Skin exposome science in practice : current evidence on hair biomonitoring and future perspectives

The skin exposome, defined as the totality of environmental exposures from conception to death that can induce or modify various skin conditions, compiles environmental, lifestyle and psychosocial exposures, as well as the resulting internal biological and physiological responses to these exposures. Biomonitoring can be used to obtain information on the internal dose of pollutants. The concentration of biomarkers in body fluids is highly variable over time due to differential elimination kinetics of chemicals, whereas they accumulate in hair. Hair analysis thus provides information on cumulative exposure over a longer period of time, and so can be used for assessing chronic exposure to pollutants. Studies on hair samples collected from 204 women living in two cities in China with different levels of pollution demonstrated that hair damage and the skin microbiome are biomarkers of a polluted city and long-term exposure to pollution and UV can increase signs of facial ageing. Adopting an exposome approach to skin health requires assessing multiple exposures and biological consequences, possibly in relation to longitudinally followed-up health outcomes. Leveraging “omics” data (e.g. metabolomics, proteomics, genomics and microbiome) and big data analytics, in particular multivariate analysis, will help to further understand the impact of pollution on skin and the combined effects with other exposome factors, including solar radiation and other environmental exposures.     

Sebum,inflammasomes and the skin: current concepts and future perspective

Increasing evidence has identified ultraviolet radiation (UVR) as the skins most potent mutagen as over exposure results in sunburn, inflammation and DNA damage, thus contributing to a photo‐ageing phenotype and possibly skin carcinogenesis. The lipid‐rich sebum secreted onto the surface of the skin plays an important physiological role in protecting the skin against external challenges. When skin is photosensitised by UVR, the lipid constituents of sebum are easily oxidised, generating several lipid photo‐oxidative products (e.g. squalene peroxides). These photo‐oxidative products have been shown to exert diverse toxicological, biological and immunological effects in the skin and have therefore been implicated in several detrimental skin alterations including premature skin ageing. The involvement of lipid peroxidation products in UVR‐induced inflammatory responses has been inadequately studied and highly controversial. Furthermore, it is unclear to what extent these oxidative products contribute to the underlying mechanisms of skin photo‐ageing. Therefore, this viewpoint essay will discuss the current knowledge on the effect of UVR exposure on skin surface lipids and how these may mediate UVR‐induced inflammatory responses which may be key contributors to photo‐damage in skin. This essay will also examine the potential role of inflammasomes (innate immune complexes) in the inflammatory response associated with UVR‐induced lipid peroxidation. Limited evidence is available on the interactions between sebaceous lipids, downstream mediators and concomitant immune response in sun‐exposed skin and clearer elucidation may lead to novel biomarkers of photo‐ageing and the incorporation of new molecules into current skin therapies which better target oxidised lipids and or downstream mediators/pathways.     

The impact of perceived stress on skin ageing

Skin ageing can be divided according to phenotypical features into intrinsic (by the passage of time) and extrinsic (with the addition of the effects of environmental factors). Photoageing is by far the most researched factor of extrinsic ageing but the additional impact of other factors such as cigarette smoking and exposure to air pollution ought to be taken into account. One of the least researched topics in relation to extrinsic skin ageing is the impact of psychological stress. A contemporary review of response of human skin to stress describes the molecular mechanisms of extrinsic skin ageing, but has fallen short of explaining resilience to stress exhibited by people. Mechanisms to regulate gene expression, define cellular identity and promote functionality are responsible for the adaptive response to stressful events. Conversely, maladaptive response of human tissues to chronic stress appears to have an impact on gene regulation. Epigenetics is the study of heritable changes in organisms due to modifications in gene activity and expression, as opposed to the genetic code (DNA genome). Chronic stress appears to be an important factor in determining an individual's vulnerability to ageing and age-related comorbidities via epigenetic modifications. Forerunners in epigenetic research recognized the necessity of a reliable biomarker in order to develop a better understanding of the role of epigenomics in ageing. Genomic DNA methylation patterns (DNAm) appear to be valuable in age prediction but variability in specificity exists across species of mammals, human races and tissues. Neuroscience research appears to be leading the way in epigenomics whilst the lack of a valid and reliable DNAm-associated age predictor compatible with human skin tissue hinders research endeavours for the epigenetics of skin ageing.     

