Genetic Differences in PCB-Induced Behavior

PCB 引起的行为的遗传差异

基本信息

  • 批准号:
    7384892
  • 负责人:
  • 金额:
    $ 24.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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):已知人类和实验室动物在环境中接触多氯联苯(PCB)会导致免疫抑制、甲状腺疾病、内分泌紊乱和中枢神经系统损伤。并非所有的人类或实验室动物对相同剂量的反应都相似--这表明个体间的遗传差异。在啮齿类动物中,平面多氯联苯必须结合并激活芳烃受体(AHR)才能引发这些病理。尽管平面PCB介导的AHR激活在毒性中具有压倒性的作用,但AHR上调CYP 1A 2,CYP 1A 2在肝脏中隔离并保护远端组织免受平面PCB的侵害。AHR和CYP 1A 2在人类中都是多态性的:AHR在配体结合亲和力方面表现出>12倍的差异;肝脏基础CYP 1A 2在没有已知暴露于诱导剂的受试者中表现出>60倍的差异。关于胎儿暴露,我们在小鼠中的研究表明,平面TCDD的出生缺陷的风险取决于高亲和力AHR,也大大增加了缺乏CYP 1A 2的母鼠所携带的胎儿。多氯联苯是由几十种不同同系物组成的混合物;哪种同系物有毒,人体的吸收、代谢和排泄率难以确定,大多数实验室动物研究都着眼于单一同系物。我们研究了具有高(Ahrb,B6)与低(B6.D2-Ahrd)亲和力AHR的小鼠,以及具有或不具有Cyp 1a 2基因的小鼠。使用这些小鼠,我们假设Cyp 1a 2(-/-)母鼠携带的Ahrb胎儿最容易受到影响,Cyp 1a 2(+/+)母鼠携带的Ahrd胎儿最抵抗,对平面PCB引起的学习,记忆和其他行为的缺陷。在资助期内,我们建议:[1]确定八种多氯联苯同系物的组织分布情况(与人类最相关)作为混合物给予-比较B6与B6.D2-Ahrd,Cyp 1a 2(+/+)与Cyp 1a 2(-/-)母鼠及其后代;和[2]评价这种口服PCB混合物对学习,记忆,以及这些处理母鼠的后代在出生后第60天开始的其他行为。这些研究将确定胎儿基础对成人疾病的影响。这些小鼠中的Ahr和Cyp 1a 2基因型代表了这两种基因在人群中的极端变异性。在小鼠(和人类)群体中存在遗传差异,这代表了风险个体的梯度。项目叙述:多氯联苯(PCBs)是一种广泛存在的持久性有机污染物,与许多人类健康问题有关,包括母亲接触的儿童的学习和记忆缺陷。我们的小鼠模型中的Ahr和Cyp 1a 2基因型代表了这两个基因在人群中变异性的极端,这两个基因可能在PCB暴露后的易感性中发挥作用。这些研究将确定成人疾病的胎儿基础,并有助于确定受多氯联苯诱导的神经毒性影响风险最大的个体。

项目成果

期刊论文数量(0)
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Daniel W. Nebert其他文献

