Unlike “light” cylobutane pyrimidine dimers (CPD) formed during ultraviolet radiation (UVR) expos... more Unlike “light” cylobutane pyrimidine dimers (CPD) formed during ultraviolet radiation (UVR) exposure, dark CPD (dCPD) are formed afterwards. Studies have attributed this to delayed melanin sensitization. There are no data on the role of melanin in dCPD formation in human skin.
Particular requirements for appliances for skin exposure to ultraviolet and infrared radiation" 3... more Particular requirements for appliances for skin exposure to ultraviolet and infrared radiation" 3 Article 95 of the EC Treaty see: www.europa.eu.int/eur-lex/en/treaties/selected/livre221.html 4 "Administrative co-operation" working group in the area of the LVD, consisting of the Market Surveillance representatives from all Member States and the European Commission 6. Please specify the limit values of total dose of artificial UV-A, UV-B and UV-C radiation above which adverse health effects will occur, taking into account skin phototype, intensity of exposure, duration of exposure and associated uncertainties. Supporting documents • Spanish formal objection against European harmonised standard EN 60335-2-27
UVA1 radiation (340–400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assess... more UVA1 radiation (340–400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assessing sun protection due to its low sunburning potential, but it generates reactive oxygen species (ROS) and is poorly attenuated by sunscreens. This study aimed to investigate if α-tocopherol phosphate, (α-TP) a promising new antioxidant, could protect against long-wave UVA1 induced cell death and scavenge UVA1 induced ROS in a skin cell model. HaCaT keratinocyte cell viability (24 h) was assessed with Alamar Blue and Neutral Red assays. The metabolism of α-TP into α-T, assessed using mass spectrometry, and the compound's radical scavenging efficacy, assessed by the dichlorodihydrofluorescein (H2DCFDA) ROS detection assay, was monitored in HaCaTs. The mechanism of α-TP ROS scavenging was determined using non-cell based DPPH and ORAC assays. In HaCaT keratinocytes, irradiated with 226 J/cm2 UVA1 in low-serum (2%, starved) cell culture medium, pretreatment with 80 µM α-TP significantly ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 2, 2018
Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte canc... more Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte cancers (KCs). Large differences in KC incidence (20- to 60-fold) between white and black populations are largely attributable to epidermal melanin photoprotection in the latter. The cyclobutane pyrimidine dimer (CPD) is the most mutagenic DNA photolesion; however, most studies suggest that melanin photoprotection against CPD is modest and cannot explain the considerable skin color-based differences in KC incidence. Along with melanin quantity, solar-simulated radiation-induced CPD assessed immediately postexposure in the overall epidermis and within 3 epidermal zones was compared in black West Africans and fair Europeans. Melanin in black skin protected against CPD by 8.0-fold in the overall epidermis and by 59.0-, 16.5-, and 5.0-fold in the basal, middle, and upper epidermis, respectively. Protection was related to the distribution of melanin, which was most concentrated in the basal layer...
Exposure to ultra violet radiation (UVR) is associated with significant long-term deleterious eff... more Exposure to ultra violet radiation (UVR) is associated with significant long-term deleterious effects such as skin cancer. A well-recognised short-term consequence of UVR is increased skin pigmentation. Pigmentation, whether constitutive or facultative, has widely been viewed as photoprotective, largely because darkly pigmented skin is at a lower risk of photocarcinogenesis than fair skin. Research is increasingly suggesting that the relationship between pigmentation and photoprotection may be far more complex than previously assumed. For example, photoprotection against erythema and DNA damage has been shown to be independent of level of induced pigmentation in human white skin types. Growing evidence now suggests that UVR induced DNA photodamage, and its repair is one of the signals that stimulates melanogenesis and studies suggest that repeated exposure in skin type IV results in faster DNA repair in comparison to skin type II. These findings suggest that tanning may be a measure...
Alkaline elution has been used to detect ultraviolet radiation (UVR)-induced DNA damage in the ep... more Alkaline elution has been used to detect ultraviolet radiation (UVR)-induced DNA damage in the epidermis of C3H/Tif hr/hr mice. This technique detects DNA damage in the form of singlestrand breaks and alkali-labile sites (SSB) formed directly by UVA (320-400 nm) or indirectly by UVB (280-320 nm). The latter induces DNA damage such as cyclobutane pyrimidine dimers and pyrimidinepyrimidone (6-4)-photoproducts, which are then converted into transient SSB by cellular endonucleases, during nucleotide excision repair (NER). The irradiation system used had a spectral output similar in effect to solar UVR, with the UVB component inducing 94% of the edema response observed in mice. Consequently, the majority of SSB detected were those formed via NER of UVB-induced photoadducts. The number of SSB detected immediately after 8 M/m2 (2.7 minimum erythema doses determined at 48 h post-UVR [MED]) was low, indicating the formation of only small numbers of transient SSB. When DNA repair inhibitors hydroxyurea and 1-@-D-arabinofuranosylcytosine were administered (intrapentoneally) to mice 30 min before UVR, they prevented sealing of the DNA SSB formed during NER. A four-fold increase in the number of SSB detected resulted, which was found to be linearly related to the UVR dose. The SSB induced by 2 M/m2 (less than an MED) were readily detected, with the ear showing lower numbers of SSB than the dorsum. When repair inhibitors were added post-UVR, the rate of formation of SSB declined rapidly with time of administration, reflecting repair of DNA lesions. After a UVR dose of 6 kJ/m2 (2 MED), 50% of the initial repair-dependent SSB had been removed after approximately 2 h in the ear and 4 h in the dorsum; no more SSB appeared to be incised by 24 h post-UVR. The technique described is an efficient and highly sensitive one for the quantification of SSB induced in UV-irradiated skin samples in vivo.