Photodamage to human skin by suberythemal exposure to solar ultraviolet radiation can be attenuated by sunscreens: a review

The effects of acute or repeated suberythemal solar ultraviolet radiation (UVR) exposure on human skin have been insufficiently investigated. Such exposure almost certainly has important long-term consequences that include skin ageing and skin cancer. This review summarizes the published data on the biological effects of suberythemal exposure using a wide range of clinical, cellular and molecular endpoints, some of which may be considered as biomarkers for skin cancer and photoageing. We also include some recent unpublished results from our laboratories. The effects of UVA (320-400 nm), UVB (290-320 nm) and total solar UVR (290-400 nm) are compared. We demonstrate that avoiding sunburn does not prevent many indicators of cutaneous biological damage and that use of low sun protection factor (SPF) sunscreen can inhibit much of the damages induced by suberythemal exposure to UVR. However, even when applied correctly, sunscreen use will result in suberythemal exposure. The degree and spectral quality of such exposure will depend on the SPF and absorption spectrum of the sunscreen, but nonetheless it may contribute to cumulative photodamage. This review may help to determine the level of photoprotection required in sunscreens and daily use products, as well as the ideal ratio of UVB/UVA protection, to improve long-term photoprotection outcomes.     

Antioxidants and the response of skin to oxidative stress: vitamin E as a key indicator

As the outermost barrier of the body, the skin is directly and frequently exposed to a prooxidative environment, including solar UVA and UVB radiation, and air pollution. The skin is equipped with an elaborate system of antioxidant substances and enzymes that includes a network of redox active antioxidants. Among these, vitamin E has been identified as the predominant antioxidant both in murine and human skin and shows a characteristic gradient with lower levels towards the outer stratum corneum layers. Skin exposure to UV and ozone alone and in combination resulted in a significant potentiation of the UV-induced vitamin E depletion. Oxidants and antioxidants play an important role in maintaining a balance between free radicals produced by metabolism or derived from environmental sources. Cellular antioxidants may change their redox state, be targeted for destruction, regulate oxidative process involved in signal transduction, affect gene expression and pathways of cell proliferation and death. Here we provide an overview of the antioxidant system with a special relevance to skin.     

Atmospheric skin aging—Contributors and inhibitors

Cutaneous aging is a complex biological process consisting of 2 elements: intrinsic aging, which is primarily determined by genetics, and extrinsic aging, which is largely caused by atmospheric factors, such as exposure to sunlight and air pollution, and lifestyle choices, such as diet and smoking. The role of the solar spectrum, comprised of ultraviolet light, specifically UVB (290‐320 nm) and UVA (320‐400) in causing skin damage, including skin cancers, has been well documented. In recent years, the contribution of visible light (400‐700 nm) and infrared radiation (above 800 nm) in causing skin damage, similar to the photodamage caused by UV light, is also being elucidated. In addition, other atmospheric factors such as air pollution (smog, ozone, particulate matter, etc.) have been implicated in premature skin aging. The skin damage caused by environmental exposure is largely attributable to a complex cascade of reactions inside the skin initiated by the generation of reactive oxygen species (ROS), which causes oxidative damage to cellular components such as proteins, lipids, and nucleic acids. These damaged skin cells initiate inflammatory responses leading to the eventual damage manifested in chronically exposed skin. Novel therapeutic strategies to combat ROS species generation are being developed to prevent the skin damage caused by atmospheric factors. In addition to protecting skin from solar radiation using sunscreens, other approaches using topically applied ingredients, particularly antioxidants that penetrate the skin and protect the skin from within, have also been well documented. This review summarizes current knowledge of atmospheric aggressors, including UVA, UVB, visible light, infrared radiation (IR), and ozone on skin damage, and proposes new avenues for future research in the prevention and treatment of premature skin aging caused by such atmospheric factors. New therapeutic modalities currently being developed are also discussed.     

