Early Disease Biomarkers of PCB-exposed Human Population

接触 PCB 人群的早期疾病生物标志物

• 批准号: 7631158
• 负责人: SISIR K DUTTA
• 金额: $ 41.63万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631158
• 关键词: Adverse effects; Affinity; Age; Aliquot; Animals; Area; Binding; Biochemical; Biological; Biological Markers; Birth; Birth Rate; Birth Weight; Blood; Blood - brain barrier anatomy; Blood specimen; Body Burden; CYP1A1 gene; California; Candidate Disease Gene; Cell Respiration; Cell physiology; Cells; Cessation of life; Chemicals; Child; Chronic; Chronic Disease; Clinical; Clinical Markers; Cognitive; Control Groups; Cytochrome P450; Data; Databases; Developed Countries; Developing Countries; Development; Disease; District of Columbia; Dose; Early Diagnosis; Early identification; Early treatment; Endocrine Disruptors; Endocrine disruption; Enrollment; Environmental Exposure; Epidemiologic Studies; Epidemiology; Evaluation; Exposure to; Fetus; Fibrosis; Freezing; Functional RNA; Funding; Future; Gene Expression; Genes; Genomics; Goals; Growth; Health; Health system; Hormones; Human; Human Genome; Immune response; Impaired cognition; In Vitro; Individual; Infant; Liver; Longitudinal Studies; Measures; Mediating; Medical; Microarray Analysis; Mitochondria; Motor Neuron Disease; Newborn Infant; Oligonucleotide Microarrays; Oxidative Stress; Pathogenesis; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Placenta; Plants; Poisoning; Polychlorinated Biphenyls; Population; Population Study; Prealbumin; Predisposition; Primary carcinoma of the liver cells; Principal Investigator; Process; Production; Publishing; Randomized; Relative (related person); Reporting; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Serum; Slovakia; Stable Disease; Staging; Stress; Techniques; Testing; Thyroid Hormones; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; United States National Institutes of Health; Universities; Validation; Work; base; candidate marker; cohort; comparative; data sharing; design; early childhood; exposed human population; fetal; fetal polychlorinated biphenyl exposure; gene environment interaction; genetic risk factor; genome-wide; human disease; human subject; improved; in vitro testing; kidney cell; neurobehavioral; neurodevelopment; non-genetic; polycystic liver disease; population based; postnatal; prenatal; prenatal exposure; programs; receptor; repository; response; tool; toxicant; wasting

DESCRIPTION (provided by applicant): Current studies suggest that several human diseases involve gene-environment interaction. Polychlorinated biphenyls (PCBs) are neurodevelopmental and immunological toxicants in experimental animals treated prenatally. Association with neurobehavioral deficits is found in some but not in all epidemiological studies of environmental exposures, with data suggesting the prenatal period to be the most sensitive. The majority of the studies evaluating the impact of PCBs on chronic health conditions, however, have been epidemiological. The proposed study therefore evaluates prenatal and postnatal PCB exposure in relation to identification of disease biomarkers through particular gene expressions at birth and at early childhood. The purpose of this research is to identify biomarkers for PCB induced diseases through gene expression studies that can be used globally in the future for early diagnosis of diseases in humans following environmental stress. This proposal hypothesizes that exposure to PCBs for individuals in the Michalovce district of the Slovak Republic is associated with diseases caused by oxidative stresses, endocrine disruption, and mitochondrial poisoning. This hypothesis is based on the following observations. First, there are several PCBs and metabolites of PCBs that have been isolated from human blood and tissues, and the gene cytochrome P450 (CYP1A1), which mediates production of OH-PCB by oxidative metabolism, has been found to be 65-fold increased by PCB-77 in cellular studies in vitro in the Pi's lab. Second, these metabolites are able to transmit across the placental barrier and be transferred to the human fetus. Third, with few exceptions, most adverse effects of background levels of PCBs were primarily related to prenatal exposure. Reported effects of background exposures in infants include reduced birth weight, less postnatal growth, impaired development, impaired immune-response, and lower thyroid hormone level. It is unknown whether these effects are caused by the PCBs themselves or by their metabolites. Fourth, high affinity binding of hydroxylated PCBs to Transthyretin (TTR) results in selective delivery of these hormones over the blood-brain barrier and over the placenta to the fetal compartment where they produce a hypothyroid effect. Fifth, in vitro tests with human liver and kidney cells clearly show that PCBs alter gene expression which has been connected with specific diseases. These diseases are not related to non-genetic factors, and Sixth, several animal and epidemiological studies suggest that prenatal exposure to PCBs and related compounds results in lower birth rates. The aims to achieve our goal in this proposal are AIM 1: To refine and confirm prior genome-wide gene expression patterns upon exposure of PCBs or its metabolites in human Peripheral Blood Mononuclear Cells (PBMC) (in vitro) to correlate risk to that of PCBs. AIM 2: To obtain genomic biomarkers of diseases caused by PCBs or its metabolites in early childhood. AIM 3: to validate candidate biomarkers in randomized studies in large scale population studies. The goal would be to improve our ability to study this process in its early stages before the clinical sign arises. These personalized measures of exposures will be combined with genomic information to decipher environmental and genetic risk factors for disease development and progression. Affymetrix oligonucleotide arrays, followed by real-time RT-PCR will be used for human gene expression studies. Epidemiological studies will include the current body burden, and time-dependent changes in congener profiles in longitudinal studies in newborn babies using Slovak population. The Slovak population is the worst hit by the PCBs comparing any other parts of the world. Besides, co-principal investigators have excellent epidemiological database funded by US-NIH, which provide unique opportunities for the proposed genomic biomarkers using PCB-exposed human population. The complementary database will be established to find correlation of PCBs and disease development for comparative statistical analysis. The proposed collaborative studies are expected to facilitate ongoing epidemiological and health effect studies of polychlorinated biphenyls (PCBs) to develop early disease biomarkers and are important for understanding the potential health risk from these compounds in general. This research will also reside with its ability to use non-invasive gene expression tools to study the early pathogenesis of the disease and to help the nation develop early intervention for multiple chronic disease that continue to burden our health system.

