Biological Effects of Exposure to UV Radiation Relevant to Carcinogenesis

Home , Indirect DNA damage, Photoprotection

Biological effects of exposure to UV radiation relevant to carcinogenesis

A large body of literature documents the effects the UVA energy to DNA via mutagenic oxidative of UV radiation on different living organisms, intermediates such as 8-hydroxydeoxyguanosine including humans, animals and bacteria. (8-OHdG). DNA damage by UVA radiation typi- Experimental as well as epidemiological data cally consists of T→G transversions, called "UVA strongly indicate that the spectrum of UV fingerprint" or "UVA signature" lesions (Dobretsky radiation reaching the Earth’s surface is involved et al., 1995). in the development of melanoma (IARC, 1992). One study in hamster fibroblasts showed that The biological effects of exposure to UV UVB produces numerous immediate mutations, radiation were described in detail in an IARC whereas UVA produces fewer immediate muta- Monograph on UV radiation (IARC, 1992), and tions and more delayed mutations than UVB the molecular effects in recent review articles (Dahle & Kvam, 2003). (Griffiths et al., 1998; Pfeifer et al., 2005). In this section, we summarize the aspects most relevant (b) Effects on humans: The mutagenic properties to the understanding of the biological issues of UVA in humans have been confirmed in several associated with exposure to artificial sources of studies (Robert et al., 1996; see Pfeifer et al., UV radiation. 2005; Halliday, 2005 for reviews). The possibility that indirect DNA damage induced by UVA could play a major role in melanoma occurrence is Biological lesions induced by UVA and UVB underlined by reports of multiple cutaneous radiation melanomas developing in patients genetically DNA damage highly susceptible to oxidative agents (Pavel et al., 2003). (a) Experimental systems: UVB is a complete Experiments in human volunteers conducted carcinogen that is absorbed by DNA and can during the last decade have shown that commer- directly damage DNA. DNA damage induced cial tanning lamps produce the types of DNA by UVB irradiation typically includes the damage associated with photocarcinogenesis in formation of cyclobutane pyrimidine dimers human cells. Volunteers whose skin was exposed (CPD) and 6-4 photoproducts (6-4P). If repair mechanisms fail to restore genomic integrity, to UVA lamps used in tanning appliances show mutations are likely to occur and persist through DNA damage, p53 mutations induced by oxida- subsequent cell divisions. These mutations are tive damage, and alterations of the p53 protein C → T and CC → TT transversions, commonly similar to those observed after sun exposure or referred to as "UVB fingerprint" or "UVB after UV exposure of experimental animals signature" mutations. UVB can also induce the (Woollons et al., 1997; Whitmore et al., 2001; - formation of singlet oxygen species (O2 ), an Persson et al., 2002). oxidative compound that is highly reactive and Studies in humans show that a pre-vacation can cause DNA damage indirectly (Griffiths et al., artificially-induced tan offers little or no protection 1998). against sun-induced DNA damage (Hemminki et UVA is not readily absorbed by DNA and thus al., 1999; Bykov et al., 2001; Ruegemer et al., 2002). has no direct impact on DNA. Instead, UVA induces DNA damage indirectly through the Cell damage absorption of UVA photons by other cellular structures (chromophores), with formation of UVA and UVB radiation can cause cell damage reactive oxygen species (such as singlet oxygen through different mechanisms: both UVA and and hydrogen peroxide [H2O2]) that can transfer UVB lead to differential expression of p53 and 7 Exposure to Artificial UV Radiation and Skin Cancer bcl-2 proteins, which may play an important role Accordingly, before 1990, only UVB, and not in regulating UV-induced apoptosis (Wang et al., UVA, was considered to be carcinogenic. 1998). DNA repair and apoptosis protect the In the 1990s, studies in newborn rodents and cell’s integrity against UV-induced damage. One on human foreskin grafted on immunosup- study conducted in cells from medaka fish sug- pressed nude mice have provided compelling gested that different apoptotic pathways exist evidence that high UVB doses were required in depending on the wavelength, i.e. for long- (UVA) the genesis of melanoma or of melanocytic and for short- (UVB or UVC) wavelength radia- tumours considered to be precursor lesions of tions (Nishigaki et al., 1999). Irradiation of melanoma (Mintz & Silvers, 1993; Atillasoy et al., melanocytes with UVA or UVB leads to alter- 1998; Robinson et al., 1998; Sauter et al., 1998; ations of different intracellular proteins, suggesting Robinson et al., 2000a; Noonan et al., 2001; van that UVA and UVB may induce initiation of Schanke et al., 2005). At the same time, several melanoma via separate intracellular pathways in-vivo studies showed that UVA can induce (Zhang & Rosdahl, 2003). melanoma in backcross hybrids of freshwater fishes of the genus Xiphophorus (platyfish and UVA, UVB and human skin swordtail; Setlow et al., 1993) and melanocytic tumours in the South American opossum In humans UVA penetrates deeper into the skin Monodelphis domestica (Ley, 1997, 2001). than does UVB. Because UVA represents the However, UVA was less efficient than UVB for the majority of the UV spectrum of tanning appli- induction of melanocytic tumours in Monodelphis ances and of solar radiation reaching the Earth’s domestica (Ley 2001), and experiments with UVA surface, far more UVA than UVB reaches the on newborn rodents and on human foreskin could basal layers of the epidermis, where skin not reproduce the results obtained with UVB keratinocytic stem cells and melanocytes are (Robinson et al., 2000b; Berking et al., 2002; de located. DNA analysis of human squamous cell Fabo et al., 2004; van Schanke et al., 2005). carcinoma (SCC) and solar keratosis showed Other studies showed that radiation emitted that UVA fingerprint mutations are mostly detect- by lamps used in tanning appliances (mainly ed in the basal germinative layer of these lesions, UVA) could significantly increase the carcino- whereas UVB fingerprint mutations are found genic effect of broad-spectrum UV radiation predominantly more superficially in these lesions (Bech-Thomsen et al., 1991, 1992), indicating (Agar et al., 2004). the possibility of a complex interplay between UVA and UVB radiation in human skin.

