Ultraviolet A within Sunlight Induces Mutations in the Epidermal Basal Layer of Engineered Human Skin

Abstract

The ultraviolet B (UVB) waveband within sunlight is an important carcinogen; however, UVA is also likely to be involved. By ascribing mutations to being either UVB or UVA induced, we have previously shown that human skin cancers contain similar numbers of UVBand UVA-induced mutations, and, importantly, the UVA mutations were at the base of the epidermis of the tumors. To determine whether these mutations occurred in response to UV, we exposed engineered human skin (EHS) to UVA, UVB, or a mixture that resembled sunlight, and then detected mutations by both denaturing high-performance liquid chromatography and DNA sequencing. EHS resembles human skin, modeling differential waveband penetration to the basal, dividing keratinocytes. We administered only four low doses of UV exposure. Both UVA and UVB induced p53 mutations in irradiated EHS, suggesting that sunlight doses that are achievable during normal daily activities are mutagenic. UVA-but not UVB-induced mutations predominated in the basal epidermis that contains dividing keratinocytes and are thought to give rise to skin tumors. These studies indicate that both UVA and UVB at physiological doses are mutagenic to keratinocytes in EHS. (Am J Pathol

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

“…The solar UV spectrum is made up of a combination of UVA (ϳ95%) and UVB (ϳ5%) wavelengths, both of which make significant contributions to skin cancer development by damaging DNA 70,71 and suppressing adaptive immune responses. 18,46,72 The presence of IL-33-producing cells deep within the dermis of UVB but not UVAexposed skin suggested that a UVB-induced soluble factor was responsible.…”

Photoinduced Damage to Cellular DNA: Direct and Photosensitized Reactions†

“…It is now well documented that DNA is the main critical cellular macromolecule for determining the carcinogenic effects of solar radiation (7)(8)(9). This received strong support from the delineation of mutagenic effects of UVB and UVA components (10)(11)(12)(13)(14) with the observation of UVB-induced C fi T transition and CC fi TT mutations at bipyrimidine sites in p53 genes of skin tumors (8,15). It has been also shown that C fi T transitions are generated in human skin by UV radiation within the 310-340 nm range at 5-methylcytosine containing bipyrimidine sites in CpG rich sequences (10,16).…”

Ultraviolet Light as a Modulator of Melanoma Development

“…Results of another study suggest that T-G transversion is a UVA "signature" (Drobetsky et al, 1995). UVA-specific lesions in the p53 gene have been detected in skin constructs and squamous tumours (Agar et al, 2004;Huang et al, 2009). In contrast, in vivo studies using "Big Blue" mice, and in vitro data, suggests that UVA-induced mutations are mainly of the pyrimidine dimer type (Mouret et al, 2006;Besaratinia & Pfeifer, 2008;Runger & Kappes, 2008).…”