor disease progression and develop a stratified treatment strategy. Potential biomarkers of exposure to alkaline products and oxidative stress in exhaled breath condensate were identified in occupational cleaners without clinical symptoms of respiratory diseases.²⁴⁵Laundry detergents contain phosphates, surfactants, and various enzymes (proteases, lipases, amylases, cellulase).²⁴¹ Cellulase, lipase, and amylase, derived from Bacillus licheniformis, are considered as potent allergens as proteases. The addition of surfactants and enzymes to detergents dates back to the 1960s. They are widely used in detergent washing powders and are suspected to cause occupational asthma in the detergent industry.^242,243 Even at low concentrations, laundry detergents and rinse residue are cytotoxic in a dose-dependent manner and directly impair TJ barrier integrity of NHBECs while upregulating lipid metabolism and apoptosis-related genes.²⁴⁴

Processed food: surfactants, emulsifiers and advanced glycation endproducts

The modern Western diet is characterized by its high intake of processed foods with potentially harmful ingredients that have been implicated in the development of several chronic inflammatory diseases, including inflammatory bowel disease and metabolic syndrome.²⁴⁶ A common feature of highly processed foods is the presence of AGEs and artificial additives such as emulsifiers. Among its many uses, emulsifiers are frequently added to food products to prevent phase separation and extend shelf-life.²⁴⁷

The food additives such as synthetic colorants, preservatives, stabilizers, surfactants, emulsifiers, texturizers and AGEs -due to heat processing step- work together to cause significant damage to the epithelial cells and epithelial barrier and cause microbial dysbiosis at the same time (Table 3).^4,43,248 They show direct epithelial cell toxicity and change in surface tension stretch the epithelial cells and open the barriers. Anti-microbial molecules that act as preservatives increase the shelf life of packaged food but in the meantime show the same bacteria killing activity to commensals in the gastrointestinal tract.^43,248,249 Emulsifiers thicken the mucosal lining fluid and trap the microbiome and cause the death of commensals. In this way, the healthy interaction of commensal bacteria with the epithelium such as healthy and physiological, metabolite, vitamin and nutrient exchange cannot take place.²⁵⁰ There is accumulating evidence on the health hazards of dietary emulsifiers as they can increase intestinal barrier permeability, most extensively evaluated with the synthetic emulsifiers polysorbate 80 (P80) and carboxymethylcellulose (CMC). Roberts et al. generated M-cell monolayers using a co-culture of Caco-2 and Raji B cells and reported that P80 promoted translocation of E. coli across M-cells, an event that may be implicated in the pathogenesis of Crohn's disease.²⁵¹ Further in vivo studies by Zhu et al. indicate that chronic exposure to P80 decreases the expressions of mucus and TJ proteins and disturbs the intestinal epithelial cell integrity and mucosal barrier.²⁵² Similarly, in vivo and in vitro studies have demonstrated that P80 and CMC alter the amount and thickness of mucus in rat intestinal tissue and in mucus-producing cell cultures.²⁵⁰ In addition, administration of these two emulsifiers altered microbiota composition to a more pro-inflammatory state, as indicated by increased levels of bioactive flagellin, and increased intestinal permeability in mice,²⁵³ and in a mucosal simulator of the human intestinal microbial ecosystem model.²⁵⁴ In a recent randomized controlled study, consumption of a diet containing CMC induced gut microbiota dysbiosis in humans and reduced SCFA levels in the fecal metabolome, a metabolite from bacteria known for its anti-inflammatory properties.²⁵⁵

Table 3.

In vitro and in vivo models of gastrointestinal system epithelial barrier disruption.