Further Studies on Genetically Mediated Differences in Monooxygenase Activities and Spin State of Cytochrome P<sub>450</sub> Iron from Rabbit, Rat, and Mouse Liver
  • DOI:
    10.1016/s0021-9258(19)43238-9
  • 发表时间:
    1973-11-25
  • 期刊:
  • 影响因子:
  • 作者:
    Daniel W. Nebert;Joseph R. Robinson;Hideo Kon
  • 通讯作者:
    Hideo Kon
Aryl Hydrocarbon Hydroxylase Induction in Mammalian Liver Cell Culture: III. EFFECTS OF VARIOUS SERA, HORMONES, BIOGENIC AMINES, AND OTHER ENDOGENOUS COMPOUNDS ON THE ENZYME ACTIVITY
  • DOI:
    10.1016/s0021-9258(19)44566-3
  • 发表时间:
    1972-12-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jacques E. Gielen;Daniel W. Nebert
  • 通讯作者:
    Daniel W. Nebert
Measurements of the cytosolic Ah receptor among four strains of Drosophila melanogaster
  • DOI:
    10.1007/bf00295157
  • 发表时间:
    1985-02-01
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Sanford W. Bigelow;Jakob A. Zijlstra;Ekkehart W. Vogel;Daniel W. Nebert
  • 通讯作者:
    Daniel W. Nebert
Genetic Regulation of Aryl Hydrocarbon Hydroxylase Induction: V. SPECIFIC CHANGES IN SPIN STATE OF CYTOCHROME P<sub>450</sub> FROM GENETICALLY RESPONSIVE ANIMALS
  • DOI:
    10.1016/s0021-9258(19)44459-1
  • 发表时间:
    1973-01-10
  • 期刊:
  • 影响因子:
  • 作者:
    Daniel W. Nebert;Hideo Kon
  • 通讯作者:
    Hideo Kon
Genetic Expression of Aryl Hydrocarbon Hydroxylase Induction: EVIDENCE FOR THE INVOLVEMENT OF OTHER GENETIC LOCI
  • DOI:
    10.1016/s0021-9258(20)79896-0
  • 发表时间:
    1974-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Joseph R. Robinson;Noreen Considine;Daniel W. Nebert
  • 通讯作者:
    Daniel W. Nebert

Daniel W. Nebert的其他文献

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{{ truncateString('Daniel W. Nebert', 18)}}的其他基金

Gene-Environment Interactinos Training Program
基因-环境相互作用培训计划
  • 批准号:
    7464173
  • 财政年份:
    2008
  • 资助金额:
    $ 24.56万
  • 项目类别:
Gene-Environment Interactinos Training Program
基因-环境相互作用培训计划
  • 批准号:
    7647114
  • 财政年份:
    2008
  • 资助金额:
    $ 24.56万
  • 项目类别:
Gene-Environment Interactinos Training Program
基因-环境相互作用培训计划
  • 批准号:
    7885547
  • 财政年份:
    2008
  • 资助金额:
    $ 24.56万
  • 项目类别:
Gene-Environment Interactinos Training Program
基因-环境相互作用培训计划
  • 批准号:
    8103268
  • 财政年份:
    2008
  • 资助金额:
    $ 24.56万
  • 项目类别:
Genetic Differences in PCB-Induced Behavior
PCB 引起的行为的遗传差异
  • 批准号:
    7540365
  • 财政年份:
    2007
  • 资助金额:
    $ 24.56万
  • 项目类别:
Human HNSCC: CYP1B1/1A1/1A2 and AHR Gene Polymorphisms
人类 HNSCC:CYP1B1/1A1/1A2 和 AHR 基因多态性
  • 批准号:
    7392834
  • 财政年份:
    2006
  • 资助金额:
    $ 24.56万
  • 项目类别:
Human HNSCC: CYP1B1/1A1/1A2 & AHR Gene Polymorphisms
人类 HNSCC:CYP1B1/1A1/1A2
  • 批准号:
    7092720
  • 财政年份:
    2006
  • 资助金额:
    $ 24.56万
  • 项目类别:
PAHs: Balance of Detoxication vs Metabolic Activation
PAH:解毒与代谢激活的平衡
  • 批准号:
    7188660
  • 财政年份:
    2006
  • 资助金额:
    $ 24.56万
  • 项目类别:
PAHs: Balance of Detoxication vs Metabolic Activation
PAH:解毒与代谢激活的平衡
  • 批准号:
    7354105
  • 财政年份:
    2006
  • 资助金额:
    $ 24.56万
  • 项目类别:
PAHs: Balance of Detoxication vs Metabolic Activation
PAH:解毒与代谢激活的平衡
  • 批准号:
    7018611
  • 财政年份:
    2006
  • 资助金额:
    $ 24.56万
  • 项目类别:

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