Folate nutrition is critical in humans and a high dietary
folate intake is associated with a diminished risk of many types of
cancer. Both synthetic
folic acid and the most biologically abundant extracellular reduced
folate,
5-methyltetrahydrofolate, are degraded under conditions of ultraviolet radiation (UVR) exposure. Skin is a proliferative tissue with increased
folate nutrient demands due to a dependence upon continuous epidermal cell proliferation and differentiation to maintain homeostasis. Regions of skin are also chronically exposed to UVR, which penetrates to the actively dividing basal layer of the epidermis, increasing the
folate nutrient demands in order to replace
folate species degraded by UVR exposure and to supply the
folate cofactors required for repair of photo-damaged
DNA. Localized
folate deficiencies of skin are a likely consequence of UVR exposure. We report here a cultured keratinocyte model of
folate deficiency that has been applied to examine possible effects of
folate nutritional deficiencies in skin. Utilizing this model, we were able to quantify the concentrations of key intracellular
folate species during
folate depletion and repletion. We investigated the hypotheses that the
genomic instability observed under conditions of
folate deficiency in other cell types extends to skin, adversely effecting cellular capacity to handle UVR insult and that optimizing
folate levels in skin is beneficial in preventing or repairing the pro-carcinogenic effects of UVR exposure.
Folate restriction leads to rapid depletion of intracellular reduced folates resulting in S-phase growth arrest, increased levels of inherent DNA damage, and increased
uracil misincorporation into
DNA, without a significant losses in overall cellular viability.
Folate depleted keratinocytes were sensitized toward UVR induced apoptosis and displayed a diminished capacity to remove DNA breaks resulting from both photo and oxidative DNA damage. Thus,
folate deficiency creates a permissive environment for
genomic instability, an early event in the process of skin
carcinogenesis. The effects of
folate restriction, even in severely depleted, growth-arrested keratinocytes, were reversible by repletion with
folic acid. Overall, these results indicate that skin health can be positively influenced by optimal
folate nutriture.