Biological processes in solar lentigo: insights brought by experimental models

Common in ageing patient, the solar lentigo is a macular hyperpigmented skin lesion that results from chronic exposure to ultraviolet irradiations. Despite sharing numerous features with other pigmented spots, the diagnostic of this benign lesion is well characterized at the tissue level. Recent studies shed lights on several factors and their pathogenic mechanisms involved in the development of the solar lentigo. This review summarizes how diverse experimental approaches allowed the identification of several biomarkers, which contribute to a better understanding on the initiation and the maintenance of this pigmentary disorder.     

Multiple senile lentigos of the face, a skin ageing pattern resulting from a life excess of intermittent sun exposure in dark-skinned caucasians: a case-control study

BACKGROUND: Different patterns of skin ageing can be described depending on the predominant lesions, i.e. wrinkles, laxity, atrophy, senile lentigos (SLs), etc. They may correspond to different epidemiological contexts. OBJECTIVES: To identify and assess the epidemiological factors for a skin ageing pattern characterized by a high density of SLs on the face, or 'lentigo ageing pattern' (LAP). METHODS: An age- and sex-matched case-control study was conducted in individuals aged between 60 and 80 years, comparing cases (n = 118) with a very high number of SLs on the face for their age, and controls (n = 118) with no or very few SLs for their age. The cases and controls were recruited in two hospitals. RESULTS: In univariate and multivariate analysis, LAP was associated with skin types III and IV, with frequent sunburns, and with the part of the lifetime cumulative sun exposure which was received during vacations. Conversely, there was no link with the occupational and everyday exposures and the total cumulative exposure. LAP was associated with multiple solar lentigos of the upper back. No relationship was found with postmenopausal hormonal therapy, number of naevi, or freckles. CONCLUSIONS: Different epidemiological factors may account for the different skin ageing patterns. LAP seems to develop preferentially in dark-skinned caucasians who have repeatedly received intermittent and intense sun irradiations throughout their life, and have often developed solar lentigos on the upper back earlier in life, whereas the 'prominent wrinkling' pattern is known to affect light-skinned people and smokers with a life excess of continuous exposure.     

Bad air gets under your skin

Air pollution is increasing beyond previous estimates and is viewed as the world's largest environmental health risk factor. Numerous clinical and epidemiological studies have highlighted the adverse effects of environmental pollutants on health. Although there is comparatively less research investigating the cutaneous effects of ambient pollution, there is growing recognition of the adverse effects on skin. In this article, we provide an overview of the nature of environmental pollution and highlight the current evidence detailing the effects on cutaneous health. There is convincing evidence demonstrating that air pollution has a detrimental impact on skin and can exacerbate skin disease. Further epidemiological and experimental studies are required to assess the short‐ and long‐term deleterious effects of ambient pollutant exposure on skin. The future challenge would be to use this evidence to develop specific strategies to protect against pollution‐induced damage and prevent the effects of “bad air getting under our skin.”     

Association between smoking and cutaneous ageing in a Brazilian population

Objective This study aims to determine the relationship between smoking and cutaneous ageing. Methods A cross‐sectional study was carried out on 301 subjects (191 women and 110 men, aged between 25 and 86 years), of which 165 were non‐smokers and 136 were smokers and ex‐smokers. The association between tabagism and cutaneous ageing was controlled for other variables (solar exposure, age, skin phototype, sex, sunscreen use, alcohol consumption, coffee consumption, sports participation, body mass index, and history of relatives with precocious ageing). Results Analysis revealed that age, chronic solar exposure, skin phototype and tobacco load significantly contributed to the formation of facial wrinkles. The larger the tobacco load, the larger was the amount of facial wrinkling, with an odds ratio of 3.92 in ‘heavy’ smokers (> 40 packs/year) in relation to non‐smokers. Conclusion The results of this study point to smoking as one of the main factors involved in facial wrinkling. The relationship between smoking and cutaneous ageing is an important element in educational campaigns against tabagism.     

