Skin, the largest part of the human integumentary system constituting about 15% of the total adult body mass, is positioned at the interface between environment and the body’s internal organs (1). The skin is a crucial and dynamic barrier against the constantly changing environment, autonomously maintaining organ-level and systemic homeostasis. As one of the key barriers of defense against physical, chemical, and microbial stressors, the skin is a complex organ functioning in tissue regeneration and wound healing, hydro-, osmo-, and thermoregulation, endocrine and sensory functions, biosynthesis, metabolism, innate and adaptive immunity, circadian rhythmicity, and neuro-psychosocial communication (1–8). Among various environmental factors relevant to human health, solar exposure is known to impact tissue homeostasis modulating many of these cutaneous functions. Indeed, skin barrier dysfunction is a hallmark of numerous cutaneous pathologies including allergic reactions, microbial infection, photoaging, and photocarcinogenesis.

As an outer surface organ, human skin is ubiquitously exposed to solar ultraviolet (UV) radiation. UV exposure has both positive and negative effects on human health (9). It is responsible for the biosynthesis of vitamin D₃, can stimulate the production of photoprotective melanin, and is used therapeutically to treat inflammatory skin diseases (such as psoriasis, vitiligo, localized scleroderma, and atopic dermatitis). At the same time, solar UV is a potent environmental human carcinogen (10–12). The mechanisms by which solar UV-radiation causes skin photodamage are wavelength-dependent (11). UVB (290-320 nm) is thought to cause direct structural damage to DNA in the form of epidermal cyclobutane pyrimidine dimers (CPDs) and other photoproducts. Most of the solar UV energy incident on human skin derives from the deeply penetrating UVA region (≥ 95%, 320-400 nm) not directly absorbed by DNA, and UVA-induced photodamage occurs by oxidative mechanisms mediated by reactive oxygen species (ROS). Contributing to the adverse effects of solar UV exposure is its known action as a systemic immunosuppressant, compromising an individual’s immune response with mechanistic implications for photocarcinogenesis (13).

UV and other environmental toxicants can be conceptualized as components of the overall skin exposome ( Figure 1 ), a term integrating all environmental cutaneous exposures and consequent biological effects including antagonism and potentiation that may result from co-exposures (14): (i) physical (such as thermal and mechanical trauma), (ii) chemical/xenobiotic [such as industrial pollutants, topical and systemic drugs, disinfectants, pharmaceuticals and personal care products (PPCPs)], (iii) microbiomic (originating from commensal and pathogenic microbes), (iv) allergenic (either of chemical or biological nature), and (v) life style-associated (such as tobacco product use, dietary choices, circadian rhythmicity, sleep pattern etc.) factors. Importantly, the complete skin exposome is subject to cross-talk with intrinsic factors (i.e. an individual’s primary biological determinants of skin structure and function) including: (i) genetics (as associated with ethnicity, sex as a biological variable (SABV), disease vulnerabilities etc.), (ii) pathobiological occurrences [such as infections, metabolic dysregulation (including diabetes), and autoimmune disturbances], and (iii) chronological aging (7, 15–20). Certain aspects and subcategories of the skin exposome have been expertly reviewed including the skin microbiome and the skin redoxome (7, 8).

Molecular crosstalk and mechanistic overlap between various components of the extrinsic skin exposome is well substantiated at the molecular level. For example, potentiation of solar UV-induced cutaneous and systemic injury by co-exposure to other environmental toxicants/pollutants has attracted much attention due to its negative impact on public health worldwide. Indeed, common environmental toxicants such as heavy metals (e.g. cadmium), metalloids (e.g. arsenic), and organic xenobiotics (e.g. benzo[a]pyrene, TCDD) are established potentiators of solar UV damage and skin carcinogenesis (21–23). Co-carcinogenicity of various exposome factors potentiating solar UV-induced skin photocarcinogenicity is firmly documented, as applicable to: (i) pollutants such as polyaromatic hydrocarbons including benz[a]pyrene (from cigarette smoke and combustion engines), (ii) arsenic (from drinking water), (iii) hypercaloric dietary intake/metabolic dysregulation, (iv) molecular therapeutics [acting as photosensitizers or immunosuppressants], (v) and microbial infection (HPV, Merkel cell polyoma virus, Malassezia spp.) (21–28). To the contrary, dietary intake of specific phytochemicals representing an extrinsic exposome-related factor might enhance skin barrier function and antagonize photo-carcinogenesis, acting through modulation of specific molecular pathways associated with enhancement of antioxidant stress response (with involvement of the Keap1/NRF2 pathway) and suppression of inflammatory signaling (NFκB and AP-1) (9, 29).

