Mechanisms in Perinatal Carcinogenesis

围产期致癌机制

• 批准号: 7337845
• 负责人: Lucy M Anderson
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7337845
• 关键词: Mechanisms; Perinatal; Carcinogenesis

Perinatal exposures may lead to increased risk of childhood cancers, as well as those later in life. Preconceptional parental, transplacental, and/or neonatal exposures may be involved. Studies with animal models are utilized to increase understanding of underlying cellular and molecular mechanisms. A possible mechanism of paternal effects on childhood cancer is male-mediated transgenerational carcinogenesis. Exposure of male mice to chromium(III), an environmental/occupational metal, results in increased neoplasms and other lesions in the offspring. The nature of these changes suggested hormonal involvement, and we have discovered alterations in serum glucose, corticosterone, IGF1, and the thyroid hormone T3. It is also important to discover the molecular mechanism in the sperm, by which changes-in-gene-expression signals are passed to offspring. Use of representational difference analysis, bisulfite sequencing, and pyrosequencing has revealed hypomethylation in the spacer-promoter region of the ribosomal RNA gene in sperm from Cr(III)-treated males. Ribosomal RNA is implicated in both growth and cancer. In lung tissues of offspring, gene methylation is decreased, and ribosomal RNA increased. Further detailed characterization is in progress, as well as work with cultured mouse and human lung cells that will allow molecular manipulation and controlled endpoint analysis.Effects on offspring glucose, hormones, and body weights suggested that the Cr(III) effects could be related to energy metabolism. Therefore another protocol has been tried, involving limited diet restriction of fathers (24 hr fasting). Remarkably, this treatment 2 weeks before mating results in a highly significant reduction in average serum glucose in both male and female offspring. Alterations in offspring corticosterone, IGF1, and body weight are also noted though more variably. These results suggest that physiological transgenerational effects may be common and have implications for many widespread diseases in addition to cancer.

围产期暴露可能会导致儿童癌症以及以后生活的风险增加。可能会涉及预感的父母，移植和/或新生儿暴露。使用动物模型的研究用于增加对潜在的细胞和分子机制的理解。父亲对儿童癌症作用的可能机制是男性介导的跨代癌发生。雄性小鼠暴露于铬（III）（一种环境/职业金属）导致后代肿瘤和其他病变增加。这些变化的性质表明激素受累，我们发现了血清葡萄糖，皮质酮，IGF1和甲状腺激素T3的改变。在精子中发现分子机制也很重要，将基因表达信号传递给后代。使用代表性差异分析，亚硫酸盐测序和焦磷酸测序的使用揭示了来自CR（III）处理过的雄性精子中核糖体RNA基因的间隔促促促启动区的低甲基化。核糖体RNA与生长和癌症有关。在后代的肺组织中，基因甲基化降低，核糖体RNA增加。进一步详细的表征正在进行中，以及与培养的小鼠和人类肺细胞一起工作，这些细胞将允许分子操纵和受控终点分析。对后代葡萄糖，激素和体重的影响表明CR（III）的作用可能与CR（III）效应有关能量代谢。因此，已经尝试了另一种方案，涉及父亲的饮食限制有限（24小时禁食）。值得注意的是，在交配前2周，男性和女性后代的平均血清葡萄糖平均葡萄糖的平均葡萄糖降低了2周。尽管更可变，但也注意到后代皮质酮，IGF1和体重的改变。这些结果表明，生理跨代作用可能很常见，并且对许多广泛的疾病也具有影响。