Genetic Differences in PCB-Induced Behavior

PCB 引起的行为的遗传差异

• 批准号: 7384892
• 负责人: Daniel W. Nebert
• 金额: $ 24.56万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384892
• 关键词: Address; Adult; Affect; Affinity; Amnesia; Animals; Aroclor; Aroclors; Aromatic Hydrocarbons; Aryl Hydrocarbon Receptor; Barker Hypothesis; Behavior; Binding; Biological Models; CYP1A2 gene; Chemicals; Child; Chronic; Class; Complex Mixtures; Confusion; Congenital Abnormality; Data; Dioxins; Disease; Distant; Dose; Dreams; Drowsiness; Drug Kinetics; Drug or chemical Tissue Distribution; Eating; Endocrine disruption; Environment; Environmental Exposure; Environmental Pollutants; Excretory function; Exhibits; Exposure to; Fetus; Fishes; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Halogens; Health; Hepatic; Human; Hyperactive behavior; Immunosuppression; Individual; Japan; Laboratory Animals; Lead; Learning; Ligand Binding; Link; Liver; Mammals; Measures; Mediating; Memory; Memory impairment; Metabolism; Mothers; Mus; Nervous System Trauma; Neuraxis; Pathology; Patient currently pregnant; Perinatal Exposure; Play; Polybrominated Biphenyls; Polychlorinated Biphenyls; Population; Positioning Attribute; Predisposition; Preventive; Public Health; Rate; Receptor Activation; Resistance; Risk; Rodent; Role; Structure-Activity Relationship; Tetrachlorodibenzodioxin; Therapeutic Intervention; Therapeutic immunosuppression; Thyroid Diseases; Tissues; Toxic effect; carcinogenicity; day; diphenyl; embryo/fetus; fetal; human AHR protein; human study; immunotoxicity; improved; in utero; mouse model; neurotoxicity; pollutant; postnatal; response; uptake; Address; Adult; Affect; Affinity; Amnesia; Animals; Aroclor; Aroclors; Aromatic Hydrocarbons; Aryl Hydrocarbon Receptor; Barker Hypothesis; Behavior; Binding; Biological Models; CYP1A2 gene; Chemicals; Child; Chronic; Class; Complex Mixtures; Confusion; Congenital Abnormality; Data; Dioxins; Disease; Distant; Dose; Dreams; Drowsiness; Drug Kinetics; Drug or chemical Tissue Distribution; Eating; Endocrine disruption; Environment; Environmental Exposure; Environmental Pollutants; Excretory function; Exhibits; Exposure to; Fetus; Fishes; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Halogens; Health; Hepatic; Human; Hyperactive behavior; Immunosuppression; Individual; Japan; Laboratory Animals; Lead; Learning; Ligand Binding; Link; Liver; Mammals; Measures; Mediating; Memory; Memory impairment; Metabolism; Mothers; Mus; Nervous System Trauma; Neuraxis; Pathology; Patient currently pregnant; Perinatal Exposure; Play; Polybrominated Biphenyls; Polychlorinated Biphenyls; Population; Positioning Attribute; Predisposition; Preventive; Public Health; Rate; Receptor Activation; Resistance; Risk; Rodent; Role; Structure-Activity Relationship; Tetrachlorodibenzodioxin; Therapeutic Intervention; Therapeutic immunosuppression; Thyroid Diseases; Tissues; Toxic effect; carcinogenicity; day; diphenyl; embryo/fetus; fetal; human AHR protein; human study; immunotoxicity; improved; in utero; mouse model; neurotoxicity; pollutant; postnatal; response; uptake