Likewise, impairment of skin barrier function and health can result from the overlap of extrinsic (exposome-related) and intrinsic factors that interact and potentially synergize in complex ways. For example, it is well documented that smoking (an external exposomal factor) accelerates skin aging (intrinsic factor) (30). Likewise, human skin photoaging represents the overlap of intrinsic factors (such as cellular senescence as a function of chronological age) and structural/functional alterations due to environmental solar exposure (31). In the context of co-carcinogenicity, it has long been known that intrinsic genetic alterations that impair DNA repair capacity are associated with an increased UV-induced skin cancer incidence as substantiated paradigmatically by xeroderma pigmentosum patients with excision repair deficiencies underlying a pronounced increase in skin cancer risk (32, 33).

Recently, hypochlorous acid (HOCl) has been identified as an environmental toxicant relevant to cutaneous exposures (34–36). Here, given the ubiquitous use of topical HOCl-based disinfection strategies combined with its established biological role as an essential determinant of neutrophil-related innate immunity, we review the role of this powerful electrophile as an understudied chemical component of the skin exposome with special emphasis on novel data that substantiate HOCl-dependent modulation of solar UV-induced skin carcinogenesis.

Chlorination stress that occurs under physiological or environmental exposure-relevant conditions impacts structure and function of numerous classes of biomolecules, either through covalent introduction of chlorine (and chlorine-derived substituents) or through indirect oxidative insult. HOCl, in equilibrium at physiological pH with its anionic form [hypochlorite (OCl⁻)], may also induce tissue damage at sites of inflammation involving the oxidation and chlorination of biomolecules targeting peptides (e.g. glutathione), proteins, lipids, and nucleic acids (39, 42, 43, 47, 76, 77).

Previous research has identified key molecular modifications downstream of chlorination stress targeting amino acids, peptides, and proteins as dominant targets of biologically-relevant chlorination stress ( Figure 3A ). For illustration, a hypothetical heptapeptide [H₂N-Tyr-Trp-His-Lys-Met-Cys-Arg-COOH] has been envisioned that exemplifies the range of possible amino acid modifications induced by HOCl exposure including dichloro-tyrosine, hydroxy-tryptophan, histidine chloramine, lysine mono- or dichloramine, methionine sulfoxide, cysteine sulfenic/sulfinic/sulfonic acid, and arginine chloramine (78). Protein chlorination has been associated with structural changes of target proteins including fragmentation, crosslinking, aggregation, unfolding, and modulation of specific functions such as immunogenicity, enzymatic activity and ligand-receptor interaction (48, 79). Numerous proteins are subject to chlorination stress-induced modulation through chemical changes under physiological conditions, including plasma proteins [e.g. HSA, alpha2M], histones, heat shock/ER stress response mediators and calcium signaling components (e.g. GRP78, SERCA), inflammatory signaling molecules (e.g. IL-6, IKK) and mediators of tissue remodeling (e.g. MMP7, TIMP-1), causing effects that are mostly consistent with modulation, attenuation, and resolution of inflammatory tissue responses (35, 80–89). Specifically, inactivation of IKK (inhibitor of IκB kinase) through oxidation (Cys114/115) is thought to cause the hypochlorite-dependent attenuation of psoriasis observable upon topical application (35). Similarly, GRP78 (glucose-regulated protein 78, HSPA5) modification through chloramine adduction (Lys 353) has been suggested to modulate autophagy and apoptosis in A549 lung cancer cells, and N-chlorination of HSA (human serum albumin) converts plasma proteins into efficient activators of the phagocytic respiratory burst (46, 86). In addition, biogenic amines, mostly through chloramine formation, have been demonstrated to serve as biomolecular targets of chlorination stress including histamine, serotonin, melatonin, and taurine among others (90, 91).

