Environmental plastics in the context of UV radiation, climate change, and the Montreal Protocol.

There are close links between solar UV radiation, climate change, and plastic pollution. UV-driven weathering is a key process leading to the degradation of plastics in the environment but also the formation of potentially harmful plastic fragments such as micro- and nanoplastic particles. Estimates of the environmental persistence of plastic pollution, and the formation of fragments, will need to take in account plastic dispersal around the globe, as well as projected UV radiation levels and climate change factors.

Enzymes for dermatological use.

Skin is the ultimate barrier between body and environment and prevents water loss and penetration of pathogens and toxins. Internal and external stressors, such as ultraviolet radiation (UVR), can damage skin integrity and lead to disorders. Therefore, skin health and skin ageing are important concerns and increased research from cosmetic and pharmaceutical sectors aims to improve skin conditions and provide new anti-ageing treatments. Biomolecules, compared to low molecular weight drugs and cosmetic ingredients, can offer high levels of specificity. Topically applied enzymes have been investigated to treat the adverse effects of sunlight, pollution and other external agents. Enzymes, with a diverse range of targets, present potential for dermatological use such as antioxidant enzymes, proteases and repairing enzymes. In this review, we discuss enzymes for dermatological applications and the challenges associated in this growing field.

Plastics in the environment in the context of UV radiation, climate change and the Montreal Protocol: UNEP Environmental Effects Assessment Panel, Update 2023.

This Assessment Update by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) considers the interactive effects of solar UV radiation, global warming, and other weathering factors on plastics. The Assessment illustrates the significance of solar UV radiation in decreasing the durability of plastic materials, degradation of plastic debris, formation of micro- and nanoplastic particles and accompanying leaching of potential toxic compounds. Micro- and nanoplastics have been found in all ecosystems, the atmosphere, and in humans. While the potential biological risks are not yet well-established, the widespread and increasing occurrence of plastic pollution is reason for continuing research and monitoring. Plastic debris persists after its intended life in soils, water bodies and the atmosphere as well as in living organisms. To counteract accumulation of plastics in the environment, the lifetime of novel plastics or plastic alternatives should better match the functional life of products, with eventual breakdown releasing harmless substances to the environment.

A revised action spectrum for vitamin D synthesis by suberythemal UV radiation exposure in humans in vivo.

Action spectra are important biological weighting functions for risk/benefit analyses of ultraviolet (UV) radiation (UVR) exposure. One important human benefit of exposure to terrestrial solar UVB radiation (∼295 to 315 nm) is the cutaneous synthesis of vitamin D3 that is initiated by the photoconversion of 7-dehydrocholesterol to previtamin D3 An action spectrum for this process that is followed by other nonphotochemical steps to achieve biologically active vitamin D3 has been established from ex vivo data and is widely used, although its validity has been questioned. We tested this action spectrum in vivo by full- or partial-body suberythemal irradiation of 75 healthy young volunteers with five different polychromatic UVR spectra on five serial occasions. Serum 25-hydroxyvitamin D3 [25(OH)D3] levels, as the most accurate measure of vitamin D3 status, were assessed before, during, and after the exposures. These were then used to generate linear dose-response curves that were different for each UVR spectrum. It was established that the previtamin D3 action spectrum was not valid when related to the serum 25(OH)D3 levels, as weighting the UVR doses with this action spectrum did not result in a common regression line unless it was adjusted by a blue shift, with 5 nm giving the best fit. Such a blue shift is in accord with the published in vitro action spectra for vitamin D3 synthesis. Thus, calculations regarding the risk (typically erythema) versus the benefit of exposure to solar UVR based on the ex vivo previtamin D3 action spectrum require revision.

The adverse consequences of not using sunscreens.

