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The influence of exposome on acne

Abstract Background Acne vulgaris is one of the main reasons for dermatological consultations. Severity and response to treatment may be impacted by various external factors or exposome. Aim To assess the impact of environmental factors on acne and to provide a comprehensive overview of the acne exposome. Methods Two consensus meetings of five European dermatologists and a comprehensive literature search on exposome factors triggering acne served as a basis for this review. Results Acne exposome was defined as the sum of all environmental factors influencing the occurrence, duration and severity of acne. Exposome factors impact on the response and the frequency of relapse to treatments by interacting with the skin barrier, sebaceous gland, innate immunity and cutaneous microbiota. They may be classified into the following six main categories: nutrition, psychological and lifestyle factors, occupational factors including cosmetics, as well as pollutants, medication and climatic factors. Moreover, practical considerations for the dermatologist's clinical practice are proposed. Conclusion Exposome factors including nutrition, medication, occupational factors, pollutants, climatic factors, and psychosocial and lifestyle factors may impact on the course and severity of acne and on treatment efficacy. Identifying and reducing the impact of exposome is important for an adequate acne disease management.


Introduction
The term 'exposome' was used for the first time by Wild in 2005 to describe the sum of environmental exposures to which an individual is subjected from conception to death. 1 The definition of exposome varied over time (Table 1). [1][2][3][4][5] In 2014, Miller and Jones refined this term as 'the cumulative measure of environmental influences and the associated biological responses throughout the lifespan, including exposures from the environment, diet, behaviour, and endogenous processes'. 2 In 2016, the impact of exposome on chronic diseases was estimated at almost 80%; conversely, that of genomewide-associated diseases did not exceed 20%. 6 Exposome-wide association studies may allow discovering factors that, over time, cause complex chronic diseases.
Skin is one of the major interfaces between the body and the external environment and one of the main routes of penetration of environmental factors and pathogens. It plays a protective role due to its barrier function and its microbiota. 7 Until recently, the role of exposome in dermatology was not investigated. In 2017, Krutmann et al. studied the role of exposome in skin ageing and proposed that environmental factors belonging to the skin ageing exposome fall into the following categories: (i) sun radiations: ultraviolet radiation, visible light and infrared radiation; (ii) air pollution, (iii) tobacco smoke; (iv) nutrition; (v) a number of less well-studied, miscellaneous factors; as well as (vi) cosmetic products. 8 Acne is one of the main reasons for dermatologic consultation. It is an inflammatory disease of the pilosebaceous follicle occurring commonly in adolescents and some adults. It is associated with hyperseborrhoea altering the epithelium of the follicle with formation of comedones, a modification of the microbiote called dysbiosis targeting mainly Propionibacterium acnes (P. acnes) causing an activation of the innate immunity and thus inflammation. 9 A family factor is frequently associated with acne severity. 10 However, severity and response to treatment may also be impacted by different external or environmental factors.
With this article, we aimed at assessing the influence of environmental factors on acne and at providing a comprehensive overview of the acne exposome. Moreover, we propose practical considerations for the dermatologist's clinical practice.

Methodology
This article results from two consensus meetings of a board of European dermatologists held in July and October 2017.
Prior to the meetings, we conducted a comprehensive literature search through PubMed, combining the following key words: acne and exposome, sunlight, UV radiation, UVB radiation, UVA radiation, visible light, infrared radiation, air pollution, ozone, PM 10 , PM 2.5 , pollutants, tar, oil, nitrogen dioxide, tobacco, cannabis, smoking, stress, physical activity, occupation, nutrition, diet, alcohol, oil, whey proteins, hydrocarbons, cosmetics, skin care, make-up, cosmetic procedures, heat, cold, climate, water, lack of sleep. All relevant articles including epidemiological, in vitro, ex vivo and clinical studies were selected.
During the meetings, we defined and analysed key elements of acne exposome factors based on published literature (Fig. 1).

Definition of the acne exposome
We defined acne exposome as the sum of all environmental factors influencing the occurrence, duration and severity of acne. Exposome factors impact on the response and the frequency of relapse to treatments by interacting with the skin barrier, sebaceous gland, innate immunity and cutaneous microbiota. 11,12 They may be classified into the following six main categories: nutrition, medication, occupational factors including cosmetics, pollutants, climatic factors, and psychological and lifestyle factors.