The photoprotective properties of furocoumarin plus UVA-induced epidermal melanogenesis were asse... more The photoprotective properties of furocoumarin plus UVA-induced epidermal melanogenesis were assessed in hairless mice. The ear and dorsal surfaces were topically treated with 6,4,4'-trimethylangelicin (TMA), 5-methoxypsoralen (SMOP), 8-methoxypsoralen (8-MOP) or psoralen and exposed to UVA for 12 consecutive weekdays. The TMA treatment induced intense tanning whereas modest tanning was seen with the other compounds. Seven days after the last treatment, the mice were challenged with a DNA damaging dose of UV radiation. Single strand breaks (SSB) in epidermal DNA were assessed by alkaline elution. Photoprotection was assessed by comparing SSB in furocoumarin-treated mice with control mice (vehicle plus UVA and also no treatment). No photoprotection was seen, with any compound, in dorsal epidermis despite intense pigmentation induced by TMA. Modest photoprotection with all compounds was seen in ear epidermis that was independent of the level of pigmentation. These data show that induced melanogenesis is not always associated with photoprotection.
Photochemical & Photobiological Sciences, 2002
The sunburn cell (SBC), with its pyknotic nucleus and eosinophilic cytoplasm, is characteristic o... more The sunburn cell (SBC), with its pyknotic nucleus and eosinophilic cytoplasm, is characteristic of mammalian epidermis after exposure to UVC and UVB radiation or UVA radiation in the presence of psoralens. SBC may be regarded as an example of apoptosis: controlled individual cell death. Since the discovery of apoptosis over thirty years ago, there has been a considerable increase in the knowledge of mechanisms involved in this process. DNA damage has been shown to be a major determinant of SBC production both in a p53-dependent and-independent manner. Extranuclear events such as activation of membrane bound death receptors also contribute to SBC formation. The development of new technologies and techniques has resulted in a better understanding of the mechanisms and machinery involved in apoptosis, triggered by various stimuli and in different cell types. Of particular importance has been the elucidation of regulatory molecules such as caspases, inhibitor of apoptosis proteins (IAP) and the role of mitochondria as key to the process of apoptosis and consequent production of SBC. This review attempts to give an update on those mechanisms involved and the occurrence and relevance of SBC in mammalian skin are discussed.
Photochemical & Photobiological Sciences, 2012
Photochemotherapy, in which ultraviolet radiation (UVR: 280-400 nm) or visible light is combined ... more Photochemotherapy, in which ultraviolet radiation (UVR: 280-400 nm) or visible light is combined with a photosensitizing drug to produce a therapeutic effect that neither drug or radiation can achieve alone, is a proven therapeutic strategy for a number of non-malignant hyperproliferative skin conditions and various cancers. Examples are psoralen plus UVA (320-400 nm) radiation (PUVA) and photodynamic therapy (PDT). All existing photochemotherapies have drawbacks-for example the association of PUVA with the development of skin cancer, and pain that is often associated with PDT treatment of skin lesions. There is a clear need to develop alternative approaches that involve lower radiation doses and/or improved selectivity for target cells. In this review, we explore the possibility to address this need by exploiting thionucleoside-mediated DNA photosensitisation to low, non toxic doses of UVA radiation.
We have examined the effects of low-dose monochromatic UVB irradiation (295 ± 5 nm), biologically... more We have examined the effects of low-dose monochromatic UVB irradiation (295 ± 5 nm), biologically equivalent to that generally incident on the skin during a 12-session sun-bed course, on the expression of the CDla epidermal Langerhans cell surface marker in human skin in vivo. In five subjects, 1-5 minimal erythema doses (MEDs) at 295 nm depleted its expression by 50%, In five further subjects, a single 1-5 MED dose, 1-5 MEDs in 10 equal fractions on alternate days, and a single 1-5 MED dose at one-tenth the previously used irradiance, delivered to separate sites, also led to variable but significant depletion of CDla expression of around. 30-50%, Thus, low-dose UVB irradiation, whether received rapidly or slowly, appears significantly and approximately equally to deplete human epidermal Langerhans cell numbers as measured by CDla expression.