The adverse effects of solar ultraviolet radiation (UVR) on normal skin are well established, especially in those with poorly melanized skin. Clinically, these effects may be classified as acute, such as erythema or chronic such as keratinocyte and melanocyte skin cancers. Apart from skin type genetics, clinical responses to solar UVR are dependent on geophysical (e.g., solar intensity) and behavioural factors. The latter are especially important because they may result in 'solar overload' with unwanted clinical consequences and ever greater burdens to healthcare systems. Correctly used, sunscreens can mitigate the acute and chronic effects of solar UVR exposure. Laboratory studies also show that sunscreens can inhibit the initial molecular and cellular events that are responsible for clinical outcomes. Despite public health campaigns, global trends continue to show increasing incidence of all types of skin cancer. Large-scale epidemiological studies have shown the benefits of sunscreen use in preventing skin cancer, though it is likely that sunscreen use has not been optimal in such studies. It is evident that without substantial changes in sun-seeking behaviour, sunscreen use is a very important part of the defence against the acute and chronic effects of solar exposure. Ideally, sunscreens should be able to provide the level of protection that reduces the risk of skin cancer in susceptible skin types to that observed in heavily melanized skin.

Les effets indésirables des rayons ultraviolets (UVR) du soleil sur une peau saine sont bien établis, en particulier chez les personnes dont la peau est faiblement concentrée en mélanine. Sur le plan clinique, ces effets peuvent être classés comme aigus, comme un érythème, ou chroniques, comme des cancers de la peau kératinocytaires et mélanocytaires. Outre la génétique du type de peau, les réponses cliniques aux UVR du soleil dépendent de facteurs géophysiques (par exemple, intensité du soleil) et comportementaux. Ces réponses sont particulièrement importantes, car elles peuvent entraîner un « trop-plein de soleil ¼ avec des conséquences cliniques indésirables et des charges de plus en plus importantes pour les systèmes de santé. Utilisés correctement, les protections solaires peuvent atténuer les effets aigus et chroniques de l'exposition aux UV du soleil. Des études en laboratoire montrent également que les protections solaires peuvent inhiber les événements moléculaires et cellulaires initiaux, qui sont responsables des effets cliniques. Malgré les campagnes de santé publique, les tendances mondiales continuent de montrer une incidence croissante de tous les types de cancer de la peau. Des études épidémiologiques à grande échelle ont montré les bénéfices de l'utilisation d'une protection solaire dans la prévention du cancer de la peau, même s'il est probable que l'utilisation d'une protection solaire n'a pas été optimale dans ces études. Il est évident que, sans changements substantiels du comportement d'exposition au soleil, l'utilisation d'une protection solaire est un aspect très important de la défense contre les effets aigus et chroniques de l'exposition au soleil. Idéalement, les protections solaires devraient pouvoir offrir aux types de peau sensibles le niveau de protection qui réduit le risque de cancer de la peau observé pour les peaux fortement concentrées en mélanine.

Innovative digital solution supporting sun protection and vitamin D synthesis by using satellite-based monitoring of solar radiation.

Public health campaigns advise minimising UV radiation (UVR) exposure to prevent skin cancer and precancer, e.g. actinic keratosis (AK). A 3-day clinical field study, in Brazil, was performed to evaluate the mobile app Sun4Health® by siHealth Ltd. The app performs real-time monitoring of both erythemal and vitamin D-effective solar radiation doses using satellite data, enabling personalised recommendations on optimal sun exposure time and sunscreen use. When coupled to a wearable device, the app also provides body-site specific recommendations ("3D" version). 59 healthy volunteers were randomised into 3 groups, each given a different app providing: (1) ultraviolet index only (control app), (2) personalised recommendations and sun overexposure alerts (Sun4Health® app), (3) as (2) but connected via Bluetooth to a wearable device to monitor sun exposure in 3D (Sun4Health®-3D app). Participants were offered sunscreens (SPF 30 and 50) to use at their discretion. Erythema, quantified by reflectance spectroscopy, was assessed daily in the mornings and evenings on six body sites. Serum vitamin D (25(OH)D3) was measured before and after the study. Mean increase of erythema (Mexameter® units ± SD) of all exposed body sites combined over 3 days showed 55.76 ± 47.47 for group 1, 40.27 ± 37.91 for group 2 and 37.12 ± 30.69 for group 3 (p < 0.05 for all groups). Mean increase of serum 25(OH)D3 (nmol/l ± SD) showed 1.32 ± 36.49 for group 1, 6.38 ± 21.19 for group 2 and 18.68 ± 35.45 for group 3 (p > 0.05 for all groups). The results show that the Sun4Health® app is safe to use and can modify behaviour to reduce skin erythema (sunburn) yet not decreasing vitamin D status.