How to prevent skin damage from air pollution. Part 1: Exposure assessment

Both epidemiological and experimental studies have demonstrated the crucial connection between air pollution exposure and skin disorders. The exact mechanisms by which air pollutants mediate skin damage remain largely unknown. Therefore, it is very necessary to investigate the mechanism of air pollution‐induced skin damage and explore some potential protective and therapeutic methods. In this review, we focus on the qualitative and quantitative skin exposure assessment methodologies—a relatively new field of interdisciplinary research.     

The environment‐pathogen‐host axis in communicable and non‐communicable diseases: Recent advances in experimental and clinical research

Allergies and autoimmune diseases are spreading worldwide. Control of infections, on the other hand, remains an issue, even in the post‐antibiotic era. Chronic or poorly controlled infections occur in immune compromised individuals such as HIV patients, hospitalized patients exposed to multi‐resistant bacteria, or patients on immunosuppressive treatment. They may become an even more emerging issue in an ageing population. At the same time, profound environmental changes such as global warming, urbanization, increasing environmental pollution and novel food engineering technologies may alter the abundance or aggressiveness of allergens/allergen carriers in our environment. Likewise, changes in dietary habits – and possibly also use of antibiotics – have an impact on the composition of our natural microbial flora in the gut, airways and skin, which may alter susceptibility for common diseases, among them allergies, asthma and atopic eczema. At the recently founded Institute of Environmental Medicine of the Technische Universität Munich, located in Augsburg at the UNIKA‐T, experimental, clinical and translational research is focused on the complex interactions of environment, pathogen and host in expression or control of communicable and non‐communicable diseases. We present our research concept and recent findings in environment – host interactions.     

A study of the role of house dust mite in atopic dermatitis

Subjects with positive skin-prick tests to house dust mite (HDM) solution, including those with and without atopic dermatitis, participated in a double-blind, controlled study of the role of HDM exposure in the pathogenesis of atopic dermatitis. HDM solution and diluent control were applied daily to mildly eczematous or clinically uninvolved skin of the antecubital or popliteal fossae, without prior abrasion, for 5 days. Responses were assessed by a clinical grading system and by measurement of area of dermatitis; pruritus was recorded on visual analogue scales. The clinical grading system showed that marked or moderate delayed local reactions developed in one third of patients with atopic dermatitis in response to HDM application to both mildly eczematous and clinically uninvolved skin. Relative to control sites, significant increases in area of dermatitis and degree of pruritus were also recorded in response to HDM application to mildly eczematous sites. Application of HDM solution to normal, unabraded skin of prick test positive subjects without a history of dermatitis, produced pruritus and immediate urticarial responses which were not seen at control sites, findings which demonstrate that HDM antigen may be rapidly absorbed in normal skin. Application of vehicle or antigen solution to which subjects were negative on prick testing, produced no significant local reactions. This study provides objective evidence for a role for cutaneous HDM exposure in the pathogenesis of atopic dermatitis.     

Alitretinoin treatment of lichen amyloidosis

Lichen amyloidosis (LA) is characterized by the deposition of amyloid that may respond to chronic scratching that may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Despite the development of several therapeutic strategies, including topical steroids, oral antihistamines, cyclosporine, and retinoids, an effective treatment for LA has not been established. A 49‐year‐old woman who has been treated irregularly for atopic dermatitis for 7 years presented with localized brownish papules on the left forearm and right elbow. They developed 3 months prior and were becoming more prominent despite of treatment with cyclosporine, oral antihistamines, and topical steroids for 5 months prior to presentation. A skin biopsy revealed amyloid deposition in the dermal papillae and the patient was diagnosed with LA associated with atopic dermatitis. A 6‐month course of daily oral alitretinoin 30 mg produced marked improvement in the thickness and color of the hyperkeratotic papules without aggravation of the patient's atopic dermatitis. Histologic evaluation showed clearance of amyloid deposition and almost normalization of the epidermal changes. Herein, we report a case of LA treated with alitretinoin and suggest that it could be a potential treatment option for LA, especially in patients with inflammatory skin diseases including atopic dermatitis.     

