Year: 2015
Type: article
Abstract: Dear Editor, Exposure to sunlight, especially its ultraviolet (UV) component, is a major risk factor for several forms of skin cancer.1 Both the more energetic UVB and the more abundant and deeply penetrating UVA (used in modern tanning beds) stimulate the progression of melanoma. Long duration or high frequency use of tanning beds and sunlamps has been associated with increased risk for basal and squamous cell carcinoma, while meta‐analysis also suggests a link to melanoma. Skin colour has been proposed to have evolved to balance the need for vitamin D biosynthesis at higher latitudes with protecting not only DNA but also folate from the more intense radiation near the equator.2 It has been suggested that skin cancer could have been responsible for early development of protective pigmentation.3 By slowing photodegradation of the folate pool, dark skin may also help prevent birth defects.2 Blood folate levels have been reported in several studies to not decrease following exposure of humans to UVA or sunlight,4 except in subjects consuming folic acid supplements,5 folic acid itself being a photosensitizer6. 5–Methyltetrahydrofolate (5–MTHF, the predominant folate in the epidermis7 and circulation) quenches photosensitizers and scavenges singlet oxygen (thus protecting DNA from strand breaks during UV irradiation6). 5–MTHF may be lost specifically in the skin while blocking photo‐oxidation reactions (Fig. 1). Damage by UV irradiation to DNA in skin is well documented. While folate loss in keratinocytes has also been studied,8 nothing is understood about the effect of UV on folate directly in skin, the largest of human organs. Therefore, to reveal the potential vulnerability of skin folate, after obtaining Institutional Review Board approval, we undertook a pilot experiment exposing fresh ex vivo whole human skin to UVA (Data S1 and S2; see Supporting Information). The metabolic products of the folate pathways are thymidylate, the purines and methionine needed for S‐adenosylmethionine (SAM) biosysnthesis. A depleted folate pool can hinder DNA repair as demonstrated in cell culture.8 Moreover, SAM is used for methylation reactions which, in part, regulate DNA transcription. In addition to remethylating homocysteine, 5–methyltetrahydrofolate (5–MTHF) also rapidly quenches excited photosensitizers (Photosensitizers*) and scavenges singlet oxygen.6 The photoprotective activity of 5–MTHF is largely sacrificial, although much of its initial oxidation product can be recaptured by sufficient levels of ascorbic acid, although it is also depleted from skin by UV irradiation.10 5,10–Methylene‐THF occupies a central juncture in one‐carbon metabolism, being used for nucleotide biosynthesis or conversion to 5‐MTHF at the expense of nicotinamide adenine dinucleotide phosphate (NADPH). Depletion of the latter by UV induction of NADPH oxidase may be related to the observed build‐up of THF and/or 5,10‐Methylene‐THF during irradiation of skin (these two species are not distinguished by the high‐performance liquid chromatography analysis). Relative to an unexposed section of skin subjected to the same conditions, total folate decreased by about 28% after 187 J cm−2 UVA (similar to the maximal daily UVA dose at sea level near the equator) (Fig. 2a; Data S3; see Supporting Information). The average loss of total folate from the epidermal samples (210 pmol g−1 tissue) signifies a decrease of about 120 nmol upon exposure of the total body skin area. This is a very small portion of the folate in the whole body (60–225 μmol).9 Therefore, after reaching homeostasis with the other organs, a single dose of UVA, as used in the current study, would not be expected to produce a major change in overall folate status. However, folate loss could be meaningful for people regularly exposed to strong sunlight or who have a high need for folate, such as during pregnancy. Thus, the high UV radiation that can occur near the equator might put enough pressure on folate stores to promote evolution of increased eumelanin pigmentation for protection from cancer and/or birth defects, especially when foods rich in folate are not readily available. No loss of total folate was observed in our samples of black skin. Although consistent with the hypothesis that dark skin colour helps to protect against degradation of this essential nutrient,2 not enough samples of black skin were available for our study to judge statistical significance. The effect of increasing ultraviolet (UV)A exposure on the loss of folate in ex vivo white human epidermis and dermis. (a) The change in total folate in skin expressed as percentage of nonexposed control [average of controls: 715 ± 66 and 90 ± 44 pmol g−1 wet weight of tissue (mean ± SD) in epidermis and dermis, respectively]. The rate of decrease from the control in the epidermis was significantly different from zero (P =0·003), with 18% and 28% losses after exposure to 125 and 187 J cm−2, respectively. (b) The change in 5–methyltetrahydrofolate (5‐MTHF) compared with nonexposed control (average of controls: 512 ± 37 and 39·5 ± 14·6 pmol g−1 wet weight of tissue in epidermis and dermis, respectively). The rate of loss of 5–MTHF in the epidermis was significant (P < 0·001) with 40% and 56% loss resulting from exposure to 125 and 187 J cm−2, respectively. (c) The percentage increase in the sum of tetrahydrofolic acid (THF) and 5,10‐methylene–THF. The average of control nonexposed skin: 54 ± 15 and 28 ± 