Measurements of sun sensitivity in five European countries confirm the relative nature of Fitzpatrick skin phototype scale.

BACKGROUND/PURPOSE: Skin colour and sun sensitivity are highly related to the distance to the equator: people in southern latitudes are usually darker and less sensitive to sun than in northern latitudes. Whether differences in sun sensitivity can be found in a relatively homogenous European population is unclear. We aimed to objectively measure sun sensitivity (assessed as pigment protection factor (PPF)) in five European countries, relate it to self-assessed Fitzpatrick skin phototype (FST) and to determine whether PPF levels in the different FST categories are dependent on the investigated countries. METHODS: Volunteers (n = 569) were recruited in Copenhagen (Denmark), Dublin (Ireland), London (England), Münster (Germany) and Ioannina (Greece). Skin phototype was self-assessed using the FST scale. PPF was measured at both sun-protected buttocks and five sun-exposed skin sites by a skin reflectance spectrophotometer. RESULTS: Overall, there were statistically significant differences in PPF of the buttocks, inner arm, outer arm, forehead, chest and back between the five countries (P ≤ .031). Generally, PPF level was lower in northern than in southern latitudes. PPF of the buttocks was similar in all countries for those who identified as FST I (P = .723). However, it was statistically significantly different (P ≤ 2.913*10-4 ) and country-dependent for those who identified as FST II-IV. CONCLUSION: Objectively measured sun sensitivity is higher (lower PPF) in northern compared with southern latitudes. The choice of self-identified FST category is influenced by a person's immediate environment. Therefore, we confirmed the relative nature of the FST scale and the need to standardise the skin phototype assessment procedure.

Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes.

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 of black skin. These results may explain, at least in part, the considerable skin color differences in KC incidence. These data suggest that a DNA protection factor of at least 60 is necessary in sunscreens to reduce white skin KC incidence to a level that is comparable with that of black skin.-Fajuyigbe, D., Lwin, S. M., Diffey, B. L., Baker, R., Tobin, D. J., Sarkany, R. P. E., Young, A. R. Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes.

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.

Sub-optimal Application of a High SPF Sunscreen Prevents Epidermal DNA Damage in Vivo.

The cyclobutane pyrimidine dimer (CPD) is a potentially mutagenic DNA photolesion that is the basis of most skin cancers. There are no data on DNA protection by sunscreens under typical conditions of use. The study aim was to determine such protection, in phototypes I/II, with representative sunscreen-user application. A very high SPF formulation was applied at 0.75, 1.3 and 2.0 mg/cm2. Unprotected control skin was exposed to 4 standard erythema doses (SED) of solar simulated UVR, and sunscreen-treated sites to 30 SED. Holiday behaviour was also simulated by UVR exposure for 5 consecutive days. Control skin received 1 SED daily, and sunscreen-treated sites received 15 (all 3 application thicknesses) or 30 (2.0 mg/cm2) SED daily. CPD were assessed by quantitative HPLC-tandem mass spectrometry (HPLC-MS/MS) and semi-quantitative immunostaining. In comparison with unprotected control sites, sunscreen significantly (p ≤ 0.001-0.05) reduced DNA damage at 1.3 and 2.0 mg/cm2 in all cases. However, reduction with typical sunscreen use (0.75 mg/cm2) was non-significant, with the exception of HPLC-MS/MS data for the 5-day study (p <0.001). Overall, these results support sunscreen use as a strategy to reduce skin cancer, and demonstrate that public health messages must stress better sunscreen application to get maximal benefit.

ASTHMA - comparing the impact of vitamin D versus UVR on clinical and immune parameters.