The effects on 31 normal subjects following exposure to sunbeds containing UVA lamps with minimal... more The effects on 31 normal subjects following exposure to sunbeds containing UVA lamps with minimal UVB emission have been compared in a double-blind study with the efFects on nine control subjects of a similar exposure course three times weekly for 4 weeks to sunbeds emitting visible light. On previously untanned areas, all those subjects on active treatment developed a mild tan; in tanned areas they all developed a moderate tan, while all control subjects developed a minimal to mild tan. The mean protection factor against later UVB-induced erythema was 3 2 ± 03 after the active course and 1 6 ± 02 among the controls. Significantly more frequent adverse cutaneous effects for active subjects were pruritus, erythema, freckling, burning sensation, dryness and polymorphic light eruption. Cutaneous Langerhans cell numbers, and blood CD3 ' (pan T-cell) and CD4 * (helper T-cell) lymphocyte subsets were reduced in both active and control groups. CD8^ (cytotoxic/suppressor T-cell) counts were similarly but not significantly reduced in both groups. Pityrosporum yeast counts were significantly reduced in both groups. The changes found in both groups seem attributable to small amounts of UVB emission from both active and control lamps. The use of cosmetic ultraviolet (UV) irradiation skin tanning units, especially lie-on UVA (315-380 nm) sunbeds, has rapidly increased in recent years,'"'' mainly because of the belief that they tan the skin without burning or other significant adverse effect. However, short-term effects of such irradiation have in fact included erythema, pruritus, polymorphic light eruption, photosensitization reactions,"* pyrimidine dimer formation,'^ exacerbation of light-sensitive dermatoses such as lupus erythematosus*" and impairment of immune function,^ whereas prolonged UVA exposure has caused animal^-^ and human'" dermal degenerative effects, and, at least in animals, accelerated development of skin cancer." '^ Corneal and lens damage may also occur.' ^ Furthermore, only a third of subjects in one study received significant tanning after a sunbed treatment course and tolerance induced against UVB erythema was only moderate.' Recent reports of possible pityriasis versicolor,'*'^ atypical lentigines,"'
Photochemical & Photobiological Sciences, 2012
Matrix metalloproteinase 1 (MMP-1) is widely regarded as a biomarker of photoageing. We tested th... more Matrix metalloproteinase 1 (MMP-1) is widely regarded as a biomarker of photoageing. We tested the hypothesis that MMP-1 mRNA expression and erythema share a common action spectrum by comparing the effects of erythemally equivalent doses of UVB, UVA1 and solar simulated radiation (SSR) on acute MMP-1 mRNA expression in whole human skin in vivo. Our results show comparable MMP-1 expression with all three spectra, which supports our hypothesis. The sharing of an action spectrum implies common chromophores, one of which is likely to be DNA. We have previously shown that all spectra that we used readily induce cyclobutane thymine dimers (T<>T) in human epidermis in vivo but we lack quantitative data on damage to dermal DNA. This is important because we do not know if dermal MMP-1 induction occurs via direct damage to the dermis, or indirectly via damage to the epidermis. Our results show that UVB induces about 3 times more T<>T compared with erythemally equivalent doses of UVA1, which is similar to our published epidermal data. This supports previously published work that also implicates an unknown UVA1 chromophore for erythema and MMP-1 induction. However, the distribution of the dermal DNA damage varies considerably with spectrum. In the case of UVB it is primarily in the upper dermis, but with UVA1 it is evenly distributed. Thus, irrespective of chromophores, MMP-1 induction by direct dermal damage by both spectra is possible. The practical conclusions of our data are that the small (<5%) UVB content of solar UVR is likely to be the main cause of photoageing, at least in terms of MMP-1 expression. Furthermore, prevention of erythema by sunscreen use is likely to result in reduced MMP-1 expression.
Erythema is widely considered an indicator of skin cancer susceptibility but assessments is chall... more Erythema is widely considered an indicator of skin cancer susceptibility but assessments is challenging in black skin because melanin can mask erythema under traditional visual and advanced objective Commission Internationale de l'Eclairage (CIE) L*a*b* assessments. Using spectral measurements (400-700nm) from a spectrophotometer, an algorithm was developed to measure erythema in white Caucasians (n=9) and black West Africans (n=11) 19-24h post-solar simulated radiation (SSR) exposures to the volar forearm. The derived spectrum achieved showed a strong Accepted Article This article is protected by copyright. All rights reserved. maximum peak for haemoglobin at 580nm and a linear slope between 650-700nm for melanin absorption, as reported by other authors. Absorption by haemoglobin at 580nm was used as a proxy for erythema and melanin was quantified between 650-700nm. Our algorithm corrected the erythema measurements for stray specular (mirror-like) reflection and the melanin masking effect. A linear relationship between SSR exposure and erythema was evident (p<0.0001 for white and black skin) and white skin is 8.4 times more responsive to SSR compared to black skin. The prediction of ultraviolet radiation sensitivity is vital in both clinical and investigative dermatology especially in the determination of starting phototherapy doses. Our methodology allows for the accurate assessment of erythema independent of constitutive pigmentation.
International Journal of Environmental Research and Public Health, 2020
This article aims to alert the medical community and public health authorities to accumulating ev... more This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer’s disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide f...