Substance	Evidence	Reference(s)
Microplastics	Polystyrene MPs affect gut microbiota dysbiosis, intestinal epithelial barrier dysfunction and bile acid metabolism disorders in vivo.202	202
	Polyethylene MPs induce visible swelling in the lamina propria and increase the inflammatory response in vivo.	203
	MPs show cytotoxic effects on Caco-2 cells in vitro.	204
Nanoplastics	Polystyrene NPs upregulate IL-6 and IL-8 genes in gastric adenocarcinoma cells in vitro.206	206
	Polystyrene NPs cause remodeling of intestinal villi in vitro and in vivo intestinal loop models.207	207
Nanoparticles	TiO2 nanoparticles disrupts epithelial barrier integrity of Caco-2 cells.	209
	Silica nanoparticles causes oxidative stress and epithelial barrier integrity impairment on Caco-2 cells.	210
	Ag nanoparticles causes alterations on intestinal epithelial barrier permeability genes ex vivo.	214
	Carbon nanotubes are toxic and disrupt the intestinal epithelial barrier at high concentrations.	215
Surfactant and emulsifiers	P80 induces translocation of E. coli across M-cells.251	251
	P80 and CMC alter intestinal epithelial barrier in vivo and in vitro.	250, 252
	P80 and CMC alter mice and human microbiota composition.	253, 254
	CMC modifies the microbiota composition and metabolome in humans.	255
Heat processed foods (AGEs containing foods)	AGE-containing foods impairs the intestinal epithelial barrier integrity and cause gut dysbiosis in vivo.43	43

Ag: silver; CMC: carboxymethylcellulose; IL: interleukin; MP: microplastics, NP: nanoplastics; P80: polysorbate 80; SiO₂: silicon dioxide; TiO₂: titanium dioxide; ZnO: zinc oxide

The ubiquitously used thermal processing methods in the food industry induce chemical changes in the food that generate potentially toxic AGEs.²⁵⁶ Snelson et al. demonstrate that consuming AGE-containing foods increases the risk of chronic kidney disease, disrupting the intestinal epithelial barrier integrity and reshaping of the gut microbiota in a mouse model.⁴³ These events drive inflammation and promote kidney injury. In a mouse model of diabetes, a high resistant starch fiber diet mitigated the inflammatory events and restored gut microbiota homeostasis.⁴³

Contact allergens, hand sanitizers, and disinfectants

Isothiazolinones are added as preservatives to prevent the growth of microorganisms in cosmetic, household, and industrial products. In the past, isothiazolinones were also used very often in our daily life products like shampoos, cleaning detergents, and cosmetics that elicit (airborne) allergic contact dermatitis.^257–259 The usage of isothiazolinones is now restricted in consumer products in Europe, but occupational allergic contact dermatitis related to isothiazolinones is still on the rise.^260,261

Daily detergent use directly affects the integrity of the skin (Table 4). Enzyme detergents may pose a safety hazard due to their multienzyme formulation and surfactant properties. Surfactants can act as an adjuvant for immune response to enzymes in animal studies.²⁶⁵ After 72 h of stimulation, even nontoxic doses of anionic surfactants (SDS and sodium dodecylbenzene sulfonate [SDBS]), increase the paracellular flux in normal human epidermal keratinocytes in a dose-dependent manner. Moreover, disruption to the TJ barrier integrity of normal human epidermal keratinocytes was also observed through downregulation of occludin, and claudin-1 as measured by immunofluorescence staining and Western blotting.²⁶² A recent study demonstrated that sodium dodecyl sulfate exposure causes eosinophilic inflammation and epithelial barrier damage in the esophagus in vivo.²⁶⁶

Table 4.

In vitro and in vivo studies of skin barrier disruption with detergents and disinfectants.

Substance	Evidence	Reference(s)
Sodium dodecyl sulfate and sodium dodecyl benzene sulfonate	Increase the paracellular flux in normal human epidermal keratinocytes with downregulation of occludin and claudin-1.262	263
Professional cleaning detergents	High skin transepidermal water loss in cleaning professionals.263	265
Hand sanitizers and disinfectants	Increased prevalence of hand eczema in children and health care workers during the COVID-19 pandemic.264	266, 267

COVID-19: Coronavirus disease 2019

In a prospective study, high transepidermal water loss was found in detergent-exposed skin of professional cleaners due to a disrupted skin barrier, which was associated with an increased risk of work-related hand dermatitis in occupational cleaners.²⁶³

During the COVID-19 pandemic, the WHO recommended frequent hand hygiene practices as a sanitary measure to prevent contact transmission of severe acute respiratory syndrome coronavirus 2. Unfortunately, this has also increased the prevalence of hand eczema in children and health care workers during the COVID-19 pandemic.^264,267 In a randomized clinical trial, soap- or alcohol-based disinfectants were found to cause less transepidermal water loss increases than disinfectant-based wipes.²⁶⁸

