Folate Nutrition In Human Skin: Implications For Cancer Prevention

Abstract

The folates are a family of structurally similar, water-soluble, B vitamins, documented to play prominently in human health and disease. The potential impact of folate nutrition has been demonstrated by large-scale epidemiological and nutritional studies indicating that decreased folate intake increases the risk of cancer development. Human skin is particularly prone to the development of carcinomas and it is established that skin cancer risk correlates with exposure to the complete carcinogen ultraviolet radiation (UVR) in the form of sunlight. Recently a link between skin, sunlight, and folate has emerged from studies demonstrating that folate species are degraded by exposure to wavelengths of UVR contained within the solar spectrum. It is hypothesized that the unique physiology, function, and environment of skin combine to make skin tissue prone to folate deficiencies and that folate supplementation is a promising strategy for the prevention of skin cancer. However, many questions regarding folate nutrition within human skin must be answered before strategies to modulate folate nutrition may be rationally designed and safely implemented. This work presents novel means to examine skin-specific folate nutrition, including an analytical method to quantify individual folate species in human keratinocytes adaptable for the analysis of intact skin tissue and innovative cultured keratinocyte models of both acute and chronic folate deficiencies. It is demonstrated that folate deficiencies in skin tissue are possible and even likely as proliferating human keratinocytes are unable to maintain intracellular folate concentrations when nutrient conditions are limited and exposure to UVR results in biologically relevant folate degradation. Folate deficiency in human keratinocytes is observed to have potential pro-carcinogenic consequences including S-phase proliferation arrest, increased inherent DNA strand breaks, increased uracil misincorporation into DNA, and deficiencies in DNA damage repair, which are reversed when folate nutrient levels are optimized. The presented work characterizes the relationship between intracellular folate species and environmental carcinogens known to induce skin cancer and addresses challenges facing supplementation strategies for specifically improving folate nutriture in human skin. In total, this report broadens our understanding of folate nutrition in human skin and demonstrates that optimization of folate nutrition holds promise as a cancer preventive strategy.