This article contains a typographical error in the Introduction section, "This spectral region pe... more This article contains a typographical error in the Introduction section, "This spectral region penetrates the skin deeper that UVB (280-320 nm), readily reaching the dermal collagen and elastic fibres 2. "
Background Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutation... more Background Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutations and skin cancer. Skin can adapt to these adverse effects by DNA repair, apoptosis, keratinization and tanning. Objectives To investigate the transcriptional response to fluorescent solar-simulated radiation (FSSR) in sun-sensitive human skin in vivo. Methods Seven healthy male volunteers were exposed to 0, 3 and 6 standard erythemal doses (SED). Skin biopsies were taken at 6 h and 24 h after exposure. Gene and microRNA expression were quantified with next generation sequencing. A set of candidate genes was validated by quantitative polymerase chain reaction (qPCR); and wavelength dependence was examined in other volunteers through microarrays. Results The number of differentially expressed genes increased with FSSR dose and decreased between 6 and 24 h. Six hours after 6 SED, 4071 genes were differentially expressed, but only 16 genes were affected at 24 h after 3 SED. Genes for apoptosis and keratinization were prominent at 6 h, whereas inflammation and immunoregulation genes were predominant at 24 h. Validation by qPCR confirmed the altered expression of nine genes detected under all conditions; genes related to DNA repair and apoptosis; immunity and inflammation; pigmentation; and vitamin D synthesis. In general, candidate genes also responded to UVA1 (340-400 nm) and/or UVB (300 nm), but with variations in wavelength dependence and peak expression time. Only four microRNAs were differentially expressed by FSSR. Conclusions The UV radiation doses of this acute study are readily achieved daily during holidays in the sun, suggesting that the skin transcriptional profile of 'typical' holiday makers is markedly deregulated. What's already known about this topic? • The skin's transcriptional profile underpins its adverse (i.e. inflammation) and adaptive molecular, cellular and clinical responses (i.e. tanning, hyperkeratosis) to solar ultraviolet radiation. • Few studies have assessed microRNA and gene expression in vivo in humans, and there is a lack of information on dose, time and waveband effects.
Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorp... more Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. OBJECTIVE To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. INTERVENTIONS Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm 2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. MAIN OUTCOMES AND MEASURES The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. RESULTS Among 24 participants randomized (mean age, 35.5 [SD, 10.5] years; 12 [50%] women; 14 [58%] black or African American), 23 (96%) completed the trial. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash (1 participant with each sunscreen). Geometric Mean Maximum Plasma Concentration, ng/mL (Coefficient of Variation, %) Avobenzone Oxybenzone Octocrylene Ecamsule Spray 1 4.0 (60.9) 209.6 (66.8) 2.9 (102) Not applicable Spray 2 3.4 (77.3) 194.9 (52.4) 7.8 (113.3) Not applicable Lotion 4.3 (46.1) 169.3 (44.5) 5.7 (66.3) Not applicable Cream 1.8 (32.1) Not applicable 5.7 (47.1) 1.5 (166.1) CONCLUSIONS AND RELEVANCE In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen.
Bulleted statements What's already known about this topic? Knowledge of the relationship betwee... more Bulleted statements What's already known about this topic? Knowledge of the relationship between solar exposure behaviour, sunscreen use, and vitamin D is important for public health but there is confusion about optimal vitamin D status and the safest way to achieve this. Practical recommendations on the potential impact of daily and/or recreational sunscreens on vitamin D status are lacking for healthy people. What does this consensus add? Judicious use of daily broad-spectrum sunscreens with high UVA protection will not compromise vitamin D status in healthy people. However, photoprotection strategies for patients with photosensitivity disorders that include high SPF sunscreens with high UVA protection, along with protective clothing and shade seeking are likely to compromise vitamin D status. Screening for vitamin D status and supplementation are recommended in this group.
What is known about this topic? Action spectra (wavelength dependence) for erythema and the cut... more What is known about this topic? Action spectra (wavelength dependence) for erythema and the cutaneous formation of vitamin D overlap considerably in the UVB region. Theoretically, sunscreens that inhibit erythema should also inhibit vitamin D synthesis. Studies to date on the inhibitory effects of sunscreens on vitamin D synthesis have given conflicting results; possibly in part because people typically apply sunscreen sub-optimally. Many studies have design flaws. What does this study add? Sunscreens (SPF = 15) applied at sufficient thickness to inhibit sunburn during a week-long holiday with a very high UV index still allow a highly significant improvement of 25(OH)D3 concentration. An SPF=15 formulation with high UVA protection enables better vitamin D synthesis than a low UVA protection product. The former allows more UVB transmission. What is the translational message? The UVB dose necessary for vitamin D synthesis is very low when a large fraction of body surface area is exposed. The benefits of sunscreen use can be advocated without concern about compromising vitamin D status, at least with SPF=15 used optimally. It is possible to tailor the optical properties of sunscreens to optimize the benefits and risks of solar UVR exposure.