Detection of skin barrier function

The assessment of skin barrier function is of great clinical value to monitor AD severity and responsiveness to treatment. Infantile eczema is one of the epithelial barrier-related diseases and its prevalence is increasing.²⁶⁹ Early prediction of infantile eczema development at the early months of the life of the babies such as the first and fourth months and taking protective measures is an important research aim in this area.^270,271 We recently reported a novel method to assess the in vivo status of the epithelial barrier directly using electrical impedance spectroscopy (EIS).^272,273 The skin EIS score provided a direct measurement of the epithelial barrier damage triggered by tape stripping, cholera toxin, papain, and trypsin. EIS could also distinguish the skin of healthy individuals without AD from the non-lesional skin of AD patients with precision using artificial intelligence-based models. Furthermore, EIS could assess skin lesion healing in response to treatment, correlating with the Alzheimer’s disease score, pruritus score, and inflammatory serum biomarkers. Confocal Raman spectroscopy has also been used as a noninvasive tool for skin characterization. Recently, this technique was used to elucidate the molecular mechanisms by which nonionic PEG-20 ethers reduce the lipid content of the skin and disrupt lipid organization.²⁷⁴

5. Conclusion

Environmental exposure to hazardous substances and their health-related effects and global warming and climate change are the two main challenges in front of humanity and nature of the world. The detrimental impact of anthropogenic influences on the environment has in turn adversely affected human health by damaging the epithelial barriers present in the respiratory tract, intestine and skin. The evidence presented in this review article points to the disruption of the epithelial barrier integrity as a key driver of microbial dysbiosis, pathological bacterial colonization, immune response to opportunistic pathogens and commensals and tissue inflammation. The inflammatory cascade of events originating from an impaired epithelial barrier is strongly implicated in the development of allergic diseases, autoimmune diseases, and metabolic disorders^1,7,80 Taking an interdisciplinary holistic perspective focusing on planetary health is imperative.²⁰ There is a current need to find novel therapeutic strategies to restore the barrier function, strengthening tissue-specific barriers, inhibiting dysbiosis and opportunistic pathogen colonization. It is essential to implement governmental policies first to fully avoid exposure and then to mitigate the cellular and molecular effects of exposure to toxic/barrier-damaging substances (Table 5). One of the main aims in this context will be to discover nontoxic substances as alternatives to toxic substances. Awareness and education of the public and political bodies is an essential in this fight. Identification of novel biomarkers for leaky barriers would facilitate personalized therapeutic interventions is also a major part of identifying barrier leaky individuals, substances and conditions. The scientific evidence presented in this review article stresses the need to raise awareness of the important role of the epithelial barrier on the pathogenesis of chronic immune-related diseases.

Table 5.

Future steps to prevent exposure to epithelial barrier damaging substances.

(1) Dose control and avoidance

(2) Development of less-toxic products

(3) Studies on the epithelial barrier to advance our understanding of its mechanisms

(4) Development of novel therapeutic approaches for strengthening the mucosal and skin epithelial barrier

(5) Biomarker discovery for the identification of individuals with a leaky epithelial barrier

(6) Raising awareness (conferences, community talks, social media networks)

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Abbreviations

AGEs

Advanced glycation endproducts

AR

Allergic rhinitis

AhR

Aryl hydrocarbon receptor

AD

Atopic dermatitis

CO

Carbon monoxide

CNMS

Carbon nanomaterials

CNT

Carbon nanotubes

CMC

Carboxymethylcellulose

COPD

Chronic obstructive pulmonary disease

DEP

Diesel exhaust particulates

EIS

Electrical impedance spectroscopy

E-cigarette

Electronic cigarettes

FLG

Filaggrin

ILC

Innate lymphoid cell

IL

Interleukin

Fe₃

Iron oxide

MP

Microplastic

NP

Nanoplastic

NO

Nitric oxide

NO₂

Nitrogen dioxide

NHBECS

Normal human bronchial epithelial cells

PM

Particulate matter

P80

Polysorbate 80

PG

Propylene glycol

ROS

Reactive oxygen species

SiO

Silica dioxide

SDS

Sodium dodecyl sulphate

SDBS

Sodium dodecylbenzene sulfonate

SO₂

Sulphur dioxide

TJ

Tight junction

Th

T helper

TiO

Titanium dioxide

TLR

Toll-like receptor

VG

Vegetable glycerine

VOCS

Volatile organic compounds

WHO

World Health Organization

ZnO

Zinc oxide

ZO

Zonula occludens

Disclosure statement

No potential conflict of interest was reported by the author(s).