Biophysical and Physiological Effects of Solar Radiation on Human Skin
341
Biophysical and Physiological Effects of Solar Radiation on Human Skin
341Hardcover
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Product Details
| ISBN-13: | 9780854042890 |
|---|---|
| Publisher: | RSC |
| Publication date: | 09/19/2007 |
| Series: | Comprehensive Series in Photochemical & Photobiological Sciences , #8 |
| Pages: | 341 |
| Product dimensions: | 6.15(w) x 9.20(h) x (d) |
About the Author
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Biophysical and Physiological Effects of Solar Radiation on Human Skin
By Paolo U. Giacomoni
The Royal Society of Chemistry
Copyright © 2007 European Society of PhotobiologyAll rights reserved.
ISBN: 978-0-85404-289-0
CHAPTER 1
Damage from Acute vs Chronic Solar Exposure
Antony R. Young
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London School of Medicine at Guy's, King's College and St Thomas' Hospitals, King's College London, London, UK
Table of Contents
1.1. Introduction 5 1.2. Early Responses to Solar UV Radiation 5 1.2.1. Erythema 5 1.2.2. Pigmentary Changes 7 1.2.3. Hyperplasia 8 1.2.4. Early Responses that have a Direct Impact on Skin Cancer 8 1.2.4.1. DNA Photodamage 8 1.2.4.2. Immunomodulation 11 1.3. Late Responses to Solar UV Radiation 13 1.3.1. Adaptive Responses to Repeated Sub-erythemal Exposure 13 1.3.2. Photoaging 14 1.4. Beneficial Effects of Solar UV Radiation and the Need for Protection 15 1.4.1. Vitamin D Photosynthesis 15 1.4.2. The Role of Sunscreens in the Prevention of Acute and Chronic Photodamage 16 1.5. Concluding Remarks 17 References 18
1.1. Introduction
The acute and chronic effects of solar ultraviolet radiation (UVR) exposure are well established. The acute effects can be readily studied under controlled laboratory conditions whereas the chronic effects have been determined by epidemiology in the case of skin cancer and by clinical observation in the case of photoageing. Chronic exposure is, by definition, a series of acute (i.e. single) exposures; however, the relationship between photodamage by acute and chronic exposure is very poorly understood, mainly because this has not been extensively studied. The patterns of exposure seem to be important in long-term clinical outcome. Epidemiological research suggests that regular exposure is important in squamous cell carcinoma (SCC), which is often associated with signs of photoaging such as elastosis. In contrast, intermittent sunburning exposure seems to be important in malignant melanoma (MM) as does childhood exposure. There is also evidence that intermittent exposure is important in basal cell carcinoma (BCC).
Most UVR exposure in healthy people comes from the sun, but in recent years exposure from tanning devices has become increasingly widespread, especially amongst young women, and this has raised concern about long-term adverse effects such as MM and, to a lesser extent, SCC.
Controlled chronic UVR exposure to clinical outcome, such as skin cancer or photoageing, is neither ethical nor practicable in humans, but it is possible to carry out studies with repeated UVR exposure over relatively short periods. This mimics 'real life' more realistically than acute exposure experiments and also allows the study of adaptive responses that may influence the response to subsequent exposure. Furthermore, repeat exposure studies act as a bridge between the acute and the chronic effects of UVR and may provide a better understanding of how individual exposures result in long-term clinical outcome.
The discussion in this chapter will focus on the acute effects of physiologically and environmentally relevant UVR exposure on human skin and how these effects may be modified by repeated exposure. In addition, the possible effects of repeated exposure on long-term clinical outcome will be considered. The relationship between sunscreen photoprotection of acute and chronic photodamage will also be discussed.