Unlike “light” cylobutane pyrimidine dimers (CPD) formed during ultraviolet radiation (UVR) expos... more Unlike “light” cylobutane pyrimidine dimers (CPD) formed during ultraviolet radiation (UVR) exposure, dark CPD (dCPD) are formed afterwards. Studies have attributed this to delayed melanin sensitization. There are no data on the role of melanin in dCPD formation in human skin.
Particular requirements for appliances for skin exposure to ultraviolet and infrared radiation" 3... more Particular requirements for appliances for skin exposure to ultraviolet and infrared radiation" 3 Article 95 of the EC Treaty see: www.europa.eu.int/eur-lex/en/treaties/selected/livre221.html 4 "Administrative co-operation" working group in the area of the LVD, consisting of the Market Surveillance representatives from all Member States and the European Commission 6. Please specify the limit values of total dose of artificial UV-A, UV-B and UV-C radiation above which adverse health effects will occur, taking into account skin phototype, intensity of exposure, duration of exposure and associated uncertainties. Supporting documents • Spanish formal objection against European harmonised standard EN 60335-2-27
UVA1 radiation (340–400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assess... more UVA1 radiation (340–400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assessing sun protection due to its low sunburning potential, but it generates reactive oxygen species (ROS) and is poorly attenuated by sunscreens. This study aimed to investigate if α-tocopherol phosphate, (α-TP) a promising new antioxidant, could protect against long-wave UVA1 induced cell death and scavenge UVA1 induced ROS in a skin cell model. HaCaT keratinocyte cell viability (24 h) was assessed with Alamar Blue and Neutral Red assays. The metabolism of α-TP into α-T, assessed using mass spectrometry, and the compound's radical scavenging efficacy, assessed by the dichlorodihydrofluorescein (H2DCFDA) ROS detection assay, was monitored in HaCaTs. The mechanism of α-TP ROS scavenging was determined using non-cell based DPPH and ORAC assays. In HaCaT keratinocytes, irradiated with 226 J/cm2 UVA1 in low-serum (2%, starved) cell culture medium, pretreatment with 80 µM α-TP significantly ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Jan 2, 2018
Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte canc... more Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte cancers (KCs). Large differences in KC incidence (20- to 60-fold) between white and black populations are largely attributable to epidermal melanin photoprotection in the latter. The cyclobutane pyrimidine dimer (CPD) is the most mutagenic DNA photolesion; however, most studies suggest that melanin photoprotection against CPD is modest and cannot explain the considerable skin color-based differences in KC incidence. Along with melanin quantity, solar-simulated radiation-induced CPD assessed immediately postexposure in the overall epidermis and within 3 epidermal zones was compared in black West Africans and fair Europeans. Melanin in black skin protected against CPD by 8.0-fold in the overall epidermis and by 59.0-, 16.5-, and 5.0-fold in the basal, middle, and upper epidermis, respectively. Protection was related to the distribution of melanin, which was most concentrated in the basal layer...
Exposure to ultra violet radiation (UVR) is associated with significant long-term deleterious eff... more Exposure to ultra violet radiation (UVR) is associated with significant long-term deleterious effects such as skin cancer. A well-recognised short-term consequence of UVR is increased skin pigmentation. Pigmentation, whether constitutive or facultative, has widely been viewed as photoprotective, largely because darkly pigmented skin is at a lower risk of photocarcinogenesis than fair skin. Research is increasingly suggesting that the relationship between pigmentation and photoprotection may be far more complex than previously assumed. For example, photoprotection against erythema and DNA damage has been shown to be independent of level of induced pigmentation in human white skin types. Growing evidence now suggests that UVR induced DNA photodamage, and its repair is one of the signals that stimulates melanogenesis and studies suggest that repeated exposure in skin type IV results in faster DNA repair in comparison to skin type II. These findings suggest that tanning may be a measure...
Alkaline elution has been used to detect ultraviolet radiation (UVR)-induced DNA damage in the ep... more Alkaline elution has been used to detect ultraviolet radiation (UVR)-induced DNA damage in the epidermis of C3H/Tif hr/hr mice. This technique detects DNA damage in the form of singlestrand breaks and alkali-labile sites (SSB) formed directly by UVA (320-400 nm) or indirectly by UVB (280-320 nm). The latter induces DNA damage such as cyclobutane pyrimidine dimers and pyrimidinepyrimidone (6-4)-photoproducts, which are then converted into transient SSB by cellular endonucleases, during nucleotide excision repair (NER). The irradiation system used had a spectral output similar in effect to solar UVR, with the UVB component inducing 94% of the edema response observed in mice. Consequently, the majority of SSB detected were those formed via NER of UVB-induced photoadducts. The number of SSB detected immediately after 8 M/m2 (2.7 minimum erythema doses determined at 48 h post-UVR [MED]) was low, indicating the formation of only small numbers of transient SSB. When DNA repair inhibitors hydroxyurea and 1-@-D-arabinofuranosylcytosine were administered (intrapentoneally) to mice 30 min before UVR, they prevented sealing of the DNA SSB formed during NER. A four-fold increase in the number of SSB detected resulted, which was found to be linearly related to the UVR dose. The SSB induced by 2 M/m2 (less than an MED) were readily detected, with the ear showing lower numbers of SSB than the dorsum. When repair inhibitors were added post-UVR, the rate of formation of SSB declined rapidly with time of administration, reflecting repair of DNA lesions. After a UVR dose of 6 kJ/m2 (2 MED), 50% of the initial repair-dependent SSB had been removed after approximately 2 h in the ear and 4 h in the dorsum; no more SSB appeared to be incised by 24 h post-UVR. The technique described is an efficient and highly sensitive one for the quantification of SSB induced in UV-irradiated skin samples in vivo.