The incidence of asthma has increased markedly since the 1960s and is currently estimated to affect more than 300 million individuals worldwide. A number of environmental factors are implicated in asthma pathogenesis, one of which is vitamin D. Vitamin D deficiency is a global health concern and has increased in parallel with asthma incidence. Epidemiological studies report associations between low vitamin D status, assessed as circulating levels of 25-hydroxyvitamin D, with asthma incidence, severity, exacerbations and responses to treatment. This has led to clinical studies to test whether increasing the levels of vitamin D improves asthma management. Despite being highly variable in dosing regimens, design and outcomes, meta-analyses suggest overall positive outcomes with respect to reduced asthma exacerbations and steroid requirements. The primary mechanism for increasing vitamin D levels in the body is through exposure of the skin to the ultraviolet B (UVB) component of ultraviolet radiation (UVR), most commonly from sun exposure. However, only a limited number of studies investigating the impact of UVR on the asthmatic response have been performed; these generally report on the impact of latitude as a surrogate of sun exposure, or address this in animal models. To the best of our knowledge no comprehensive trials to assess the impact of UVB radiation on asthma outcomes have been performed. Within this review we discuss observational and clinical studies in this field, and innate and adaptive immune mechanisms through which UVR and vitamin D may impact respiratory health, and asthma. We highlight the heterogeneity of asthmatic disease, which is likely to impact upon the efficacy of interventional studies, and briefly overview more recent findings relating to the impact of vitamin D/UVR on the development of asthma.

Ultraviolet radiation and the skin: Photobiology and sunscreen photoprotection.

The efficacy of sunscreens can be measured by different methods, involving in vitro, ex vivo, or in vivo techniques. There is a need for a worldwide standardization of these methods to avoid misunderstanding and confusion among sunscreen users. The clinical benefits of sunscreens have been demonstrated in randomized controlled trials that established the role of sunscreens in the prevention of actinic keratoses, squamous cell carcinomas, nevi, and melanomas. Sunscreens also prevent photoimmunosuppression and signs of photoaging. Continued efforts in public education on the proper application of sunscreens and the practice of photoprotection in general are needed.

The acute effects of ultraviolet radiation on the blood transcriptome are independent of plasma 25OHD3.

The molecular basis of many health outcomes attributed to solar ultraviolet radiation (UVR) is unknown. We tested the hypothesis that they may originate from transcriptional changes in blood cells. This was determined by assessing the effect of fluorescent solar simulated radiation (FSSR) on the transcriptional profile of peripheral blood pre- and 6h, 24h and 48h post-exposure in nine healthy volunteers. Expression of 20 genes was down-regulated and one was up-regulated at 6h after FSSR. All recovered to baseline expression at 24h or 48h. These genes have been associated with immune regulation, cancer and blood pressure; health effects attributed to vitamin D via solar UVR exposure. Plasma 25-hydroxyvitamin D3 [25OHD3] levels increased over time after FSSR and were maximal at 48h. The increase was more pronounced in participants with low basal 25OHD3 levels. Mediation analyses suggested that changes in gene expression due to FSSR were independent of 25OHD3 and blood cell subpopulations.

UVA1 is skin deep: molecular and clinical implications.

Long wavelength UVA1 (340-400 nm) is the main component of terrestrial UVR and is increasingly used in skin phototherapy. Its damage to critical biomolecules such as DNA has been widely attributed to its ability to generate reactive oxygen species (ROS) via other chromophores. However recent studies in vitro and in vivo have shown that UVA1 has a specific ability to generate cyclobutane pyrimidine dimers (CPD), especially thymine dimers (T<>T), and that this is probably due to direct absorption of UVR. The CPD has been implicated in many aspects of skin cancer. Measuring UVB-induced CPD in the epidermis and dermis in vivo shows that, as expected, the skin attenuates UVB. In contrast, our data show that this is not the case with UVA1: in fact there is more damage with increased skin depth. This suggests that the basal layer, which contains keratinocyte stem cells and melanocytes, is more vulnerable to the carcinogenic effects of UVA1 than would be predicted by mouse models. These data support the continuing trend for better UVA1 protection by sunscreens.

Identification of potentially cytotoxic lesions induced by UVA photoactivation of DNA 4-thiothymidine in human cells.

