Mechanisms in Perinatal Carcinogenesis

围产期致癌机制

• 批准号: 7965021
• 负责人: Lucy M Anderson
• 金额: $ 68.99万
• 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/7965021
• 关键词: Acids; Adolescent; Adult; Adult Children; Affect; Alleles; Animal Model; Appearance; Attention; Bacteria; Bacterial Toxins; Birth; Bladder; Body Weight; Breeding; Carcinogens; Carcinoma; Chemicals; Child; Childhood; Chromium; Chronic; Chronic viral hepatitis; Corticosterone; DNA Damage; Development; Disease; Distant; Embryo; End Point Assay; Environment; Epidemiology; Etiology; Event; Exposure to; Fathers; Feces; Female; Gene Conversion; Gene Expression; Generations; Genes; Genetic Polymorphism; Genomics; Glucose; Growth; Helicobacter; Helicobacter hepaticus; Helicobacter pylori; Hematopoietic; Hepatic; Hepatitis; Hormonal; Human; IGF1 gene; Immune Tolerance; Incidence; Individual; Infant; Infection; Infectious Agent; Inflammation; Inherited; Insulin; Intervention; Intraperitoneal Injections; Laboratory mice; Lead; Leptin; Lesion; Life; Light; Liver; Liver neoplasms; Lung; Lymphoma; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Metals; Methylation; Modeling; Molecular; Molecular Analysis; Mothers; Mouse Strains; Mus; Nature; Neonatal; Neoplasms; Occupational; Parasites; Parents; Perinatal; Perinatal Carcinogenesis; Perinatal Exposure; Pregnant Women; Preventive; Promoter Regions; Protocols documentation; Relative (related person); Research; Ribosomal RNA; Risk; Saline; Serum; Signal Transduction; Single Nucleotide Polymorphism; Site; Stomach; Testing; Time; Tissues; Triiodothyronine; Virus; Virus Diseases; Weight; bisulfite; cancer risk; carcinogenesis; experience; exposed human population; fetal; human disease; liver infection; male; malignant stomach neoplasm; neonatal exposure; offspring; oxidative DNA damage; promoter; rRNA Genes; representational difference analysis; sperm cell; stressor; tumor; tumorigenesis; young adult

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. We have been focusing on two aspects of perinatal carcinogenesis: (1) exposure of mice during early life to a bacterium, resulting in development of liver tumors; and (2) transgenerational effects of exposures and experiences of male mice on tumorigenesis and other endpoints in offspring. (1) Perinatal exposure required for marked increase in liver tumors associated with infection by Helicobacter hepaticus. The bacterium Helicobacter hepaticus, a relative of the human stomach carcinogenic bacterium Helicobacter pylori, occurs as a natural liver infection in mouse colonies and causes liver tumors, associated with a long period of hepatic inflammation. However, Helicobacter hepaticus injected into adult mice causes few liver tumors. Early hepatic changes occurred, including an increase in oxidative DNA damage in livers, but later resolved, even though bacteria were still found in feces. These results suggested that the mice successfully defended against the liver attack by the bacteria. We pursued the hypothesis that perinatal exposure was required for tumors to develop. We found that liver tumors could be caused to develop by establishing the infection by intraperitoneal injection of female mice, then breeding these. Multiple liver tumors, including carcinoma, occurred in 40% of their male offspring. There was typical Helicobacter-associated hepatitis in these livers. Interestingly, other protocols that resulted in weaker infection, including intragastric infection of the mothers, and infection via feces in dirty cages, resulted in comparable levels of hepatitis, but few or no tumors. Thus hepatitis was separable from tumorigenesis, just as chronic viral hepatitis in humans does not always lead to liver cancer. Perinatal acquisition of the infection from strongly infected mothers, probably just after birth, established conditions that resulted months later in appearance of liver tumors. DNA damage by a bacterial toxin in the vulnerable neonatal liver, and/or induction of immune tolerance, may be among the important factors. We have established a model that can be used to explore such questions. Our results also point to the perinatal period as a particularly critical time in the acquisition of chronic human infections that are associated with cancer, including hepatic viruses, stomach bacteria, and bladder parasites. In addition, viruses are postulated to contribute to causation of childhood hematopoietic and neurogenic neoplasms. (2) Male mediated transgenerational effects: consequences of stressors. 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 in the offspring. 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 (rRNA) gene in sperm from Cr(III)-treated males. Ribosomal RNA is implicated in both growth and cancer. To test whether paternally-mediated effects are inherited by offspring, we have examined the gene in embryos and in tissues of young adult offspring, including liver and lung. Extensive statistical analyses of large numbers of litters and of offspring are now almost completed, and some surprising and interesing results are clear. Acidic saline, used as a vehicle for the Cr(III), also has had transgenerational effects. Importantly, offspring body weights and liver weights have been significantly increased as a result of the paternal treatments. The potential significance of this for several human diseases in addition to cancer is obvious. At the molecular level in studies of rRNA, single nucleotide polymorphisms, including one in the spacer-promoter and four alleles in the main promoter of the rRNA gene, are involved. The ratio of the alleles for the main promoter was actually changed by exposure of the fathers, selectively in the offspring lungs. This suggests tissue-specific genomic effects, either selective allelic expansion or gene conversion. If confirmed it will be a qualitatively new finding. The nature of the allele in the main promoter correlated with degree of methylation at five CpG sites in the spacer-promoter, in a tissue specific way. Degree of methylation was significantly affected by the paternal chromium treatment, in male offspring lungs. Importantly, these relationships between gene polymorphisms and gene methylation at a distant regulatory site were significantly modulated by treatment of the fathers. Since both the chromium(III), and the acid saline vehicle administered as a control, had clear effects, we looked for general, stressor-type effects in the males. Both chemical treatments were found to be stressors of the fathers, causing changes in serum corticosterone, insulin, leptin and glucose. Assay of these endpoints in the offspring serum is in progress, as is molecular analysis of F2 tissues, to see if the changes may be transmissable to further generations. Potential implications of these various effects for humans are obvious and worth detailed study.

