Mechanisms in Perinatal Carcinogenesis

围产期致癌机制

• 批准号: 6949809
• 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/6949809
• 关键词: chemical carcinogenesis; chromium; disease /disorder model; environment related neoplasm /cancer; laboratory mouse; methylation; microarray technology; pediatric neoplasm /cancer; representational difference analysis; ribosomal RNA

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. Microarray analysis has been utilized to identify hepatic genes whose expression changes correlate with differences in serum T3; these have included a number of genes related to growth and to tumor suppression. It is also important to discover the molecular mechanism in the sperm, by which changes-in-gene-expression signals are passed to offspring. A representational difference analysis technique has been utilized to screen for genes with altered methylation, a common mechanism for epigenetic control of gene expression. The gene for ribosomal RNA has been found to be hypomethylated in the sperm of Cr(III)-treated males, a result confirmed by bisulfite sequencing. Ribosomal RNA is implicated in both growth and cancer. Investigation of altered expression in offspring tissues is in progress. Once this molecular marker is confirmed, the hypothesis can be extended to human studies.

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。微阵列分析已用于识别其表达变化与血清T3差异相关的肝基因。这些包括许多与生长和抑制肿瘤有关的基因。 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。一种代表性差异分析技术已用于筛选甲基化改变的基因，这是基因表达表观遗传控制的常见机制。核糖体RNA的基因已被发现在CR（III）处理的雄性精子中降低了甲基化，这一结果通过亚硫酸盐测序证实。核糖体RNA与生长和癌症有关。研究后代组织中表达改变的研究正在进行中。一旦确认了该分子标记，该假设就可以扩展到人类研究。