Prenatal Arsenic Exposure Alters Keratinocyte Stem Cells' Fate and Induces Skin Tumors with Higher Malignant Potential

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SUMMARY/ABSTRACT The goal of this R03 proposal is to establish a scientific basis to understand the effect of transplacental arsenic exposure on keratinocyte stem cells (KSC) fate and the elevated rate of malignancy of skin tumors. Drinking water contamination with arsenic is a global problem and a concern in some areas of the United States, especially in the West and small areas of New England. Inorganic arsenic is considered a human carcinogen with many target tissues, including the skin. Previous reports have shown that fetal arsenic exposure increases the multiplicity and aggressiveness of mouse skin tumors. Arsenic has transplacental carcinogenic activity, and since its fetal abundance, stem cells (SCs) seem to be the main target during gestation. We have established that fetal arsenic exposure via maternal drinking water leads to decreased KSCs in offspring. Analysis of these KSCs shows increased levels of proliferative regulators such as cyclin D1 and CDK4. Supporting this observation, transgenic expression of CDK4 in KSCs mimics arsenic exposure as demonstrated by the reduced number of KSCs, decreased number of benign skin tumors, and severe rise in the rate of malignancy later in life. The central hypothesis to be tested is transplacental arsenic exposure alters components of the proliferative pathway in KSCs, leading to the selection of KSCs with high malignant potential. Thus, we expect that the work proposed in this proposal will open new research avenues for future studies to provide new cellular targets for therapeutic interventions.