Acne exposome factors
Nutrition This first category is by far the most published acne exposome factor. In the past, nutrition was not a proven cause of acne. However, recent publications show a link between some dietary factors and acne. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Nowadays, main food classes considered triggering acne are dairy products (especially skim milk) and hyperglycaemic carbohydrates. 10,[29][30][31][32][33][34][35][36][37] An average regimen of dairy products has been reported impacting on acne, and one paper indicated that cow milk impacts on acne after already two glasses per day. 38,39 Conversely, acne is not observed in native non-Westernized populations consuming low glycaemic load diet and in populations not    3 Exposome is a mixture of environmental exposures, including man-made and naturally occurring chemicals, physical agents (such as noise, vibration and temperature), macrolevel factors (including population density and sanitation) and lifestyle factors consuming refined sugars, grains, milk and dairy products. 40 Moreover, individuals with congenital deficiencies of the insulin growth factor-1 (IGF-1) have been reported to present only rarely with acne. 23 Recent papers provide additional arguments supporting the link at a transcriptional level between IGF-1, leptin and liponectin and high glycaemic index through the activation of mTOR and FOXP1 pathways. 13,14,28,29 Although there is convincing evidence of a correlation between nutritional elements and acne, there are no interventional studies supporting that dietary regimes are of clinical relevance. 37 Further research is required, in particular studies with larger sample sizes combining a low glycaemic index diet and restricted intake of cow milk products.
Nevertheless, we strongly support the idea of a subgroup of patients in whom acne severity relates to nutrition: these patients present with a moderate-to-severe acne with frequent relapses, an increased body mass index equal or superior to 25 and increased IGF-1 and decreased leptin and liponectin levels. 13 Nutritional supplements such as whey proteins containing leucine used by athletes may trigger or worsen acne. [41][42][43] Leucine stimulates the production of IGF-1. 31,[41][42][43][44] Very few controlled studies have investigated the benefit of oral probiotics in the treatment of acne. When compared to the placebo in 20 patients, the probiotic containing Lactobacillus rhamnosus SP1 provided a better clinical outcome according to the investigators. 45 An adjunctive supplementation of lyophilized Lactobacillus acidophilus and Bifidobacterium bifidum adjunctively to standard antibiotics improved acne in 40 patients. 46 Oral antibiotics and probiotics provided a synergistic benefit in inflammatory acne in decreasing both, inflammatory and noninflammatory lesions after 12 weeks compared to probiotics or oral antibiotics alone in three groups of 15 patients each. 47 The capability of oral probiotics to reduce systemic oxidative stress, to regulate cytokines and to reduce inflammatory markers may contribute to its effects on acne. 48 Despite encouraging results, further investigations are still necessary to confirm the clinical benefit of probiotics in acne.
Medications Hormonal treatments. There is evidence that in first-and second-generation oral contraceptives, progestin is changed in metabolites of testosterone that may exacerbate acne in adolescents and mainly in adult females. 49,50 The following androgenic progestins have been identified to cause or worsen acne: desogestrel and 3-cetodesogestrel, levonorgestrel, lynestrenol, norgestrienone, norethisterone, norgestrel, gestodene, norgestimate and etonogestrel.
Occupational factors Cosmetics. The use of aggressive skin care regimens and inappropriate cosmetics may cause acne flareups. These products modify the skin barrier and the skin microbiota balance especially in the sebaceous area, thus activating the innate immunity triggering inflammation.
Acne cosmetica was described for the first time by Kligman and Mills in 1972. 71 It is characterized by small scattered comedones on the face with only very few inflammatory lesions such as papules, pustules. Acne flare-up triggers in cosmetics include comedogenic ingredients, essential oils or too greasy or oily foundations, powder make-up, aggressive skin cleansers and soaps with pH of 8.0. 72,73 Some hair care products, such as brilliantine, have been reported to cause comedones and cysts on the forehead and temple. 74 Mechanical factors. Mechanical factors comprising rubbing, scrubbing, the use of home devices or medical devices such as sonic brushes, dermarollers or microneedling systems may trigger acne flare-up. 75 Dreno et al. reported that mechanical factors cause two types of mainly inflammatory cutaneous lesions: one 'folliculitis mechanica' presenting with inflammatory papules, open comedones or no comedonal lesions and the other one corresponding to a flare-up of acne in areas prone to the condition. The authors also presented a clinical case of a patient using essential oils combined with a roller-microdermabrasion device, diagnosed with severe inflammatory acne due a combination of a facial skin massage device and topical products.
