Mechanisms in Perinatal Carcinogenesis

围产期致癌机制

• 批准号: 6558898
• 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/6558898
• 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. Among the exposures of concern is environmental tobacco smoke. Cigarette smoking by fathers has been implicated in increased risk of childhood cancers in at least six epidemiological studies. We investigated transplacental oxidative DNA damage, in the form of the promutagenic DNA adduct 8-oxo-dG, in fetuses of pregnant rats exposed to environmental tobacco smoke at a concentration within the range experienced by humans. There was organ- and gestation-stage specific increase in these adducts: kidneys were affected when exposure was stopped at gestation day 16 (mid-third trimester), whereas there were increases in fetal liver and brain 8-oxo-dG when exposure continued until the end of gestation. Pregnant mothers also showed damage in liver and kidney on day 16. The increases in 8-oxo-dG were highly significant and were of the same magnitude as increases in childhood cancer risk related to paternal smoking. Another possible mechanism of paternal effects on childhood cancer is male-mediated transgenerational carcinogenesis. We have found that treatment of male mice with a carcinogen before mating leads to changes in serum corticosterone, insulin-like growth factor 1, and glucose in their offspring, assessed at ten weeks after birth. Microarray analysis of gene expression in livers and lungs of these offspring confirm that the hormone and glucose changes are associated with tissue effects that could be related to development of neoplasms. AIDS Title:

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。 关注的暴露是环境烟草烟雾。在至少六项流行病学研究中，父亲吸烟与儿童期癌症的风险增加有关。我们以正当的DNA加合物8-oxo-dg的形式研究了移植氧化DNA损伤，该损伤是在人类经历的范围内暴露于环境烟草烟雾的怀孕大鼠的胎儿。这些加合物的器官和妊娠阶段特异性增加：肾脏在妊娠第16天停止暴露时受到影响妊娠结束。怀孕的母亲在第16天还显示出肝脏和肾脏的损害。8-oxo-DG的增加非常重要，并且与与父亲吸烟有关的儿童癌症风险的增加相同。 父亲对儿童癌症影响的另一种可能的机制是男性介导的转世癌发生。我们发现，在交配导致血清皮质酮，胰岛素样生长因子1和后代的葡萄糖变化之前，用致癌物治疗雄性小鼠，在出生后十周进行评估。这些后代肝中基因表达和肺中基因表达的微阵列分析证实，激素和葡萄糖的变化与可能与肿瘤发展有关的组织效应有关。 艾滋病标题：