The photoprotective properties of furocoumarin plus UVA-induced epidermal melanogenesis were asse... more The photoprotective properties of furocoumarin plus UVA-induced epidermal melanogenesis were assessed in hairless mice. The ear and dorsal surfaces were topically treated with 6,4,4'-trimethylangelicin (TMA), 5-methoxypsoralen (SMOP), 8-methoxypsoralen (8-MOP) or psoralen and exposed to UVA for 12 consecutive weekdays. The TMA treatment induced intense tanning whereas modest tanning was seen with the other compounds. Seven days after the last treatment, the mice were challenged with a DNA damaging dose of UV radiation. Single strand breaks (SSB) in epidermal DNA were assessed by alkaline elution. Photoprotection was assessed by comparing SSB in furocoumarin-treated mice with control mice (vehicle plus UVA and also no treatment). No photoprotection was seen, with any compound, in dorsal epidermis despite intense pigmentation induced by TMA. Modest photoprotection with all compounds was seen in ear epidermis that was independent of the level of pigmentation. These data show that induced melanogenesis is not always associated with photoprotection.
Photochemical & Photobiological Sciences, 2002
The sunburn cell (SBC), with its pyknotic nucleus and eosinophilic cytoplasm, is characteristic o... more The sunburn cell (SBC), with its pyknotic nucleus and eosinophilic cytoplasm, is characteristic of mammalian epidermis after exposure to UVC and UVB radiation or UVA radiation in the presence of psoralens. SBC may be regarded as an example of apoptosis: controlled individual cell death. Since the discovery of apoptosis over thirty years ago, there has been a considerable increase in the knowledge of mechanisms involved in this process. DNA damage has been shown to be a major determinant of SBC production both in a p53-dependent and-independent manner. Extranuclear events such as activation of membrane bound death receptors also contribute to SBC formation. The development of new technologies and techniques has resulted in a better understanding of the mechanisms and machinery involved in apoptosis, triggered by various stimuli and in different cell types. Of particular importance has been the elucidation of regulatory molecules such as caspases, inhibitor of apoptosis proteins (IAP) and the role of mitochondria as key to the process of apoptosis and consequent production of SBC. This review attempts to give an update on those mechanisms involved and the occurrence and relevance of SBC in mammalian skin are discussed.
Photochemical & Photobiological Sciences, 2012
Photochemotherapy, in which ultraviolet radiation (UVR: 280-400 nm) or visible light is combined ... more Photochemotherapy, in which ultraviolet radiation (UVR: 280-400 nm) or visible light is combined with a photosensitizing drug to produce a therapeutic effect that neither drug or radiation can achieve alone, is a proven therapeutic strategy for a number of non-malignant hyperproliferative skin conditions and various cancers. Examples are psoralen plus UVA (320-400 nm) radiation (PUVA) and photodynamic therapy (PDT). All existing photochemotherapies have drawbacks-for example the association of PUVA with the development of skin cancer, and pain that is often associated with PDT treatment of skin lesions. There is a clear need to develop alternative approaches that involve lower radiation doses and/or improved selectivity for target cells. In this review, we explore the possibility to address this need by exploiting thionucleoside-mediated DNA photosensitisation to low, non toxic doses of UVA radiation.
We have examined the effects of low-dose monochromatic UVB irradiation (295 ± 5 nm), biologically... more We have examined the effects of low-dose monochromatic UVB irradiation (295 ± 5 nm), biologically equivalent to that generally incident on the skin during a 12-session sun-bed course, on the expression of the CDla epidermal Langerhans cell surface marker in human skin in vivo. In five subjects, 1-5 minimal erythema doses (MEDs) at 295 nm depleted its expression by 50%, In five further subjects, a single 1-5 MED dose, 1-5 MEDs in 10 equal fractions on alternate days, and a single 1-5 MED dose at one-tenth the previously used irradiance, delivered to separate sites, also led to variable but significant depletion of CDla expression of around. 30-50%, Thus, low-dose UVB irradiation, whether received rapidly or slowly, appears significantly and approximately equally to deplete human epidermal Langerhans cell numbers as measured by CDla expression.