描述（由申请人提供）： 目前的研究表明，一些人类疾病涉及基因-环境相互作用。多氯联苯（PCBs）是产前处理的实验动物神经发育和免疫毒性物质。与神经行为缺陷的关联被发现在一些但不是所有的环境暴露的流行病学研究，数据表明，产前时期是最敏感的。然而，大多数评估多氯联苯对慢性健康状况影响的研究都是流行病学研究。因此，拟议的研究评估出生前和出生后的多氯联苯接触有关的疾病生物标志物，通过特定的基因表达在出生时和幼儿期。本研究的目的是通过基因表达研究确定PCB诱导疾病的生物标志物，这些生物标志物可在未来全球范围内用于环境压力下人类疾病的早期诊断。该提案假设斯洛伐克共和国米哈洛夫采地区的个人接触多氯联苯与氧化应激、内分泌紊乱和线粒体中毒引起的疾病有关。这一假设基于以下观察。首先，从人体血液和组织中分离出几种PCB和PCB的代谢物，在Pi实验室的体外细胞研究中，发现通过氧化代谢介导OH-PCB产生的基因细胞色素P450（CYP 1A 1）被PCB-77增加了65倍。其次，这些代谢物能够穿过胎盘屏障并转移到人类胎儿。第三，除了少数例外，多氯联苯背景水平的大多数不利影响主要与产前接触有关。据报告，背景照射对婴儿造成的影响包括出生体重减轻、出生后生长迟缓、发育受损、免疫反应受损和甲状腺激素水平降低。目前尚不清楚这些影响是由多氯联苯本身还是其代谢物引起的。第四，羟基化多氯联苯与甲状腺素运载蛋白（TTR）的高亲和力结合导致这些激素选择性地越过血脑屏障和胎盘到达胎儿室，在那里它们产生甲状腺功能减退的作用。第五，对人类肝脏和肾脏细胞的体外试验清楚地表明，多氯联苯改变了与特定疾病有关的基因表达。这些疾病与非遗传因素无关，第六，一些动物和流行病学研究表明，产前接触多氯联苯和相关化合物会导致出生率降低。我们的目标是实现我们的目标，在这一建议的目的1：完善和确认先前的全基因组基因表达模式后，暴露的多氯联苯或其代谢物在人外周血单核细胞（PBMC）（体外），以关联风险的多氯联苯。目的2：获得儿童早期多氯联苯及其代谢产物所致疾病的基因组生物标志物。目的3：在大规模人群研究的随机研究中验证候选生物标志物。我们的目标是提高我们在临床症状出现之前的早期阶段研究这一过程的能力。这些个性化的暴露措施将与基因组信息相结合，以破译疾病发展和进展的环境和遗传风险因素。将使用亲和寡核苷酸阵列，然后进行实时RT-PCR，用于人类基因表达研究。流行病学研究将包括目前的身体负荷，以及在斯洛伐克人口中对新生儿进行的纵向研究中同系物概况随时间的变化。与世界其他地区相比，斯洛伐克人口受到多氯联苯的影响最严重。此外，共同主要研究者拥有由US-NIH资助的优秀流行病学数据库，这为使用PCB暴露人群的拟议基因组生物标志物提供了独特的机会。将建立补充数据库，以找到多氯联苯与疾病发展的相关性，进行比较统计分析。预计拟议的合作研究将促进正在进行的多氯联苯（PCB）的流行病学和健康影响研究，以开发早期疾病生物标志物，并对了解这些化合物的潜在健康风险具有重要意义。这项研究还将利用非侵入性基因表达工具来研究疾病的早期发病机制，并帮助国家制定对继续给我们的卫生系统带来负担的多种慢性疾病的早期干预措施。