1.2. Early Responses to Solar UV Radiation
1.2.1. Erythema
Erythema (inflammation) is the most obvious clinical sign of UVR exposure and is apparent from about 6 hours after exposure and is maximal at about 24 hours. Its action spectrum is maximal at about 300 nm, which is about three orders of magnitude more effective than UVA. This peak has been made into a plateau in the widely used mathematically derived curve known as the Commission Internationale de l'Eclairage (CIE) erythema reference action spectrum. The minimal erythema dose (MED) is used as a means of defining personal sensitivity to UVR, and is defined as the UVR dose (J/m2), of a given spectrum, that causes a (just) perceptible skin reddening. In other words, the MED is the visual threshold of UVR dose-response of which erythema becomes more intense with higher doses. This can be demonstrated by visual grading or by the measure of redness by reflectance spectroscopy. The MED is widely used as a biological dose unit of exposure in clinical and experimental photodermatology and is based on a single acute UVR exposure. The MED is also used in the determination of the sun protection factor (SPF) of a sunscreen.
Whilst the MED is convenient indicator of individual sensitivity to UVR, the classification of people into skin phototype, as shown in Table 1.1, is a useful way of defining population acute and chronic sensitivity to UVR, and has been valuable in skin cancer epidemiology. An acute erythemal exposure, whether caused by solar simulating radiation (SSR) or UVA, is also associated with significantly increased sensitivity to mechanical and thermal stimuli. In general, the higher the skin phototype the higher the MED but it must be stressed that neither skin phototype nor MED is predictive of each other on an individual basis because there is a considerable overlap of MED within skin phototypes. Furthermore, it must be stressed that difference between the mean MEDs of sun-tolerant and sun-sensitive white skin phototypes is relatively modest. Typically, the MED of phototypes III/IV is about twice that of phototypes I/II. Erythema from an acute erythemal exposure (5 MED) has been reported as being more persistent in skin phototype I compared with IV and this may be related, in some as yet unknown way, to skin cancer susceptibility.
By definition, a single sub-erythemal exposure is below the threshold of detection by the eye. However, this does not mean that it has no effects because repeated daily sub-erythemal exposure results in clinically visible erythema after 2–3 exposures especially in sun-sensitive skin phototypes I and II, but less so with phototypes III/IV, even with dose as low as 0.25MED. Thus, the MED is not a useful concept for the evaluation of erythema from repeated exposure that is best done with reflectance spectroscopy. This also highlights a limitation of the concept of SPF because a cumulative erythema can appear after a few days of correct sunscreen use that has resulted in daily sub-erythemal exposures.
Acute erythemal exposures of UVB and UVA result in a marked inflammatory infiltrate including neutrophils. In one study an acute dose of 0.5 MED UVA, which did not result in any inflammatory infiltrate, was compared with repeated exposures of 0.5MED, 5 days/week for 6 weeks, which resulted in the presence of perivascular lymphocytes, some histiocytes and numerous mast cells.
COX dependent prostaglandin E2 (PGE2) is believed to be one of the mediators of UVR-induced erythema. Epidermal COX-1 and COX-2 proteins are induced by an acute exposure of 3MED of a UVB-rich broad-spectrum source at a level that is comparable to ten consecutive exposures of 0.7MED, even though no erythema was reported with this protocol.
Overall, there is evidence that the effects of repeated sub-erythemal UVR on the skin are cumulative and that the regulation of erythema (inflammation) is better controlled in skin phototypes III/IV compared with I/II.
1.2.2. Pigmentary Changes
Epidermal melanin composition is a variable mixture of lighter alkali soluble, sulphur-containing phaeomelanin and darker insoluble eumelanin; skin photo -types that tan well have more eumelanin. Acute exposure to UVA induces a rapid but transitory grayish color known as immediate pigment darkening (IPD) which probably results from the photo-oxidation of existing melanins and the redistribution of melanocytic melanosomes from a perinuclear position into the peripheral dendrites. IPD progresses into persistent pigment darkening (PPD), which may remain stable for up to 2 h post exposure. The biological functions of IPD and PPD are not known.