Irradiation of skin with visible light induces reactive oxygen species and matrix-degrading enzymes

Daily skin exposure to solar radiation causes cells to produce reactive oxygen species (ROS), which are a primary factor in skin damage. Although the contribution of the UV component to skin damage has been established, few studies have examined the effects of non-UV solar radiation on skin physiology. Solar radiation comprises <10% of UV, and thus the purpose of this study was to examine the physiological response of skin to visible light (400-700 nm). Irradiation of human skin equivalents with visible light induced production of ROS, proinflammatory cytokines, and matrix metalloproteinase (MMP)-1 expression. Commercially available sunscreens were found to have minimal effects on reducing visible light-induced ROS, suggesting that UVA/UVB sunscreens do not protect the skin from visible light-induced responses. Using clinical models to assess the generation of free radicals from oxidative stress, higher levels of free radical activity were found after visible light exposure. Pretreatment with a photostable UVA/UVB sunscreen containing an antioxidant combination significantly reduced the production of ROS, cytokines, and MMP expression in vitro, and decreased oxidative stress in human subjects after visible light irradiation. Taken together, these findings suggest that other portions of the solar spectrum aside from UV, particularly visible light, may also contribute to signs of premature photoaging in skin.     

Nicotinamide and the skin

Nicotinamide, an amide form of vitamin B3, boosts cellular energy and regulates poly‐ADP‐ribose‐polymerase 1, an enzyme with important roles in DNA repair and the expression of inflammatory cytokines. Nicotinamide shows promise for the treatment of a wide range of dermatological conditions, including autoimmune blistering disorders, acne, rosacea, ageing skin and atopic dermatitis. In particular, recent studies have also shown it to be a potential agent for reducing actinic keratoses and preventing skin cancers.     

Dissecting the role of infections in atopic dermatitis

In patients with atopic dermatitis the skin is highly susceptible to infection by bacteria, fungi and viruses. Increasing knowledge about the complex immune network that regulates anti-microbial responses has helped to dissect further the role of infections in atopic dermatitis. Conserved patterns of microbes are recognized by the innate immune system, which mediates microbicidal activity, either directly or through inflammatory responses. New evidence suggests that components of the innate immune system, such as anti-microbial peptides, humoural lectins, nucleotide-binding oligomerization domain-containing (NOD) proteins, and Toll-like receptors not only protect from microbial invasion, but contribute to skin inflammation in atopic dermatitis. In addition, atopic patients tend to develop Th2-dominated immune responses that weaken anti-microbial immunity. This impairment of an appropriate anti-microbial defence compounded by amplified microbe-driven innate and adaptive immune responses leads to the vicious circle of skin inflammation. New microbial management in atopic dermatitis will foster a well-balanced microbial flora, which establishes natural defence mechanisms to maintain immuno-surveillance of the skin. In addition to anti-microbial therapies, other innate immune stimuli may suppress pro-inflammatory signals and help to break the vicious circle of cutaneous inflammation. To elucidate further these different interactions of the skin immune system and microbes in atopic dermatitis, clinical studies and further efforts in basic research are needed.     

Infrared radiation does not enhance the frequency of ultraviolet radiation-induced skin tumors, but their growth behaviour in mice

