Genetic Differences in PCB-Induced Behavior

描述(由申请人提供)：已知在环境中暴露于多氯联苯(PCB)在人类和实验室动物中会导致免疫抑制、甲状腺疾病、内分泌紊乱和中枢神经系统损伤。并不是所有的人类或实验动物对相同剂量的反应相似，这表明个体间的遗传差异。在啮齿动物中，平面多氯联苯必须与芳香烃受体(AHR)结合并激活，才能引起这些病理变化。尽管平面多氯联苯介导的AHR激活在毒性中起着压倒一切的作用，但AHR上调了CYP1A2的表达，后者在肝脏中隔离并保护远处组织免受平面多氯联苯的伤害。AHR和CYP1A2在人类中都是多态的：AHR在配体结合亲和力方面表现出12倍的差异；肝脏基础CYP1A2在未接触诱导剂的受试者中显示出60倍的差异。关于胎儿暴露，我们在小鼠身上的研究表明，平面TCDD导致出生缺陷的风险取决于高亲和力的AHR，并且在缺乏CYP1A2的母体携带的胎儿中也会大大增加。多氯联苯代表含有数十种不同同系物的混合物；哪种同系物是有毒的，很难确定人类的摄取、新陈代谢和排泄速度，而且大多数在实验室动物中的研究都着眼于单一的同系物。我们研究了具有高(Ahrb，B6)和低(B6.D2-AHRD)亲和力的AHR的小鼠，以及是否带有CYP1A2基因。通过使用这些小鼠，我们假设由CYP1A2(-/-)母猪携带的Ahrb胎儿将最容易受到平面多氯联苯引起的学习、记忆和其他行为缺陷的影响，而由CYP1A2(+/+)母鼠携带的AHRD胎儿将最具抵抗力。在资助期间，我们建议：[1]确定作为混合物给予的8个多氯联苯同系物(与人类最相关)中的每一个的组织分布-比较B6与B6.D2-AHRD，以及CYP1A2(+/+)与CYP1A2(-/-)母鼠及其后代的组织分布；[2]从出生后60天开始，评估口服多氯联苯混合物对这些受试者后代的学习、记忆和其他行为的宫内和哺乳期影响。这些研究将确定胎儿基础对成人疾病的影响。这些小鼠的AhR和CYP1A2基因类型代表了这两个基因在人类群体中变异的极端。在老鼠(和人类)种群中存在遗传差异，这代表了高危个体的梯度。项目简介：多氯联苯(PCB)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，包括接触过的母亲的孩子出现学习和记忆障碍。在我们的小鼠模型中，AhR和CYP1A2基因代表了这两个基因在人类群体中变异的极端，这两个基因可能在多氯联苯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，并有助于识别多氯联苯引起神经毒性的最大风险个体。

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.