Currently, the physiopathology of inflammatory cutaneous lesions caused by mechanical injury remains to be elucidated. Two different mechanisms may be involved: a first mechanism results in thickening of the epidermis leading to hyperkeratosis, with a modification of the stratum corneum, reduced water content, irritation and, finally, a disturbed skin barrier. 75,76 A second mechanism impacts on the microbiome and the innate immunity. Repeated pressure, friction and rubbing may cause both a modification of the lipid film at the surface of the corneocytes and of the cutaneous microbiome. 75 Pollutants Air pollutants. Air pollutants exert a harmful effect on the skin by increasing oxidative stress inducing severe alterations of the normal functions of lipids, deoxyribonucleic acid and/or proteins in the human skin. 77 This phenomenon is more marked in acne patients as in this population the skin lipid film on the surface of the stratum corneum is altered through an increase in oxidized squalene and a decrease in linoleic acid. 78 Two clinical studies comparing subjects in the Shanghai area and Mexico City, both highly polluted to less polluted areas, found skin quality changes with chronic exposure to ambient pollution. 79,80 Vitamin E and squalene levels, both signs of sebum oxidation, were reduced. Although the Mexican study did not measure clinical signs of acne, raised sebum levels were observed. 79 Another Chinese study, conducted during 8 weeks on 64 acne patients, showed a relationship between exposure to environmental pollutants and increased sebum levels and a higher number of inflammatory and non-inflammatory acne lesions. 80 Even though there is growing evidence that air pollutants exert their harmful effects by means of reactive oxygen species and inflammation, 77 more research is needed to better understand the link between air pollution and acne.
Industrial pollutants. Acne has been frequently observed in industry workers after prolonged exposure to certain organic molecules, such as coal tar or crude oil. [81][82][83][84][85] Today, exposure to these molecules has become less common. 86 Only sparse information about their impact on acne aetiology is available from the literature: it seems as if these insoluble products obstruct the sebaceous follicle by a mixture of coal tar or oil and keratin products. 83,[86][87][88] Males are more commonly affected than females. This can be linked to the fact that males are more prone to acne or have been more frequently exposed. 89 Chloracne, a chronic type of acneiform eruption, is induced by halogenated aromatic hydrocarbons and is a differential diagnosis with acne vulgaris. 81,83,90,91 Human-dependent pollutants. Tobacco and cannabis consumption may be considered human-dependent pollutants which may play a role in acne.
To date, the link between acne and tobacco is not confirmed. While Capitanio et al. reported that tobacco smoking may have an impact on acne, two recent online surveys reported contradictory information with a protective effect on acne. [92][93][94][95] Cigarette smoke (CS) is a highly complex aerosol composed of thousands of chemical substances, including nicotine, carbon monoxide, tar, formaldehyde, cyanhydric acid, ammonia, mercury, lead and cadmium. [96][97][98] These chemical substances from CS increase transepidermal water loss, degeneration of connective tissue in the skin and upregulation of matrix metalloproteinases 1 and 3 which degrade collagen and elastic fibres, and lastly impact on the natural skin barrier. [99][100][101] To date, it is still unclear how CS may trigger acne. 102 Tobacco consumption may prompt acne by inducing interleukin-1a and exacerbate comedogenesis and inflammatory changes in comedones that results in oxidative stress and the subsequent accumulation of lipid peroxide. 94,95,103,104 In keratinocytes and/or sebocytes cultures, CS exposure induced a scavenger receptor class B member 1 (SRB1 protein) loss. CSinduced SRB1 protein loss caused an alteration of the sebocyte lipid content. 105,106 Regular use of cannabis was highly associated with acne (odds ratio of 2.88 (95% CI: 1.55-5.37)) according to a French survey in more than 10 000 subjects. 92 No further data about acne and cannabis consumption has been published to date. However, our own clinical experience corroborates this observed relationship.
Climatic conditions Climatic conditions and seasonal variations resulting in a combination of heat, humidity and intensive UVR may trigger inflammatory acne flare-up, which has been called acne tropicana, acne majorca or tropical acne. [107][108][109][110][111] One of the major environmental factors affecting the skin is ultraviolet radiation (UVR). Both UVB and UVA have been reported to cause hyperplasia of the sebaceous gland, thickening of the stratum corneum, increase in sebum secretion and in the number of comedones. [112][113][114][115][116] By targeting the cells and molecules within the skin, UVR triggers the production and release of antimicrobial peptides, activates the innate immune system and ultimately suppresses the adaptive cellular immune response. As a consequence, skin microbiota may be altered and P. acnes may overcolonize the skin causing flares of acne. Alternately, or in concert with this, direct UVR-induced DNA and membrane damage to the microbiome may cause pathogen-associated molecular patterns that interfere with UVR-induced immune suppression. 117 Psychosocial and lifestyle factors Clinical evidence about the impact of psychosocial and lifestyle factors on acne is sparse and clinical wisdom and experience, as well as anecdotal observations and uncontrolled case series support this situation. [118][119][120][121][122][123] Nevertheless, there is some evidence that psychosocial and lifestyle factors including stress, emotions, sleep deprivation and modern lifestyle impact on inflammatory skin diseases. 119,121,122,[124][125][126][127][128][129][130] Cultural factors may influence the experience and presentation of acne. 118,131 Corticotropin-releasing hormones and neuropeptides are present in the sebaceous glands, possibly activating pathways affecting immune and inflammatory processes leading to the development and stress-and neurologically induced exacerbation of acne. 132,133 Short wavelength visible light emitted from smartphones and tablets has been reported to increase the proliferation of Staphylococcus aureus thus unbalancing the skin microbiota and thus impacting on acne. 123,134 Therefore, modern lifestyle, defined as stressful situations including urban noises, socioeconomic pressures and light exposure, may play a role in acne.