There is increasing concern about the interaction between infrared radiation (IR) and ultraviolet radiation (UVR) with regard to carcinogenesis because prolonged solar exposure is associated with an increased cumulative load not only of UVR but also of IR. We recently demonstrated that IR-pretreatment reduces UVR-induced apoptosis. As this might support the survival of UVR-damaged cells and thus carcinogenesis, we performed an in vivo photocarcinogenesis study. One group of mice were treated with IR prior to each UVR exposure; additional groups were treated with IR or UVR alone. IR alone did not induce skin cancer. UVR-induced tumor formation was not enhanced in IR-pretreated mice, but, in contrast, seemed to occur with delay. This correlated with a reduction of p53 mutated clones in the skin. However, once developed, tumors in IR-pretreated mice grew faster which was confirmed by their enhanced Ki-67 expression. The enhanced aggressiveness of tumors derived from IR-pretreated mice was associated with a higher prevalence of sarcomas than epithelial tumors. Hence, the impact of IR on UVR-induced carcinogenesis has to be interpreted with caution. Although IR may delay the onset of UVR-induced tumors, it might contribute to a worse outcome by shifting these tumors into a more aggressive phenotype.     

Pigmentation in Koreans: study of the differences from caucasians in age, gender and seasonal variations

BACKGROUND: Human skin colour shows variations throughout life, and many extrinsic and intrinsic factors influence melanogenesis. Facultative pigmentation of sun-exposed skin has been suggested to reflect cumulative lifetime ultraviolet (UV) exposure in caucasians. However, pigmentary changes due to various regulatory factors may be different in dark-skinned peoples. OBJECTIVES: To observe the variations in skin colour due to ageing, gender differences and seasonal changes in Koreans with skin type IV or V. METHODS: Skin pigmentation was measured at five body sites (buttock, glabella, the V of the neck area, inner arm and dorsal forearm) using skin reflectance spectroscopy in 497 subjects (age range 0-87 years) in winter and 311 subjects (age range 0-84 years) in summer. Among these subjects, 110 were assessed in both seasons. Three independent measurements at each site were done and the average value was used as the pigmentation level. RESULTS: Constitutive pigmentation of the buttock was highest in the first decade of life. It then decreased during the second decade and this decreased level was maintained after the third decade. In contrast to caucasians, facultative pigmentation and sun exposure index did not increase with ageing. Gender differences were significant at all body sites after the first decade. Seasonal changes were apparent in dorsal forearm pigmentation. Little difference was seen in forehead pigmentation between summer and winter. CONCLUSIONS: Basal melanogenic regulation might not be different between Asians and caucasians. However, the sun exposure index may not represent lifelong cumulative UV exposure in Koreans. Age-, gender- and season-related characteristics of skin pigmentation in Koreans imply that genetically determined basal skin colour plays an important part in characterizing later responsiveness to UV radiation and sex hormones. Understanding differences between races will be helpful in studying the regulatory mechanisms of melanogenesis.     

An evalution of atopic diseases in relation to immediate skin test reactions among schoolchildren in the Sør-Varanger community

Aim To compare the frequency of questionnaire based diagnosis of atopic diseases to those of clinical findings and sensitization and to evaluate the reliability of self-reported reactions to allergens with those confirmed by skin prick tests. Background Not only airborne allergens but also environmental indoor and outdoor air pollution are regarded as risk factors for the development of respiratory diseases in children. Metals, soot, SO₂, passive smoking and pollution from new building materials irritate both the skin and the respiratory mucosa and also increase the risk of atopic sensitization. A strong indication that atopic diseases are common in Sør-Varanger community, an area heavily polluted by the nearby Russian smelting plants, prompted us to investigate this hypothesis. Subjects The clinical and immunological examination involved 424 out of 575 schoolchildren aged 7–12 years. Results A total of 36% of the subjects were atopic; i.e. atopic dermatitis was established in 23% and mucous membrane atopy in 18%. 44% were definite non-atopies, leaving 14% not classifiable in either group and 6% latent atopies. Sensitization was confirmed by positive prick tests in 69% of children with a history of pollen allergy and 11% of those with a history of allergy to animal dander. Conclusions Skin prick tests are of little value in the diagnosis of atopic dermatitis but of major importance for the confirmation of mucous membrane atopy. In cases of controversy between history, clinical findings and sensitization, it is difficult to decide between atopies and non-atopies. Allergological examinations may be restricted to individuals with a positive symptom-based diagnosis only.