Illuminating the effects of sun exposure using explant skin.

Enjoyment of sunshine is a quintessential aspect of the human experience. Exposure can provide a myriad of health benefits, from fostering essential vitamin synthesis to enhancing overall mental well-being and extending potentially to reduced cardiovascular mortality [1]. However, it is equally vital to recognize the potential risks associated with extended sun exposure, particularly the adverse effects on the skin. Here we examine how the use of explant skin models, specifically our patented TenSkin™ platform, may be used to evaluate not only the efficacy and tolerability of sunscreens, but also to explore the underlying biological processes that arise as a result of exposure to the sun. The aim is to use such models to assess the best strategies for preserving skin integrity by understanding the mechanisms by which sun exposure affects us from the molecular level up and how most effectively to reap the benefits of sun exposure while preventing the negative effects.

Energy from the sun has effectively nurtured life on Earth, and as such the biological evolution of species has emerged in a symbiotic relationship with natural sunlight. The interesting article by Mead [2] offers a fabulous and detailed overview of the effects of sunlight on humans, the extent and significance of which cannot be overstated. When the skin is exposed to sunlight, it initiates a chain of events culminating in the synthesis of vitamin D, an invaluable nutrient that is instrumental in maintaining strong bones, bolstering the immune system, and enhancing overall well-being. Furthermore, the sun’s radiance is known to stimulate other physiological responses, including the release of serotonin (a neurotransmitter linked to mood regulation) and nitric oxide, for which there is a growing body of evidence that increased levels can result in cardiovascular benefits [1]. However, these benefits are counterbalanced by the potential risks associated with excessive exposure to the sun.

Prolonged and unprotected exposure to ultraviolet (UV) radiation can result in DNA damage, potentially leading to a myriad of skin issues, including sunburn, premature aging, and an escalated susceptibility to skin cancer. It is evident that prudent sun exposure practices are essential for reaping its rewards while minimizing its detrimental effects.

Among the notable consequences of sun exposure is its role in the aging process. Photoaging, a distinctive form of skin aging induced by chronic UV radiation exposure, leads to the degradation of collagen and elastin fibers, pivotal components responsible for skin elasticity and firmness. The outcome is a visible manifestation of fine lines, wrinkles, changes in pigmentation, and sagging skin. Notably, many of these aging effects are intrinsically linked to DNA damage. UV radiation induces mutations in the DNA of skin cells, disrupting their normal function and contributing to the breakdown of vital structural proteins. By examining the correlation between photoaging and DNA damage, we gain a deeper understanding of the importance of effective sun protection strategies.

Sunscreens stand as a formidable defense against the harmful impacts of UV radiation on the skin. Categorized into two main types, reflective and absorbing, sunscreens function as barriers to protect the skin from the full brunt of UV radiation. Reflective sunscreens harness the properties of minerals like zinc oxide and titanium dioxide to physically deflect and scatter UV rays. Absorbing sunscreens, on the other hand, employ organic compounds to absorb UV radiation, which is then converted to heat energy, which can lead to additional compounding effects [3,4]. Indeed, sunscreen ingredients have recently gained attention regarding potential adverse effects. In a US context, this led the FDA to propose an order which sets out requirements for over-the-counter sunscreen products in the future. Although not yet implemented, these new requirements would require sunscreen makers to provide additional information on the active ingredients in their products. However, as sunscreens are classed as over-the-counter drugs, rather than cosmetics, testing in animals for new ingredients is still required, severely limiting the availability of newer ingredients to the US market. A solution to this problem, and a potential welcomed shift to the general requirement of animal testing, arose earlier this year in the form of the FDA Modernization Act 3.0, following on from the Modernization Act 2.0, this will allow for development of safe, effective treatments and therapies without unnecessary animal suffering.

The advent of explant skin models has revolutionized the scientific investigation of sunscreen efficacy at the DNA level. These models emulate the complexity of human skin, allowing controlled exposure to UV radiation and offering invaluable insights into the performance of sunscreens. At Ten Bio, we have developed a full thickness human skin ex vivo model in which the skin tissue is cultured at physiological tension.  By restoring skin’s inherent mechanobiology, our unique culture system retains skin’s physiological complexity, immunocompetency, and structural integrity.  This enables a more robust evaluation of a broad range of responses (including to sun exposure and sunscreens) over longer durations (up to 2 weeks).

Several pivotal studies have harnessed explant skin models to unravel the intricate relationship between sunscreens and DNA damage:

Full thickness ex vivo skin explant studies are clearly evidencing a previously unveiled level of understanding in skin physiology when compared to other models including animal skin, reconstituted human skin, or other cultures [5]. However, the majority primarily utilize skin from middle-aged Caucasian (Fitzpatrick type I-II) female donors. This limits the generatability of the findings to the wider population. Greater donor variation becomes increasingly important when it is appreciated that significant differences exist in the extracellular matrix when comparing explants from younger and older donors or between males and females [5,6], as well as the response to the sun in Fitzpatrick skin types III-VI. It has been estimated that skin with a naturally darker pigment can remain in the sun 4-6x longer before reaching an excessive dose of UV rays [7]. Additionally, achieving a beneficial level of vitamin D requires 2-3 times the sun exposure for darker skin compared to lighter skin [7]. Ten Bio has established a network of surgical partners to allow us to offer explants from a wide range of donors which presents the opportunity to further our understanding in what can be deemed a safe vs unsafe level of UV exposure as well as the variations in molecular responses based on skin phototype.

In conclusion, the duality of sun exposure, offering both essential benefits and potential risks, underscores the necessity of strategic sun protection and exposure habits. Prudent scheduling of outdoor activities and the planned use of protective clothing and sunscreen when needed ensures that our time in the sunshine is very much about joy and fun while ensuring that we minimize the worries about the consequences so that we may have many more ‘seasons in the sun’.

References:

1.      Richard B. Weller (2024), ‘Sunlight: Time for a Rethink?’, Journal of Investigative Dermatology, https://doi.org/10.1016/j.jid.2023.12.027

2.      Mead, M.N. (2008) ‘Benefits of sunlight: A bright spot for human health’, Environmental Health Perspectives, 116(4). doi:10.1289/ehp.116-a160.

3.      Calapre, L. et al. (2016) ‘Heat-mediated reduction of apoptosis in UVB-damaged keratinocytes in vitro and in human skin ex vivo’, BMC Dermatology, 16(1). doi:10.1186/s12895-016-0043-4.

4.      Calapre, L. et al. (2017) ‘SIRT1 activation mediates heat-induced survival of UVB damaged keratinocytes’, BMC Dermatology, 17(1). doi:10.1186/s12895-017-0060-y.

5.      Neil, J.E., Brown, M.B. and Williams, A.C. (2020) ‘Human skin explant model for the investigation of topical therapeutics’, Scientific Reports, 10(1). doi:10.1038/s41598-020-78292-4.

6.      Solé-Boldo, L. et al. (2020) ‘Single-cell transcriptomes of the human skin reveal age-related loss of fibroblast priming’, Communications Biology, 3(1). doi:10.1038/s42003-020-0922-4.

7.      Abadie, S., Bedos, P. and Rouquette, J. (2019) ‘A human skin model to evaluate the protective effect of compounds against UVA damage’, International Journal of Cosmetic Science, 41(6), pp. 594–603. doi:10.1111/ics.12579.

Revised in June 2024

Dr Michael Conneely

Dr Paul Campbell