Differential effects of UVA and UVB on skin Relevance of experimental data to human cancers skin cancers Experimental systems To date, evidence obtained from experimental Several studies showed that UVA could induce studies on the involvement of high UVB doses in squamous cell cancers in nude mice, but the abil- the causation of SCC is consistent with observa- ity of UVA alone (without exogenous photosensi- tions in humans. In contrast, experimental studies tizers such as those used in PUVA therapy –– provide conflicting results on an implication of see Page 41) to induce squamous cell skin can- UVB and UVA in the induction of melanoma in cers was about 5000 to 10000 times lower than humans. The same uncertainties hold true for that of UVB alone (IARC, 1992; de Laat et al., basal cell carcinoma (BCC), a type of tumour that 1997; Griffiths et al., 1998). Both in-vitro experi- shares many of the epidemiological characteris- ments and epidemiological studies have demon- tics of melanoma. strated that long-lasting, chronic exposure to The relevance of animal models for elucidating UVB is the main cause of SCC of the skin (see the biological mechanisms involved in the IARC, 1992; Brash et al., 1996 for reviews). development of melanoma and BCC remains

8 Biological effects of exposure to UV radiation relevant to carcinogenesis questionable, as even engineered mice with al., 1995; Kelly et al., 1998). Few studies have multiple deficiencies in key genes involved in cell specifically investigated the effects of exposure to cycle regulation and growth factor synthesis do tanning appliances on the systemic and local not represent a model equivalent to the human immune systems. UV lamps similar to those used skin. In addition, experiments on animals cannot in tanning appliances are used without concomi- reproduce the complex relationship existing in tant use of photosensitizer for treating skin individuals between highly variable natural sus- conditions such as dermatitis and sun allergies, ceptibilities to UV radiation, different sun exposure illustrating the effect of that radiation spectrum on behaviours, and exposure to various sources of the skin immune system. UV radiation. In the case of indoor tanning, such Studies in volunteers have shown that expo- relationships may be critical, as users are more sure to tanning appliances induces reductions in inclined than the average population to engage in blood lymphocyte counts, changes in proportion outdoor tanning activities (Autier et al., 1991), and of lymphocyte subpopulations, immune response indoor tanning sessions often precede or follow to known carcinogens applied to the skin, and active sun exposure or outdoor tanning. changes in the skin immune system (Hersey et al., 1983, 1988; Rivers et al., 1989; Clingen et al., 2001). These studies also indicated that UVA and Changes in immune response UVB would affect the immune system via inter- acting and overlapping mechanisms, depending Several reports (IARC, 1992, 2001; Ullrich, 2005) on the amount of UVA and UVB emitted (Clingen have extensively reviewed the studies on the et al., 2001), which would then lead to the effects of UV on the immune system and of the suppression of known immune reactions underlying mechanisms. This section only refers (Nghiem et al., 2001, 2002). Hence, these stud- to studies relevant to UVA and use of indoor ies indicate that UVA can suppress established tanning facilities. immune reactions at the skin level, but it remains to be established how these effects relate to the Experimental systems induction of neoplastic processes.

