Endogenous HOCl-derived chloramines in skin inflammation and photocarcinogenesis

/ ABSTRACT Human skin is ubiquitously exposed to solar ultraviolet (UV) radiation, other environmental toxicants, and combinations thereof. Solar radiation is a potent environmental human carcinogen. Cutaneous exposure to solar ultraviolet (UV) radiation is a causative factor in skin photocarcinogenesis, and nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States with increasing incidence, a public health burden of considerable magnitude. In search of relevant environmental co-exposures that might modulate skin stress responses to solar UV, we have focused recently on skin chlorination, a largely understudied environmental exposure in the context of drinking water and recreational freshwater disinfection operative on a global scale. Our unpublished research has identified a novel chlorination product, chloro-cis-urocanic acid (Cl-cis-UCA), detectable in human skin upon co-exposure to solar UV and HOCl. Trans-urocanic acid (trans-UCA) is a major filaggrin-derived skin chromophore undergoing photoisomerization upon exposure to solar UV causing the formation of the bio-active mediator cis-urocanic acid (cis-UCA) in human skin. Even though a critical role of cis- UCA in the modulation of skin photodamage, photoimmunosuppression, and photocarcinogenesis is firmly established, occurrence and function of the novel UCA-derivative Cl-cis-UCA remain undefined. In this exploratory R21 project entitled ‘Endogenous HOCl-derived chloramines in skin inflammation and carcinogenesis’ we propose investigations focusing on this novel, heretofore unrecognized skin chloramine component (Cl-cis-UCA), formed uniquely upon co-exposure to solar UV and environmental chlorination stress. Our goal of investigating its cutaneous occurrence and potential role in skin photodamage, photoimmunosuppression, and photocarcinogenesis is pursued as follows: Aim #1 explores occurrence and function of Cl-cis-UCA in organotypic human epidermal reconstructs exposed to the isolated and combined action of solar UV and environmental chlorination stress. The analytical method pursued here is based on non- invasive tape stripping followed by Cl-cis-UCA detection amenable to rapid human translation. Aim #2 explores the role of Cl-cis-UCA exposure in established murine models of solar UV-induced photodamage (sunburn and inflammation), systemic photoimmunosuppression, and photocarcinogenesis. Given the ubiquitous nature of solar UV and chlorination stress co-exposure experienced by human skin worldwide, examining formation and function of the novel skin chlorination photoproduct Cl-cis-UCA in relevant skin models of photodamage and photocarcinogenesis addresses an urgent need to define the role of this intermediate in human skin originating from a ubiquitous environmental co-exposure. Based on our novel analytical approach and functional studies, Cl-cis-UCA might be recognized to play a role as a novel exposure biomarker, molecular target, and mediator of cutaneous responses relevant to human skin. Project Number: 1R21CA299160-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Georg Wondrak | Institution: UNIVERSITY OF ARIZONA, TUCSON, AZ | Award Amount: $399,712 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-N (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11282709