Mechanisms in Perinatal Carcinogenesis

围产期致癌机制

• 批准号: 6761533
• 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/6761533
• 关键词: DNA damage; adduct; cancer risk; carcinogenesis; carcinogens; chromium; drug related neoplasm /cancer; embryo /fetus toxicology; environmental exposure; gene environment interaction; gene mutation; hormone regulation /control mechanism; infant animal; laboratory mouse; laboratory rat; nitrosamines; pediatric neoplasm /cancer; perinatal; placental transfer; tobacco abuse

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. We have found that exposures of fathers to chromium(III) results in a highly significant 2-fold increase in average corticosterone in serum. Serum glucose was also significantly altered. Microarray analysis revealed hepatic insulin-like growth factor binding protein 1 (IGF BP1) as an important component of the effect. Hepatic IGF BP1 mRNA correlated strongly and positively with serum glucose in offspring of chromium-treated fathers, but negatively in offspring of control fathers. These results confirm striking effects of paternal exposures on hormonal and physiological parameters in offspring. Microarray was also utilized to study possible effects of chromium(III) on gene expression on Sertoli cells in culture; these cells might mediate the transgenerational effect in testis. Methods were developed for assessing the statistical significance of small changes in gene expression by microarray. The largest change was upregulation of the redox sensitive transcription factor, Bach 2. This can be pursued with in vivo studies.

围产期接触可能会导致儿童期以及晚年罹患癌症的风险增加。可能涉及孕前父母、经胎盘和/或新生儿的暴露。利用动物模型研究来增进对潜在细胞和分子机制的理解。 父亲对儿童癌症的影响的一个可能机制是男性介导的跨代致癌。雄性小鼠接触铬（III）（一种环境/职业金属）会导致后代肿瘤和其他病变增加。这些变化的性质表明荷尔蒙的参与。我们发现，父亲接触三价铬会导致血清中平均皮质酮显着增加 2 倍。血清葡萄糖也显着改变。微阵列分析显示肝脏胰岛素样生长因子结合蛋白 1 (IGF BP1) 是该效应的重要组成部分。在铬处理父亲的后代中，肝脏 IGF BP1 mRNA 与血糖呈强烈正相关，但在对照父亲的后代中呈负相关。这些结果证实了父亲暴露对后代荷尔蒙和生理参数的显着影响。 微阵列也被用来研究铬(III)对培养的支持细胞基因表达的可能影响；这些细胞可能介导睾丸中的跨代效应。开发了通过微阵列评估基因表达微小变化的统计显着性的方法。最大的变化是氧化还原敏感转录因子 Bach 2 的上调。这可以通过体内研究来实现。