Both UVA and UVB radiation can affect the immune response that may be involved in the Effects of natural and artificial UV radiation promotion of melanoma (Kripke, 1974; Singh et on human skin al., 1995), but the two types of radiation seem to Variety of skin types act differently. UVB can induce immune suppression at both local and systemic levels whereas There is a considerable range of susceptibility of UVA does not induce systemic immune suppres- the human skin to the carcinogenic effects of UV sion. However, studies have shown that a number radiation, and in humans, there is an estimated of local responses induced by UVB radiation on 1000-fold variability in DNA repair capacity after the skin could be suppressed by a UVB filter, but UV exposure (Hemminki et al., 2001). the melanoma growth stimulation effect could not Susceptibility to sun-induced skin damage is be suppressed (Donawho et al., 1994; Wolf et al., closely related to pigmentary traits, and subjects 1994). This result suggests that UVA may influ- having the following characteristics are at ence local immune responses different from increased risk for developing a skin cancer those influenced by UVB. (melanoma, SCC and BCC):

Studies in humans • Red hair, followed by blond hair, followed by light brown hair. Observations in human volunteers have demonstrated that UV exposure suppresses the • Skin phototype (Fitzpatrick, 1988): subjects induction of immunity (Cooper et al., 1992; Tie et who always burn and never tan when going

9 Exposure to Artificial UV Radiation and Skin Cancer

unprotected in the sun (skin phototype I) have Tan acquisition a much higher risk for skin cancer than subjects who never burn and always develop a The production of melanin (tanning) accounts for deep tan (skin phototype IV). Intermediate part of the protection against UV radiation, but risk categories are subjects who always burn there is mounting scientific evidence that faculta- then develop a light tan (skin phototype II), tive tan is triggered by UV-induced DNA damage and subjects who sometimes burn and always in the skin (Pedeux et al., 1998; Gilchrest & Eller develop a tan (skin phototype III). Subjects of 1999 for a review). Facultative tanning is now skin phototypes V and VI belong to popula- considered a better indicator of inducible DNA tions with natural brown or black skin, and are repair capacity than of efficient photoprotective resistant to sunlight. skin reaction. Inducible DNA repair capacity rather than pigmentation itself could result in the • Freckles (ephelides) on the face, arms or lower incidence of skin cancer observed in shoulders. The skin cancer risk increases with darker-skinned individuals (Young et al., 1998; increasing sensitivity to freckling. Agar & Young, 2005; Bohm et al., 2005). In subjects who tan easily, exposure to • Skin colour: pale colour, followed by tanning appliances will first lead to the oxidation increasing depth of pigmentation. of melanin already present in superficial keratinocytic layers of the skin (i.e. immediate • Eye colour: blue, followed by grey/green eyes, pigment darkening [IPD]). IPD is essentially trig- then by brown eyes. gered by UVA (Young, 2004). It develops rapidly after exposure during an indoor tanning session, Subjects with red hair, many freckles and and fades away after a few hours. A more who never tan are at particularly high risk for skin permanent tan is acquired with accumulation of cancer. exposure, depending on tanning ability and on the amount of UVB present in the UV spectrum of Sunburn the lamps. The permanent tan conferred by "UVA-tanning" has a uniform and less deep Sunburn is the occurrence of painful erythemal brown appearance than the tan acquired in the reaction after exposure to UV radiation. Sunburn sun. during childhood or during adulthood is a risk fac- IPD has no photoprotective effect against tor for melanoma, and the risk increases with UV-induced erythema (Black et al., 1985). A increasing number of sunburns (IARC, 1992). UVA-induced permanent tan provides practically Skin erythema or sunburns are reported by no photoprotection either (Gange et al., 1985; 18–55% of users of indoor tanning facilities in Rivers et al., 1989), and UVA-induced moderate Europe and North America (reviewed in Autier, skin thickening would afford even less photopro- 2004). Although UVB is more potent than UVA for tection than tanning (Seehan et al., 1998). triggering sunburn, high fluxes of UVA are capa- ble of inducing skin erythemal reactions after 10 to 20 minutes in subjects susceptible to sunlight and having moderate tanning ability (Fitzpatrick skin phototype II).