9 pmol g−1 wet weight of tissue (mean ± SD) in epidermis and dermis, respectively. Epidermal THF+5,10–methylene‐THF increased over the control values with 125 and 187 J cm−2 of UVA by three‐ and fourfold, respectively; slope significantly different from zero (P <0·001). (d) High‐performance liquid chromatography analysis of epidermal 5–MTHF and THF+5,10‐methylene‐THF as a function of UVA exposure. Increasing UVA caused a decrease in 5–MTHF and an increase in the peak at 9·5 min representing the sum of THF plus 5,10–methylene–THF in ex vivo skin from white subjects. The changes in total folate, 5–MTHF and THF plus 5,10–methylene–THF in the dermis were not significant. See Supporting Information for additional details. We found that the loss of epidermal 5‐MTHF occurred at nearly double the rate of total folate (Fig. 2a,b). This was due, in part, to the four‐fold increase in white, but not black, skin of epidermal tetrahydrofolic acid (THF) and/or 5,10–methylene‐THF, which in unexposed skin are only minor components (~8%) of the epidermal folate pool (Fig. 2c,d; Data S4 and S5; see Supporting Information). Part of the loss of 5–MTHF not converted to THF may be due to insufficient ascorbate to regenerate 5–MTHF from its initial photo‐oxidation product (Fig. 1). The concentration of ascorbate in the human epidermis is normally about 4 mmol L−1, a level shown to protect 5–MTHF in vitro during UVA irradiation in the presence of a photosensitizer.6 However, UV irradiation also depletes skin ascorbate.10 The subsequent loss of folate, while altering one‐carbon metabolism, may also exacerbate further photo‐oxidative damage, e.g. to DNA.6 No significant changes in folate were observed in the dermis of any sample, consistent with diminished UV penetration into this layer. The increase in epidermal THF and/or 5,10–methylene‐THF (Fig. 2c) may be related to a decreased activity of 5,10–methylenetetrahydrofolate reductase (MTHFR) which produces 5–MTHF (Fig. 1). Nicotinamide adenine dinucleotide phosphate‐oxidase is activated in human keratinocytes by UV,11 and the potential decrease of MTHFR cofactor may promote accumulation of 5,10‐methylene‐THF. It has been reported that polymorphisms in MTHFR are risk factors for skin cancer. In such individuals, a decrease in 5‐MTHF (and thus diminished S–adenosylmethionine) could ultimately lead to aberrant DNA methylation, which is also associated with skin cancer.12 The UVA irradiance in tanning beds varies considerably among manufacturers, and is often several times higher than midday summer sun in mid‐latitudes. Importantly, tanning bed intensity is often greater than that used for this study (by ~twofold), and many have hot spots surrounding the head up to fourfold higher.13 A 30‐min session under one of the more intense lamps can give an exposure similar to the 125 J cm−2 dose examined here. Although not enough to elicit a detectable decrease in plasma folate levels, local depletion and rearrangement of the epidermal folate pool can occur. The basal layer, which contains keratinocyte stem cells and melanocytes, is also a likely location for most of the epidermal folate pool, and may suffer the largest impact of its depletion leaving cellular macromolecules more susceptible to ongoing photodegradation.6 It is not known how quickly the epidermis re‐establishes its own folate homeostasis after UV irradiation. Following exposure of rabbits to UVA, only 50% of the vitamin A depleted from the epidermis was replenished within 1 day.14 The high intensity of some artificial UV sources or strong sunlight might exacerbate folate loss in light skin faster than it is restored to the epidermis from the circulation. The risk of developing squamous cell carcinoma in people with a past history of skin cancer has been reported to be lowered twofold by a high intake of green leafy vegetables. This decrease was proposed to be due to the maintenance of genetic integrity by the folate content,15 but could also be due to the photoantioxidative activity of 5‐MTHF.6 Regardless of the mechanism, protection against UV might be improved by maintaining skin folate (which is correlated with blood folate status7), at optimum levels. Moreover, a significant loss of folate which may occur during UV phototherapy, especially in conjunction with administration of a psoralen photosensitizer, may (as discussed earlier7) have implications for optimal treatment of psoriasis and atopic dermatitis and the risk for cutaneous cancer. We wish to thank Patricia B. Alverson and Scott R. Glenzer for technical assistance. Funding sources: This work was supported by National Science Foundation (0091853‐353); and a predoctoral fellowship from the Graduate Research Scholars Program of Alabama (090463 to L.Z.H.). Conflicts of interest: L.Z.H. and K.K.O. have no conflicts of interest to report; S.W.B. and J.E.A. are inventors of a patent that may benefit from the data presented here. Data S1. Exposure of human skin to UVA. Data S2. Statistical analysis. Data S3. Effect of UVA on total folate. Data S4. Effect of UVA on 5‐MTHF. Data S5. Effect of UVA on THF+5,10‐Methylene‐THF.
Source: British Journal of Dermatology
DOI: 10.1111/bjd.13885
Authors: L.Z. Hasoun, S.W. Bailey, K.K. Outlaw, J.E. Ayling
Institutions: Zarqa University, University of South Alabama, Mobile Infirmary
Language: English
Topic: Skin Protection and Aging
Subfield: Dermatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: National Science Foundation
OpenAlex ID: W1907675431