Consistent with chlorination-associated electrophilic stress, unsaturated lipids serve as major HOCl-targets under physiological conditions ( Figure 3B ) (92–99). Indeed, free fatty acids, triglycerides, phospholipids, as well as cholesterol and its derivatives, have all been validated as being susceptible to chemical modification under conditions of physiological or environmental chlorination stress conditions ( Figure 3B ). For example, HOCl-mediated modification of cholesterol forms a number of cholesterol-chlorohydrin stereoisomers as depicted; in addition, phospholipids may undergo derivatization at nitrogen-containing head groups (forming the respective chloramine) or at sites of unsaturation, followed by further oxidation/decarboxylation and N-centered free radical formation. In addition, other biochemical lipid mediators including plasmalogens, prostaglandins, and leucotrienes, involved in tissue remodeling and inflammatory signaling, have been shown to be subject to HOCl-dependent adduction with consequent alteration of signaling properties (98).

Nucleic acids are important targets of chlorination stress with possible mutagenic, genotoxic, and cytotoxic outcomes downstream of chemical modification ( Figure 3C ) (39, 100–102). Specifically, it is well documented that HOCl exposure causes chemical modification of DNA and RNA (and their respective nucleotides, nucleoside, and free nucleobases, irrespective of ribose- or deoxyribose- substitution). For example, HOCl-modification of deoxyadenosine forms 8-chlorodeoxyadenosine, and HOCl-modification of deoxyguanosine forms 8-chlorodeoxyguanosine. Interestingly, HOCl-modification of deoxycytidine forms a 5-chlorodeoxycytidine-intermediate, followed by spontaneous deamination forming stable 5-chlorodeoxyuridine causing miscoding damage downstream of chlorination stress. Indeed, chloro-derivatives of nucleic acids and their constitutive bases, apart from their functional involvement in mutagenic events, may also play an important yet underappreciated role as biomarkers of chlorination stress characteristic of specific pathological conditions.

Numerous molecular entities of endogenous or phytochemical origin have been shown to antagonize chlorination stress that occurs as a consequence of exposure to HOCl including amino acid derivatives (taurine, glutathione, serotonin, serotonin, carnosine, ovothiol, ergothioneine), phenolics (gallic acid, nordihydroguaiaretic acid, quercetin), and B₆ vitamers (pyridoxal, pyridoxine, and pridoxamine), attributed mostly to chemical reactivity (i.e. sacrificial quenching) ( Figure 4A ). In addition, antagonists of MPO enzymatic activity (such as the synthetic MPO inhibitor verdiperstat or the endogenous metabolite uric acid) blocking HOCl formation have been explored for pharmacological control of pathophysiological chlorination stress (47, 62, 91, 103–109).

Among these biomolecules, B₆-vitamers deserve special recognition since they have been shown to exert protection against chlorination stress as assessed using in vivo disease models, an effect attributed to formation of stabilized chloramine derivatives (110). Likewise, imidazole-derivatives (e.g. L-histidine, carnosine, carcinine) and thio-imidazole-derivatives (ergothioneine and sea urchin-derived ovothiol) have been identified as potent chlorination stress inhibitors (111–113).

Moreover, the cysteine-derived metabolite taurine (2-amino-ethane-sulfonic acid) has now been identified as a major endogenous HOCl-directed scavenger and antioxidant, attenuating physiologically relevant chlorination stress ( Figure 4B ). Strikingly, neutrophils represent a large reservoir of free taurine compromising approximately 50% of the cellular amino acid/amino acid-derivative pool thought to be involved in direct chemical protection against cytotoxic consequences of the respiratory burst associated with microbicidal HOCl formation (114). Taurine formation occurs as the result of enzyme-catalyzed cysteine transformation through intermediate generation of L-cysteine sulfinic acid and hypotaurine ( Figure 4B ). The consequent formation of N-chlorotaurine, representing a chlorinated adduct with attenuated reactivity, has also been interpreted as an intermediate step facilitating the extension of the phagocytic activity range, enabling enhanced stability and diffusion, spatially amplifying the range of oxidative antimicrobial effects. Indeed, attenuated chlorination reactivity of N-Chlorotaurine has been attributed to sulfonic acid-dependent electrostatic anionic shielding of the adjacent chloramine function that is amenable to chloro-transfer if attacked by biomolecular nucleophiles (115).