The effects on 31 normal subjects following exposure to sunbeds containing UVA lamps with minimal... more The effects on 31 normal subjects following exposure to sunbeds containing UVA lamps with minimal UVB emission have been compared in a double-blind study with the efFects on nine control subjects of a similar exposure course three times weekly for 4 weeks to sunbeds emitting visible light. On previously untanned areas, all those subjects on active treatment developed a mild tan; in tanned areas they all developed a moderate tan, while all control subjects developed a minimal to mild tan. The mean protection factor against later UVB-induced erythema was 3 2 ± 03 after the active course and 1 6 ± 02 among the controls. Significantly more frequent adverse cutaneous effects for active subjects were pruritus, erythema, freckling, burning sensation, dryness and polymorphic light eruption. Cutaneous Langerhans cell numbers, and blood CD3 ' (pan T-cell) and CD4 * (helper T-cell) lymphocyte subsets were reduced in both active and control groups. CD8^ (cytotoxic/suppressor T-cell) counts were similarly but not significantly reduced in both groups. Pityrosporum yeast counts were significantly reduced in both groups. The changes found in both groups seem attributable to small amounts of UVB emission from both active and control lamps. The use of cosmetic ultraviolet (UV) irradiation skin tanning units, especially lie-on UVA (315-380 nm) sunbeds, has rapidly increased in recent years,'"'' mainly because of the belief that they tan the skin without burning or other significant adverse effect. However, short-term effects of such irradiation have in fact included erythema, pruritus, polymorphic light eruption, photosensitization reactions,"* pyrimidine dimer formation,'^ exacerbation of light-sensitive dermatoses such as lupus erythematosus*" and impairment of immune function,^ whereas prolonged UVA exposure has caused animal^-^ and human'" dermal degenerative effects, and, at least in animals, accelerated development of skin cancer." '^ Corneal and lens damage may also occur.' ^ Furthermore, only a third of subjects in one study received significant tanning after a sunbed treatment course and tolerance induced against UVB erythema was only moderate.' Recent reports of possible pityriasis versicolor,'*'^ atypical lentigines,"'
Photochemical & Photobiological Sciences, 2012
Matrix metalloproteinase 1 (MMP-1) is widely regarded as a biomarker of photoageing. We tested th... more Matrix metalloproteinase 1 (MMP-1) is widely regarded as a biomarker of photoageing. We tested the hypothesis that MMP-1 mRNA expression and erythema share a common action spectrum by comparing the effects of erythemally equivalent doses of UVB, UVA1 and solar simulated radiation (SSR) on acute MMP-1 mRNA expression in whole human skin in vivo. Our results show comparable MMP-1 expression with all three spectra, which supports our hypothesis. The sharing of an action spectrum implies common chromophores, one of which is likely to be DNA. We have previously shown that all spectra that we used readily induce cyclobutane thymine dimers (T<>T) in human epidermis in vivo but we lack quantitative data on damage to dermal DNA. This is important because we do not know if dermal MMP-1 induction occurs via direct damage to the dermis, or indirectly via damage to the epidermis. Our results show that UVB induces about 3 times more T<>T compared with erythemally equivalent doses of UVA1, which is similar to our published epidermal data. This supports previously published work that also implicates an unknown UVA1 chromophore for erythema and MMP-1 induction. However, the distribution of the dermal DNA damage varies considerably with spectrum. In the case of UVB it is primarily in the upper dermis, but with UVA1 it is evenly distributed. Thus, irrespective of chromophores, MMP-1 induction by direct dermal damage by both spectra is possible. The practical conclusions of our data are that the small (<5%) UVB content of solar UVR is likely to be the main cause of photoageing, at least in terms of MMP-1 expression. Furthermore, prevention of erythema by sunscreen use is likely to result in reduced MMP-1 expression.
Erythema is widely considered an indicator of skin cancer susceptibility but assessments is chall... more Erythema is widely considered an indicator of skin cancer susceptibility but assessments is challenging in black skin because melanin can mask erythema under traditional visual and advanced objective Commission Internationale de l'Eclairage (CIE) L*a*b* assessments. Using spectral measurements (400-700nm) from a spectrophotometer, an algorithm was developed to measure erythema in white Caucasians (n=9) and black West Africans (n=11) 19-24h post-solar simulated radiation (SSR) exposures to the volar forearm. The derived spectrum achieved showed a strong Accepted Article This article is protected by copyright. All rights reserved. maximum peak for haemoglobin at 580nm and a linear slope between 650-700nm for melanin absorption, as reported by other authors. Absorption by haemoglobin at 580nm was used as a proxy for erythema and melanin was quantified between 650-700nm. Our algorithm corrected the erythema measurements for stray specular (mirror-like) reflection and the melanin masking effect. A linear relationship between SSR exposure and erythema was evident (p<0.0001 for white and black skin) and white skin is 8.4 times more responsive to SSR compared to black skin. The prediction of ultraviolet radiation sensitivity is vital in both clinical and investigative dermatology especially in the determination of starting phototherapy doses. Our methodology allows for the accurate assessment of erythema independent of constitutive pigmentation.
International Journal of Environmental Research and Public Health, 2020
This article aims to alert the medical community and public health authorities to accumulating ev... more This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer’s disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide f...
