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

总结/摘要 本R 03提案的目标是建立科学依据，以了解经胎盘砷的影响 暴露对角质形成细胞干细胞（KSC）的命运和皮肤肿瘤的恶性率升高。饮用 砷对水的污染是一个全球性的问题， 特别是在西部和新英格兰的小地区。无机砷被认为是一种人类致癌物质 包括皮肤在内的许多目标组织。以前的报告显示，胎儿砷暴露增加， 小鼠皮肤肿瘤的多样性和侵袭性。砷具有经胎盘致癌活性， 由于干细胞在胎儿期大量存在，因此干细胞似乎是妊娠期的主要靶点。我们建立 胎儿通过母亲饮用水接触砷会导致后代KSC减少。分析这些 KSC显示增殖调节因子如细胞周期蛋白D1和CDK 4的水平增加。支持这一 通过观察，KSC中CDK 4的转基因表达模拟砷暴露，如通过降低的 KSC的数量，良性皮肤肿瘤的数量减少，以及在以后的生活中恶性肿瘤的发病率严重上升。 待检验的中心假设是经胎盘砷暴露改变了增殖性甲状腺肿的成分。 在KSC中，这是一个重要的信号通路，导致选择具有高恶性潜能的KSC。 因此，我们希望本提案中提出的工作将为未来的研究开辟新的研究途径， 为治疗干预提供新的细胞靶点。

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.