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

摘要/摘要 R03建议的目标是建立一个科学基础，以了解经胎盘砷的影响 暴露于角质形成干细胞(KSC)的命运和皮肤肿瘤恶化率的升高。喝酒 水砷污染是一个全球性的问题，在美国一些地区也令人担忧， 尤其是在西部和新英格兰的一些小地区。无机砷被认为是一种人类致癌物质 有许多目标组织，包括皮肤。此前的报告表明，胎儿接触砷会增加 小鼠皮肤肿瘤的多样性和侵袭性。砷具有经胎盘致癌活性， 由于其丰富的胎儿，干细胞(SCs)似乎是怀孕期间的主要目标。我们已经确立了 孕妇饮水中的胎儿砷暴露会导致子代KSCS降低。对这些问题的分析 KSCS显示细胞周期蛋白D1和CDK4等增殖调节因子水平升高。支持这一点 观察到，CDK4在KSCS中的转基因表达模拟了砷的暴露，证明了 KSCs的数量，良性皮肤肿瘤的数量减少，以及晚年恶化率的严重上升。 需要检验的中心假设是，经胎盘暴露的砷改变了增生剂的成分 KSCs中的途径，导致了具有高恶性潜能的KSCs的选择。 因此，我们期待这项提议中提出的工作将为今后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.