Future research
Future research should be devoted to a better understanding of the interactions between the different exposome factors and between these factors and the skin barrier cells, innate immunity and skin microbiota.
Protecting the microbiota spectrum is crucial as it protects from activation of the innate immunity leading to inflammation. Moreover, besides exposome factors, genetic factors may also influence the reaction of the skin against different environmental factors. As a result, acquiring detailed knowledge about such gene/environment interactions may help identify different patient subgroups and thus allow the development of specific and efficient measures against the alteration of the microbiota and skin barrier.
Regarding the role of nutrition in acne, still many facets such as the skin-gut axis in patients with acne, the benefit of pre-and probiotics and specific regimens combining a low glycaemic index diet and restricted intake of cow milk remain to be investigated through randomized and prospective and large clinical studies. The development of validated specific nutrition recommendations will be a challenge in the future.
Regarding pollution, large clinical studies to assess its impact on acne still have to be conducted. The efficacy of topical or oral antioxidants to block the effect of pollution in acne patients remains to be demonstrated. Further improvement of cleansers and of antiparticle adhesion products could be of interest to protect the microbiota and skin barrier.
The impact of climatic factors, especially radiation other than UVR such as visible light and the role of psychosocial and modern lifestyle factors, should be more investigated through welldesigned studies.

Practical considerations
According to the above-described exposome factors that can worsen acne, we propose the following practical considerations for managing acne patients: • Prior to any prescription, identify potential negative exposome factors, especially in patients with moderate-to-severe acne as these may impact on the treatment success. Table 2 lists factors to be checked together with the patient during the first visit.
• The identified negative exposome impact should be limited as much as possible to allow the main exposome targets, the natural skin barrier and its microbiota to recover. Limitation of high glycaemic index food in predisposed patients and food supplements containing weigh proteins, decrease in smoking tobacco/cannabis, modifications of contraceptives and skin care regimens might be suggested.
• The use of topical antibiotics in monotherapy is not recommended. This is to avoid increase in antibacterial resistance and modifications in the natural skin microbiome. Topical retinoids combined or not with benzoyl peroxide should be prescribed to be applied in the evening according to current guidelines to avoid irritation and damaging of skin barrier. [135][136][137] • Patients should be reminded to avoid harsh washing of their skin (avoid scrubs or exfoliating devices) as this may damage the natural skin barrier function. Cleansers with a pH of 5.5 (syndet) should be favoured over traditional detergents (i.e. soaps) allowing for a gentle cleansing of the skin and also for a reduction of the particle load on the skin in the evening. Optimal frequency of cleansing should be twice a day. 138 • Skin care products are important for the maintenance of the healthy skin microbiota, preventing the alteration of the skin barrier and thus its inflammation through the innate immunity. Moisturizers should be used in the morning to restore/improve the natural skin barrier function in order to reduce cutaneous pollutant penetration during the day and to limit irritation, frequently observed with topical retinoids, especially during the first few weeks of therapy.
• Moreover patients should be advised to use non-comedogenic make-up and to apply sun-protecting products with a sun-protecting factor of at least 30 to prevent from postinflammatory hyperpigmentation as well as from phototoxicity reactions. Daily photoprotection is of importance as UV radiation may increase the impacts of pollutant particles on the skin. 76

Conclusion
Exposome factors including nutrition, medication occupational factors, pollutants, climatic factors and psychosocial and lifestyle factors may impact on the course and severity of acne and on the treatment efficacy. Exposome factors act on the natural skin barrier and on the skin microbiota, resulting in increased sebum production, hyperkeratinization, modification of the microbiote, activation of the innate immunity thus resulting in acne worsening.
Identifying the negative exposome factors and thus reducing their impact are mandatory for an adequate acne management.