This article contains a typographical error in the Introduction section, "This spectral region pe... more This article contains a typographical error in the Introduction section, "This spectral region penetrates the skin deeper that UVB (280-320 nm), readily reaching the dermal collagen and elastic fibres 2. "
Background Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutation... more Background Terrestrial ultraviolet (UV) radiation causes erythema, oxidative stress, DNA mutations and skin cancer. Skin can adapt to these adverse effects by DNA repair, apoptosis, keratinization and tanning. Objectives To investigate the transcriptional response to fluorescent solar-simulated radiation (FSSR) in sun-sensitive human skin in vivo. Methods Seven healthy male volunteers were exposed to 0, 3 and 6 standard erythemal doses (SED). Skin biopsies were taken at 6 h and 24 h after exposure. Gene and microRNA expression were quantified with next generation sequencing. A set of candidate genes was validated by quantitative polymerase chain reaction (qPCR); and wavelength dependence was examined in other volunteers through microarrays. Results The number of differentially expressed genes increased with FSSR dose and decreased between 6 and 24 h. Six hours after 6 SED, 4071 genes were differentially expressed, but only 16 genes were affected at 24 h after 3 SED. Genes for apoptosis and keratinization were prominent at 6 h, whereas inflammation and immunoregulation genes were predominant at 24 h. Validation by qPCR confirmed the altered expression of nine genes detected under all conditions; genes related to DNA repair and apoptosis; immunity and inflammation; pigmentation; and vitamin D synthesis. In general, candidate genes also responded to UVA1 (340-400 nm) and/or UVB (300 nm), but with variations in wavelength dependence and peak expression time. Only four microRNAs were differentially expressed by FSSR. Conclusions The UV radiation doses of this acute study are readily achieved daily during holidays in the sun, suggesting that the skin transcriptional profile of 'typical' holiday makers is markedly deregulated. What's already known about this topic? • The skin's transcriptional profile underpins its adverse (i.e. inflammation) and adaptive molecular, cellular and clinical responses (i.e. tanning, hyperkeratosis) to solar ultraviolet radiation. • Few studies have assessed microRNA and gene expression in vivo in humans, and there is a lack of information on dose, time and waveband effects.
Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorp... more Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. OBJECTIVE To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. INTERVENTIONS Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm 2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. MAIN OUTCOMES AND MEASURES The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. RESULTS Among 24 participants randomized (mean age, 35.5 [SD, 10.5] years; 12 [50%] women; 14 [58%] black or African American), 23 (96%) completed the trial. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash (1 participant with each sunscreen). Geometric Mean Maximum Plasma Concentration, ng/mL (Coefficient of Variation, %) Avobenzone Oxybenzone Octocrylene Ecamsule Spray 1 4.0 (60.9) 209.6 (66.8) 2.9 (102) Not applicable Spray 2 3.4 (77.3) 194.9 (52.4) 7.8 (113.3) Not applicable Lotion 4.3 (46.1) 169.3 (44.5) 5.7 (66.3) Not applicable Cream 1.8 (32.1) Not applicable 5.7 (47.1) 1.5 (166.1) CONCLUSIONS AND RELEVANCE In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen.
Bulleted statements What's already known about this topic? Knowledge of the relationship betwee... more Bulleted statements What's already known about this topic? Knowledge of the relationship between solar exposure behaviour, sunscreen use, and vitamin D is important for public health but there is confusion about optimal vitamin D status and the safest way to achieve this. Practical recommendations on the potential impact of daily and/or recreational sunscreens on vitamin D status are lacking for healthy people. What does this consensus add? Judicious use of daily broad-spectrum sunscreens with high UVA protection will not compromise vitamin D status in healthy people. However, photoprotection strategies for patients with photosensitivity disorders that include high SPF sunscreens with high UVA protection, along with protective clothing and shade seeking are likely to compromise vitamin D status. Screening for vitamin D status and supplementation are recommended in this group.
What is known about this topic? Action spectra (wavelength dependence) for erythema and the cut... more What is known about this topic? Action spectra (wavelength dependence) for erythema and the cutaneous formation of vitamin D overlap considerably in the UVB region. Theoretically, sunscreens that inhibit erythema should also inhibit vitamin D synthesis. Studies to date on the inhibitory effects of sunscreens on vitamin D synthesis have given conflicting results; possibly in part because people typically apply sunscreen sub-optimally. Many studies have design flaws. What does this study add? Sunscreens (SPF = 15) applied at sufficient thickness to inhibit sunburn during a week-long holiday with a very high UV index still allow a highly significant improvement of 25(OH)D3 concentration. An SPF=15 formulation with high UVA protection enables better vitamin D synthesis than a low UVA protection product. The former allows more UVB transmission. What is the translational message? The UVB dose necessary for vitamin D synthesis is very low when a large fraction of body surface area is exposed. The benefits of sunscreen use can be advocated without concern about compromising vitamin D status, at least with SPF=15 used optimally. It is possible to tailor the optical properties of sunscreens to optimize the benefits and risks of solar UVR exposure.
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