Gender differences in antioxidant activity, DNA damage, and vasculature in ultraviolet light exposed skin

B144

Approximately half of the 2+ million U.S. cancer cases diagnosed each year are non-melanoma skin cancers (NMSC). According to the American Cancer Society, men develop the more aggressive NMSC, squamous cell carcinoma (SCC) three times more than women. Because exposure to ultraviolet (UV) light is the primary etiologic agent in the development of SCC, it has been assumed that the increased risk of SCC development in men is due to more UV exposure and/or less use of UV protection. Recent studies from our lab, however, demonstrated that when equally exposed to UV light, male mice had decreased tumor latency, increased tumor burden, and increased aggressiveness in the tumors that formed compared to female mice. We have shown a significant correlation between UV induced inflammation and the development of tumors in female mice. This inflammatory response includes neutrophil activation and prostaglandin production, both of which increase reactive oxygen species (ROS), and induce oxidative DNA damage and the formation of 8-oxo-deoxyguanosine (8-oxo-dG) DNA adducts. We anticipated that male mice would have an increased inflammatory response to UV exposure compared to female mice to account for their enhanced carcinogenic response. Contrary to our hypothesis male mice actually had less edema and decreased neutrophil activation compared to female mice. Despite the differences in UV induced inflammation, male mice had increased oxidative DNA damage, specifically increased 8-oxo-dG DNA adducts. Our recent data suggests that male mice may actually have decreased levels of the 8-oxo-dG repair protein OGG1. In addition to DNA repair enzymes, antioxidant mechanisms are in place within the skin to remove ROS. Our previous studies demonstrated that the skin of male mice has significantly reduced total antioxidant capacity compared to female mice. Exposure to UV significantly decreased the antioxidant capacity of female skin and further reduced the limited antioxidant capacity of male skin. This data suggests that the increased oxidative DNA damage and carcinogenic response may be due to the decreased antioxidant and DNA repair capabilities of male skin. We further investigated gender differences in specific antioxidants. We found no gender differences in glutathione reductase and glutathione-S-transferase activity. However, male mice did have significantly less catalase activity both at baseline and following UV exposure and significantly reduced glutathione peroxidase activity in response to UV exposure compared with female mice. Our data also demonstrated increased blood vessel density, as measured by CD31 staining, in the skin and tumors of male mice compared to female mice. Our studies suggest that the increased incidence of SCC in males may be due, in part, to reduced antioxidant capacity in the skin, decreased oxidative DNA repair and increased angiogenesis. Prevention and perhaps treatment of SCC may need to be gender specific where anti-inflammatory treatment may be more effective in females while enhancing anti-oxidant capacities may be more beneficial in males.