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

产前砷暴露会改变角质形成细胞干细胞的命运并诱发具有更高恶性潜力的皮肤肿瘤

• 批准号: 10452209
• 负责人: MARCELO Luis RODRIGUEZ-PUEBLA
• 金额: $ 7.6万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-18 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452209
• 关键词: Address; Adult; Adult Children; Apoptotic; Area; Arsenic; Benign; CDK4 gene; Carcinogens; Cell Compartmentation; Cell Proliferation; Cellular Structures; Cyclin D1; Development; Disease; Epidermis; Etiology; Event; Exposure to; Feasibility Studies; Future; Genetic; Goals; Health; Hematopoietic stem cells; Human; Investigation; Lead; Life; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Mus; New England; Newborn Infant; Pathway interactions; Placenta; Pregnancy; Pregnant Women; Process; Reporting; Research; Research Project Grants; Role; Skin; Skin Cancer; Skin Neoplasms; Testing; Therapeutic Intervention; Time; Tissues; Transgenic Organisms; United States; United States National Institutes of Health; Up-Regulation; Work; base; carcinogenicity; cellular targeting; cocarcinogen; contaminated drinking water; drinking water; exhaustion; fetal; high risk; in utero; keratinocyte; mouse model; novel; offspring; pregnant; prenatal; prenatal exposure; response; stem cell fate; stem cell proliferation; stem cells

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.

摘要/摘要 该 R03 提案的目标是建立科学基础来了解经胎盘砷的影响 暴露对角质形成细胞干细胞（KSC）命运和皮肤肿瘤恶性率升高的影响。喝 砷水污染是一个全球性问题，也是美国某些地区的一个担忧， 特别是在西部和新英格兰的小地区。无机砷被认为是人类致癌物 与许多目标组织，包括皮肤。此前的报告显示，胎儿砷暴露量增加 小鼠皮肤肿瘤的多样性和侵袭性。砷具有经胎盘致癌活性，并且 由于干细胞（SC）在胎儿中含量丰富，因此似乎是妊娠期间的主要目标。我们已经建立了 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 显示细胞周期蛋白 D1 和 CDK4 等增殖调节因子水平升高。支持这个 观察发现，KSC 中 CDK4 的转基因表达模拟砷暴露，如减少的砷暴露所证明的 KSC 数量、良性皮肤肿瘤数量减少以及晚年恶性肿瘤发病率急剧上升。 要测试的中心假设是经胎盘砷暴露改变了增殖细胞的组成部分。 KSCs 中的通路，导致选择具有高恶性潜力的 KSCs。 因此，我们期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。