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。我们一直关注围产期致癌的两个方面：（1）小鼠在生命早期接触细菌，导致肝脏肿瘤的发展； (2)雄性小鼠的暴露和经历对后代肿瘤发生和其他终点的跨代影响。 (1) 与肝螺杆菌感染相关的肝脏肿瘤显着增加所需的围产期暴露。肝螺杆菌是人类胃部致癌细菌幽门螺杆菌的近亲，在小鼠群体中以自然肝脏感染的形式发生，并导致肝脏肿瘤，并与长期的肝脏炎症有关。然而，将肝螺杆菌注射到成年小鼠体内很少会引起肝脏肿瘤。早期肝脏发生了变化，包括肝脏氧化 DNA 损伤增加，但后来得到了解决，尽管粪便中仍然发现了细菌。这些结果表明小鼠成功抵御了细菌对肝脏的攻击。我们提出了这样的假设：肿瘤的形成需要围产期暴露。我们发现，通过给雌性小鼠腹腔注射建立感染，然后繁殖这些小鼠，可以引起肝脏肿瘤的发生。 40% 的雄性后代出现多种肝脏肿瘤，包括癌。这些肝脏中有典型的螺杆菌相关性肝炎。有趣的是，其他导致较弱感染的方案，包括母亲的胃内感染和通过肮脏笼子中的粪便感染，导致肝炎水平相当，但很少或没有肿瘤。 因此，肝炎与肿瘤发生是分开的，就像人类慢性病毒性肝炎并不总是导致肝癌一样。围产期从严重感染的母亲那里获得感染（可能是在出生后），形成了导致几个月后出现肝脏肿瘤的条件。脆弱的新生儿肝脏中细菌毒素造成的 DNA 损伤和/或免疫耐受的诱导可能是重要因素之一。我们建立了一个可以用来探索此类问题的模型。我们的研究结果还表明，围产期是获得与癌症相关的慢性人类感染（包括肝病毒、胃细菌和膀胱寄生虫）的特别关键时期。此外，病毒被认为是导致儿童造血和神经源性肿瘤的原因。 (2) 男性介导的跨代效应：压力源的后果。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。这些变化的本质表明与激素有关，我们发现后代的血清葡萄糖、皮质酮、IGF1 和甲状腺激素 T3 发生了变化。发现精子中基因表达信号变化传递给后代的分子机制也很重要。使用代表性差异分析、亚硫酸氢盐测序和焦磷酸测序揭示了经 Cr(III) 处理的男性精子中核糖体 RNA (rRNA) 基因的间隔启动子区域的低甲基化。 核糖体 RNA 与生长和癌症有关。为了测试父系介导的效应是否会遗传给后代，我们检查了胚胎和年轻成年后代组织（包括肝脏和肺）中的基因。对大量幼崽和后代的广泛统计分析现已基本完成，一些令人惊讶和有趣的结果已经很明显。酸性盐水用作 Cr(III) 的载体，也具有跨代效应。重要的是，由于父亲的治疗，后代的体重和肝脏重量显着增加。除癌症外，这对于多种人类疾病的潜在意义是显而易见的。在rRNA研究的分子水平上，涉及单核苷酸多态性，包括rRNA基因间隔启动子中的一个和主启动子中的四个等位基因。主要启动子等位基因的比例实际上是通过父亲的暴露而改变的，选择性地在后代肺部。这表明组织特异性基因组效应，要么是选择性等位基因扩增，要么是基因转换。如果得到证实，这将是一个质的新发现。主启动子中等位基因的性质与间隔启动子中五个 CpG 位点的甲基化程度以组织特异性方式相关。雄性后代肺部的甲基化程度受到父系铬处理的显着影响。重要的是，基因多态性和远距离调控位点的基因甲基化之间的关系受到父亲治疗的显着调节。由于铬（III）和作为对照的酸性盐水载体均具有明显的效果，因此我们在男性中寻找一般的应激源类型的效果。研究发现，这两种化学治疗都会给父亲带来压力，导致血清皮质酮、胰岛素、瘦素和葡萄糖发生变化。对后代血清中这些终点的测定正在进行中，F2 组织的分子分析也在进行中，以观察这些变化是否可以遗传给后代。这些不同影响对人类的潜在影响是显而易见的，值得详细研究。