DESCRIPTION (provided by applicant): Environmental exposures to polychlorinated biphenyls (PCBs) are known in humans as well as lab animals to cause immunosuppression, thyroid disease, endocrine disruption, and damage to the central nervous system. Not all humans or laboratory animals respond similarly to the same dose -indicating interindividual genetic differences. In rodents to elicit these pathologies, planar PCBs must bind to, and activate, the aryl hydrocarbon receptor (AHR). Despite this overriding role for planar-PCB-mediated AHR activation in toxicity, the AHR up-regulates CYP1A2, which in liver sequesters and protects distant tissues against planar PCBs. Both the AHR and CYP1A2 are polymorphic in humans: the AHR exhibits >12-fold differences in ligand-binding affinity; liver basal CYP1A2 shows >60-fold differences in subjects having no known exposure to inducers. With regard to fetal exposure, our studies in mice demonstrate that risk of birth defects by planar TCDD depends on the high-affinity AHR and is also greatly increased in fetuses carried by dams that lack CYP1A2. PCBs represent mixtures having many dozens of different congeners; which congener is toxic, and the rates of uptake, metabolism and excretion are difficult to determine in humans, and most studies in lab animals look at a single congener. We have studied mice with the high- (Ahrb, B6) vs low- (B6.D2-Ahrd) affinity AHR, and with or without the Cyp1a2 gene. Using these mice, we hypothesize that Ahrb fetuses carried by Cyp1a2(-/-) dams will be most susceptible, and Ahrd fetuses carried by Cyp1a2(+/+) dams most resistant, to deficits in learning, memory, and other behaviors caused by planar PCBs. For the funding period, we propose to: [1] determine tissue distribution of each of eight PCB congeners (most relevant to humans) given as a mixture -comparing B6 vs B6.D2-Ahrd, and Cyp1a2(+/+) vs Cyp1a2(-/-) dams and their offspring; and [2] evaluate the in utero and lactational effects of this orally administered PCB mixture on learning, memory, and other behaviors in offspring of these treated dams, starting at postnatal day 60. These studies will define the impact of a fetal basis for adult disease. The Ahr and Cyp1a2 genotypes in these mice represent the extremes for variability of these two genes in the human population. There exist genetic differences in mouse (and human) populations, which represent a gradient of at-risk individuals. Project Narrative: Polychlorinated biphenyls (PCBs) are widespread persistent organic pollutants linked to numerous human health problems, including learning and memory deficits in children of exposed mothers. The Ahr and Cyp1a2 genotypes in our mouse models represent the extremes for variability in these two genes in the human population, and both genes likely play a role in susceptibility following PCB exposure. These studies will define the fetal basis for adult disease and help to identify individuals at greatest risk of PCB-induced neurotoxicity.

描述（由申请人提供）：在人类和实验室动物中已知对多氯联苯（PCB）的环境暴露，以引起免疫抑制，甲状腺疾病，内分泌干扰和对中枢神经系统的损害。并非所有人类或实验动物都对相同剂量的构成个体遗传差异的反应类似。在引发这些病理的啮齿动物中，平面PCB必须与芳基烃受体（AHR）结合并激活。尽管Planar-PCB介导的AHR激活在毒性中的重要作用，但AHR上调了CYP1A2，在肝脏隔离器中，CYP1A2在毒性中，并保护远处的组织免受平面PCB的影响。 AHR和CYP1A2在人类中都是多态性的：AHR在配体结合亲和力的差异> 12倍。肝脏基底CYP1A2显示未知诱导剂的受试者的差异> 60倍。关于胎儿暴露，我们在小鼠中的研究表明，平面TCDD出生缺陷的风险取决于高亲和力AHR，并且缺乏CYP1A2的大坝携带的胎儿也大大增加了。 PCB代表具有数十个不同同类物的混合物。同类物是有毒的，并且在人类中很难确定摄取，代谢和排泄的速率，而实验室动物的大多数研究都看着一个同类物。我们已经使用高（AHRB，B6）与低 - （B6.D2-AHRD）亲和力AHR研究了小鼠，并且有或没有CYP1A2基因。我们假设使用这些小鼠，CYP1A2（ - / - ）大坝携带的AHRB胎儿将最易感，而CYP1A2（+/+）大坝携带的AHRD胎儿对学习，记忆和其他由平面PCB引起的学习，记忆和其他行为。在资金期间，我们建议：[1]确定八个PCB同类物（与人类最相关的）的组织分布，作为混合物的B6与B6.D2-AHRD和CYP1A2（+/+）与CYP1A2（ - / - ）大坝及其后代的组织分布； [2]评估这种口服的PCB混合物对这些经过治疗的大坝后代学习，记忆和其他行为的子宫内和泌乳作用，始于第60天。这些研究将定义胎儿对成人疾病的影响。这些小鼠中的AHR和CYP1A2基因型代表了人群中这两个基因的变异性的极端。小鼠（和人类）种群中存在遗传差异，这代表了处于危险的个体的梯度。项目叙述：多氯联苯（PCB）是与许多人类健康问题相关的广泛持久性有机污染物，包括学习和暴露母亲的儿童的记忆缺陷。我们的小鼠模型中的AHR和CYP1A2基因型代表了人群这两个基因的极端变异性，并且这两个基因在PCB暴露后可能在易感性中起作用。这些研究将定义成人疾病的胎儿基础，并有助于鉴定有PCB诱导的神经毒性风险最大的个体。