Delayed tanning, also known as melanogenesis, is primarily a response to UVB that results from increased activity and numbers of melanocytes. Tanning capacity is related to skin phototype as shown in Table 1.1. The action spectra for IPD and melanogenesis are completely different with the former showing a broad 340 nm peak in the UVA region and the latter, similar to the erythema action spectrum, showing peak activity in the UVB region which is about three orders of magnitude more effective than UVA. Melanogenesis becomes visible 3–4 days after an acute UVR exposure and is maximal from 10 days to 3–4 weeks depending on skin type and UVR dose. Melanocyte tyrosinase (the rate limiting enzyme for melanin synthesis) activity also increases, melanocyte dendrites elongate and branch, and melanosomes increase in number and size. Repeated acute sub-erythemal exposure doses also results in a gradual increase of tanning with UVB containing sources including SSR. However, repeated exposure to sub-erythemal UVA also induce delayed tanning. Melanogenesis is a multi-factorial process but there is a considerable body of evidence that DNA photodamage, and its repair, is a trigger. In other words, tanning may be a response to acute and persistent DNA photodamage.
The incidence of skin cancer is associated with skin phototype (see Table 1.1) and it is often stated that this is related to photoprotection by melanin. However, the skin phototype relationship with MED holds on vitiligenous skin through types II–VI indicating that factors other than melanin affect acute sensitivity to UVR.
1.2.3. Hyperplasia
UVR stimulates epidermal proliferation that results in stratum corneum (SC) thickening. An acute exposure of 1 MED SSR did not have any effect on Ki-67 expression, which is marker of epidermal proliferation, or epidermal thickening. Repeated sub-erythemal SSR exposure, for approximately 2 weeks, of normal skin does result in modest SC thickening, and this is independent of skin type and also results in the expression of Ki-67, even with doses as low as 0.25MED, though this dose did not result in epidermal thickening. One analysis based on the relationship between MED and SC thickness indicated that the latter was an important factor in photoprotection but this was not confirmed in a study in which volunteers were repeatedly exposed to sub -erythemal doses of SSR. One study compared the effects of up to 24 weeks (twice weekly) of erythemal exposure (1 MED) on SC thickening of previously unexposed skin with SSR and UVA and with sub-erythemal UVA equivalent to the UVA content of the SSR source. All spectra resulted in a time dependent increase of SC thickening that persisted for at least 12 weeks after the last exposure. Surprisingly, UVA including sub-erythemal UVA was more effective than SSR. There is evidence that the SC is a source of UVA-induced oxidative stress from acute exposure and that repeated sub-erythemal SSR exposure results in a decrease of SC catalase and an increase of protein oxidation, which may compromise its barrier function. Protein oxidation was not observed in the epidermis, possibly because of the epidermal induction of methionine-S-sulphoxide reductase (MSRA) which is able to repair protein damage by ROS.
1.2.4. Early Responses that have a Direct Impact on Skin Cancer
1.2.4.1. DNA Photodamage
UVR absorption by epidermal DNA results in the formation of dipyrimidine lesions such as cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproducts (6–4 PP). Solar range UVR action spectroscopy shows that UVB is orders of magnitude more effective that UVA, as would be expected from the absorption spectrum of DNA. The CPD, of which the thymine dimer (T = T) is the most common type, has been identified as critical photolesion for many of the acute and chronic effects of UVR. For example, the CPD is thought to initiate erythema, immunomodulatory cytokine release. immunosuppression, and is known to be an important lesion in the generation of highly characteristic namely C [right arrow] T or CC [right arrow] TT transition mutations in p53 that are common in actinic keratoses, BCC and SCC. BCC have also been found to harbour such mutations in the human homologue of the Drosophila "patched" Ptch gene, which suggests that this gene is important for this type of tumor. Its function is less clear than that of p53 but it is part of the hedgehog signal transduction pathway that transmits extracellular growth and differentiation signals to the nucleus. BCC are generally tumors of the elderly but the Gorlin-Goltz syndrome, a genodermatosis with autosomal dominant inheritance, predisposes to BCC at a very early age. This syndrome has been shown to be due to a mutation of the Ptch gene and Ptch[+ or -] mice develop BCC like tumors on exposure to broad spectrum UVR. Interestingly, Ptch does not seem to play a role in human SCC leaving p53 the only gene known to lead to SCC upon inactivation.