Importantly, N-chlorotaurine formation may cause the negative regulation of inflammatory processes by multiple distinct molecular mechanisms attenuating NF-kB and related cytokine signaling (88, 116). Interestingly, taurine might not only attenuate direct chemical reactivity of HOCl through sacrificial quenching, but chloro-taurine may then act as a redox-directed signaling modulator of major inflammatory targets and pathways. Indeed, it has been shown that N-chlorotaurine modulates inflammatory pathologies attributed to chemical modification of inflammatory factors, such as IL-6 and NFkB. Indeed, N-chlorotaurine exposure of IL-6 causes oxidation of residues relevant to IL6R receptor-binding (Met161 and Trp157) (88). Negative modulation of NF-κB by N-chlorotaurine (and other chloramines such as glycine chloramine) is thought to originate from oxidation of Met45 in IκB (preventing its ubiquitination and proteasomal degradation) (116, 117). Importantly, NRF2, the master transcriptional regulator of cellular antioxidant responses, has also been shown to be responsive to N-chlorotaurine-mediated chlorination stress, an effect attributed to electrophilic adduction and inactivation of Keap-1, the redox-sensitive negative regulator of this transcription factor (118).

Molecular chlorination stress relevant to human health originates from HOCl (among other endogenous hypohalous acids including HOI and HOBr, formed mostly in the context of innate immunity) and is complemented by exposure to HOCl (and related derivatives) originating from exogenous sources. Specifically, environmental exposure-relevant chlorination agents include hypochlorous acid (and its corresponding anion) as well as diverse chloramines (e.g. monochloramine, dichloramine, nitrogen trichloride, chlorinated isocyanuric acid-derivatives) formed as a result of freshwater chlorination ( Figure 5A ) (119, 120). Interestingly, trichloroisocyanuric acid as well as its di-chloro-analogue are EPA-approved under FIFRA (Federal Insecticide, Fungicide, and Rodenticide Act) regulations, used globally for drinking water and freshwater disinfection (such as in swimming pools), offering increased photostability and sustained HOCl release (44, 121). Importantly, chlorination byproducts (CBPs) including organohaloacetic acids and trihalomethanes (formed due to the presence of dissolved organic matter) and chlorite are subject to strict EPA regulation due to potential adverse health effects (122, 123). Strikingly, out of more than six hundred halogenation byproducts identified as of to date, only eleven are currently subject to strict EPA regulation (124). For example, mutagen X (3-chloro-4-(dichloromethyl)-5-hydroxy-5H-furan-2-one) is a disinfection byproduct derived from humic acids, not regulated by EPA, with suspected involvement in cancer risk elevation associated with consumption of chlorinated drinking water, an effect attributed to genotoxicity surpassing that of currently regulated CBPs (including chloroform and bromodichloromethane) (125). Additionally, PPCPs introduced into the water supply are subject to HOCl-mediated chlorination and subsequent formation of CBPs. For example, common drugs including metformin, diclofenac, and tamoxifen entering freshwater sources are subject to direct chlorination causing drinking water contamination associated with largely unexplored implications for human health (126–129). Likewise, chlorination of PPCPs including sunscreen ingredients such as the common UVA-sunscreen avobenzone are associated with formation of a dichloro-species, and cosmetics are equally subject to chlorination with unexplored effects on human health (16, 130–135).

Chlorination stress associated with HOCl/OCl^- exposure originating from innate and environmental sources has now been identified as a double-edged molecular sword, mediating essential functions in the context of innate immunity towards microbial attack and exerting effects that are either detrimental or therapeutic to human health, particularly in the context of skin anti-inflammatory and cancer photochemopreventive topical intervention. Harnessing HOCl-dependent preventive and therapeutic effects that might benefit human patients will depend on the development of novel chemical entities and advanced formulations allowing a more controlled and targeted modulation of chlorination stress (70, 181). Indeed, additional research must carefully explore dose regimens and extended release formulations that achieve anti-inflammatory and photo-chemopreventive effects while avoiding potential HOCl-induced tissue damage and irritation. In the same way, availability of specific biocompatible molecular fluorescent probes with diagnostic utility in vitro and in vivo (allowing imaging and quantitative analysis of physiological and therapeutic chlorination stress conditions) will expand our understanding of these multi-faceted versatile biochemical actors and processes as key determinants of health and disease (182).

Manuscript preparation: JS, JJ, GW. Conceptualization of work: GW. All authors contributed to the article and approved the submitted version.

Supported in part by grants from the National Institutes of Health (1R01CA229418, 1R21ES029579, 1P01CA229112, ES007091, ES006694, and UA Cancer Center Support Grant CA023074).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.