Photochemotherapy-in which a photosensitizing drug is combined with ultraviolet or visible radiation-has proven therapeutic effectiveness. Existing approaches have drawbacks, however, and there is a clinical need to develop alternatives offering improved target cell selectivity. DNA substitution by 4-thiothymidine (S(4)TdR) sensitizes cells to killing by ultraviolet A (UVA) radiation. Here, we demonstrate that UVA photoactivation of DNA S(4)TdR does not generate reactive oxygen or cause direct DNA breakage and is only minimally mutagenic. In an organotypic human skin model, UVA penetration is sufficiently robust to kill S(4)TdR-photosensitized epidermal cells. We have investigated the DNA lesions responsible for toxicity. Although thymidine is the predominant UVA photoproduct of S(4)TdR in dilute solution, more complex lesions are formed when S(4)TdR-containing oligonucleotides are irradiated. One of these, a thietane/S(5)-(6-4)T:T, is structurally related to the (6-4) pyrimidine:pyrimidone [(6-4) Py:Py] photoproducts induced by UVB/C radiation. These lesions are detectable in DNA from S(4)TdR/UVA-treated cells and are excised from DNA more efficiently by keratinocytes than by leukaemia cells. UVA irradiation also induces DNA interstrand crosslinking of S(4)TdR-containing duplex oligonucleotides. Cells defective in repairing (6-4) Py:Py DNA adducts or processing DNA crosslinks are extremely sensitive to S(4)TdR/UVA indicating that these lesions contribute significantly to S(4)TdR/UVA cytotoxicity.

Human skin CD141+ dendritic cells regulate cutaneous immunity via the neuropeptide urocortin 2.

Skin immune homeostasis is a multi-faceted process where dermal dendritic cells (DDCs) are key in orchestrating responses to environmental stressors. We have previously identified CD141+CD14+ DDCs as a skin-resident immunoregulatory population that is vitamin-D3 (VitD3) inducible from monocyte-derived DCs (moDCs), termed CD141hi VitD3 moDCs. We demonstrate that CD141+ DDCs and CD141hi VitD3 moDCs share key immunological features including cell surface markers, reduced T cell stimulation, IL-10 production, and a common transcriptomic signature. Bioinformatic analysis identified the neuroactive ligand receptor pathway and the neuropeptide, urocortin 2 (UCN2), as a potential immunoregulatory candidate molecule. Incubation with VitD3 upregulated UCN2 in CD141+ DCs and UVB irradiation induced UCN2 in CD141+ DCs in healthy skin in vivo. Notably, CD141+ DDC generation of suppressive Tregs was dependent upon the UCN2 pathway as in vivo administration of UCN2 reversed skin inflammation in humanized mice. We propose the neuropeptide UCN2 as a novel skin DC-derived immunoregulatory mediator with a potential role in UVB and VitD3-dependent skin immune homeostasis.

Determinants of vitamin D status in long-term renal transplant patients.

In this study, we explored the determinants of vitamin D status in a large cohort of stable, Long-term renal transplant (RTx) patients. Serum 25(OH)D concentrations, and bone biochemistry parameters, were retrospectively analyzed from 266 RTx patients (>10 yr post-engraftment) presenting to clinic over the course of a year. Forty-five percent of the cohort were vitamin D deficient (<37.5 nM), 38% insufficient (37.5 75-nM), and 17% sufficient (>75 nM). Serum 25(OH)D concentrations were higher in patients presenting in summer (p<0.001) and in more active patients (p<0.05). RTx patients with non-melanoma skin cancer (NMSC) (n=45) had higher 25(OH)D concentrations than patients without NMSC (n=221; p<0.05) despite these patients being older, having worse eGFR, transplanted for longer, and less active physically (p<0.05). Lower 25(OH)D concentrations were associated with higher PTH concentrations (p<0.05) which, in the setting of widespread hypovitaminosis, suggests that secondary hyperparathyroidism was common in this cohort. In conclusion, season and activity status are important determinants of vitamin D status. We report, for the first time, that NMSC is associated with higher 25(OH)D, probably through increased UV radiation exposure. Long-term RTx patients may benefit from oral vitamin D supplementation, but this requires a randomized controlled trial to confirm.

4-Thiothymidine sensitization of DNA to UVA offers potential for a novel photochemotherapy.

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.

Human erythema and matrix metalloproteinase-1 mRNA induction, in vivo, share an action spectrum which suggests common chromophores.

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.