The T = T has been identified in human epidermis in vivo in several studies and shows a UVR dose dependence in acute studies. These lesions are readily detected with acute sub-erythemal exposure in keratinocytes and melanocytes in human skin in vivo. CPD, and other types of DNA damage, initiate one of two major pathways that are regulated by the p53 protein that is induced in the epidermis after acute erythemal UVR and repeated sub-erythemal exposure. The first is nucleotide excision repair (NER) that can restore the integrity of the DNA, and is known to play a crucial role in the prevention of skin cancer. The most powerful human evidence for the major significance of DNA repair comes from the very high incidence of all types of skin cancer in xeroderma pigmentosum (XP) patients who are, to varying degrees, genetically deficient in NER. There is evidence that DNA repair capacity; assessed in lymphocytes, plays a role in skin cancer in the normal population and that this is related to skin phototype. However, the relationship between skin phototype and DNA repair capacity has not been formally explored. The NER of CPD is a relatively slow process such that many lesions are still present 24 hours post-exposure: in contrast the repair of the 6-4 PP is rapid. The second pathway is a molecular cascade that results in the apoptotic death of the damaged cell. UVR induced apoptotic cells are known as sunburn cells (SBC) that are UVR dose dependent with maximal expression at about 24 hours post-irradiation. In general, a significant increase of SBC is not seen unless the dose is approximately erythemal. Repeated daily exposure of sub-erythemal SSR that results in the accumulation of CPD (Figure 1.1a) and p53 (Figure 1.1b) does not result in the accumulation of SBC. The lack of SBC may be a means of protecting the integrity of the epidermis, at the expense of enhancing skin cancer risk. p53 expression is also seen on chronically sun-exposed skin and has been proposed as a biomarker for skin cancer.
The presence of conical clonal patches of p53-mutated keratinocytes in normal human skin provides evidence that these mutations arise from mutated cells rather than from random mutation events. These p53 mutations in these clones confer resistance to apoptosis that allows keratinocytes to accumulate further UVR-induced mutations that may lead to skin cancer. p53 clonal expansion is a function of chronic UVR exposure rather than time, because these clones regress in mouse skin in the absence of continuing exposure. Such clones are more frequent and larger in chronically sun-exposed skin but will not necessarily become a cancer. However, larger colonies provide bigger targets with a greater chance for secondary mutations that can lead to cancer. It has been suggested that p53 clonal expansion occurs by quantized colonization by the non-aggressive expansion of clones into compartments left empty by adjacent cells that have undergone UVR-induced apoptosis. Overall, our current understanding of non-melanoma skin cancer is that DNA photodamage is the initial photomolecular event that triggers a chain of cellular, mutational, and immunological events that may lead to a skin tumor.
There is emerging evidence that CPDs, but not (6–4) photoproducts, can be formed by energy transfer reactions originating from UVA chromophores, which means that some of the C [right arrow] T or CC [right arrow] TT transitions found in skin cancers, normally associated with UVB, may be attributable to UVA. In vitro and in vivo studies on human skin have demonstrated UVA -induced oxidative DNA lesions such as 8-oxo-7,8-dihydro-2'-deoxyguanosine which have been reported under laboratory conditions, and 8-hydoxy-2' -deoxyguanine and UVA signature mutations (AT [right arrow] CG transversions) have been reported in p53 in AK, BCC and SCC. The chromophores for these lesions are not known.
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Excerpted from Biophysical and Physiological Effects of Solar Radiation on Human Skin by Paolo U. Giacomoni. Copyright © 2007 European Society of Photobiology. Excerpted by permission of The Royal Society of Chemistry.
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