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提案的目的是建立科学依据，以了解移植砷的影响 在角质形成细胞细胞（KSC）命运和皮肤肿瘤恶性肿瘤率升高上暴露。喝 在美国某些地区，对砷的水污染是一个全球问题，也是一个关注 特别是在新英格兰的西部和小地区。无机砷被认为是人类致癌物 有许多靶组织，包括皮肤。先前的报告表明，胎儿砷的暴露增加 小鼠皮肤肿瘤的多样性和侵略性。砷具有移植致癌活性，并且 由于其胎儿丰度，干细胞（SC）似乎是妊娠期间的主要目标。我们已经建立了 通过母体饮用水暴露的胎儿砷暴露导致后代的KSC降低。这些分析 KSC显示了增生性调节剂（例如细胞周期蛋白D1和CDK4）的水平。支持这个 观察，Cdk4在KSC中的转基因表达模拟砷暴露，如降低所证明的 KSC的数量，良性皮肤肿瘤的数量减少以及生命后期恶性肿瘤的严重上升。 要测试的中心假设是移植砷暴露改变了增殖的成分 KSC中的途径，导致选择具有高恶性潜力的KSC。 因此，我们预计该提议中提出的工作将为以后的研究开放新的研究途径 为治疗干预提供新的细胞靶标。