Genetic Susceptibility to Developmental Benzo[a]pyrene Neurotoxicity

发育性苯并[a]芘神经毒性的遗传易感性

• 批准号: 10730699
• 负责人: Christine Perdan Curran
• 金额: $ 42万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-16 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730699
• 关键词: Acids; Adolescence; Adverse effects; Agonist; Animals; Area; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Award; Bacteria; Behavior; Benzo(a)pyrene; Bioinformatics; Brain; Brain region; CYP1A1 gene; CYP1A2 gene; CYP1B1 gene; Chemicals; Cigarette; Circulation; Cognition; Data; Development; Dose; Environment; Enzymes; Excretory function; Exposure to; Family; Food; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Hippocampus; Human; Human Activities; Impairment; Individual; Indoles; Institution; Kentucky; Knock-out; Knockout Mice; Kynurenine; Lactation; Learning; Life; Link; Mediating; Memory; Metabolic; Metabolism; Modeling; Motor; Mus; Neurotransmitters; Pathway interactions; Play; Population; Predisposition; Pregnancy; Problem behavior; Receptor Activation; Research; Research Personnel; Resistance; Risk; Risk Reduction; Role; Serotonin; Shotgun Sequencing; Signal Transduction; Smoke; Techniques; Testing; Tissues; Tryptophan; Universities; Wild Type Mouse; Wildfire; Work; adult neurogenesis; aryl hydrocarbon receptor ligand; behavior test; beta diversity; cigarette smoke; developmental neurotoxicity; disadvantaged student; early childhood; early life exposure; gut microbes; gut microbiome; gut-brain axis; high risk; interest; member; metabolomics; mouse model; nervous system disorder; neuroinflammation; neuroprotection; neurotoxic; neurotoxicity; novel; prenatal; pup; student training; traffic-related air pollution; undergraduate student

Project Summary. This is a renewal application of an initial award to explore genetic susceptibility to benzo[a]pyrene (BaP)-induced developmental neurotoxicity. BaP is a model polycyclic aromatic hydrocarbon found in traffic-related air pollution (TRAP), wildfire and cigarette smoke and grilled foods. Human studies have linked prenatal and early life exposure to PAHs with adverse effects on cognition and behavior persisting from early childhood to adolescence. Extensive animal studies have strongly implicated aryl hydrocarbon receptor (AHR) agonists including PAHs in developmental neurotoxicity. Our initial studies used mice with genetic differences in the AHR and two metabolic enzymes regulated by the AHR: CYP1A1 and CYP1A2. All three genes of interest vary in the human population and have been linked to adverse effects following exposure to TRAP. Data from our initial studies strongly supported our hypothesis that the AHR pathway plays a key role in mediating BaP developmental neurotoxicity. Both Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice had greater impairments in tests of learning and memory compared with wild type mice exposed to the same dose of BaP during gestation and lactation. Interestingly, we also found differences in behavior based on genotype alone in the knockout lines. This novel finding suggests both genes have a normal role in brain development or function. Both humans and mice have three members of the CYP1 family, so our future work will probe the significance of CYP1B1 and further explore mechanisms of neurotoxicity in the Cyp1a1 and Cyp1a2 knockouts. Aim 1: Determine the role of CYP1B1 in BaP neurotoxicity by comparing Cyp1b1(+/+) wild type and Cyp1b1(-/-) knockout mice using validated tests of learning & memory, behavior, and motor function, quantification of neurotransmitters and gene expression in brain regions governing those functions. Our initial studies uncovered increased susceptibility to developmental BaP exposure in mice lacking CYP1A1 and CYP1A2. These studies will allow us to complete the characterization of the entire CYP1 family in our mouse model. Aim 2: Identify changes in the gut microbiome and downstream metabolites associated with neuroprotection v neuroinflammation. During our initial studies, we were able to do an exploratory analysis of the gut microbiome in BaP-treated and control Cyp1a1(+/+) wild type and Cyp1a1(-/-) knockout dams and pups. We found significant differences in beta diversity in BaP-exposed knockouts. Using a targeted metabolomics approach, we also found striking differences in the tryptophan-kynurenine pathway in BaP treated Cyp1a2(-/-) knockout mice. These data and recent studies identifying links between AHR activation and dysregulation of the TRP-KYN pathway suggest a potential mechanism of neurotoxicity. As an AREA-R15 application, this will strengthen the research environment at Northern Kentucky University, a predominantly undergraduate institution in the Greater Cincinnati area serving a large percentage of diverse and disadvantaged students and support an Early Stage Investigator who can train these students in the use of bioinformatics techniques.

项目摘要。这是一项初始奖项的续展申请，旨在探索遗传易感性 苯并[a]芘（BaP）诱导的发育神经毒性。 BaP是一种典型的多环芳烃 存在于与交通相关的空气污染 (TRAP)、野火、香烟烟雾以及烧烤食品中。人类研究有 产前和生命早期接触多环芳烃与认知和行为的持续不利影响有关 幼儿期至青春期。广泛的动物研究强烈暗示芳基烃受体 (AHR) 激动剂，包括发育神经毒性中的多环芳烃。我们最初的研究使用了具有遗传基因的小鼠 AHR 和 AHR 调节的两种代谢酶：CYP1A1 和 CYP1A2 之间的差异。全部三个 感兴趣的基因在人群中各不相同，并且与接触后的不利影响有关 陷阱。我们最初研究的数据有力地支持了我们的假设，即 AHR 通路在 介导 BaP 发育神经毒性。 Cyp1a1(-/-) 和 Cyp1a2(-/-) 敲除小鼠均具有更大的 与暴露于相同剂量 BaP 的野生型小鼠相比，学习和记忆测试中出现损伤 在妊娠和哺乳期间。有趣的是，我们还发现仅基于基因型的行为差异 淘汰线。这一新发现表明这两个基因在大脑发育或功能中发挥着正常作用。 人类和小鼠都有 CYP1 家族的三个成员，因此我们未来的工作将探讨其意义 CYP1B1 并进一步探讨 Cyp1a1 和 Cyp1a2 敲除的神经毒性机制。目标 1： 通过比较 Cyp1b1(+/+) 野生型和 Cyp1b1(-/-) 确定 CYP1B1 在 BaP 神经毒性中的作用 使用经过验证的学习和记忆、行为和运动功能测试、量化 神经递质和控制这些功能的大脑区域的基因表达。我们的初步研究发现 缺乏 CYP1A1 和 CYP1A2 的小鼠对发育期 BaP 暴露的敏感性增加。这些研究 将使我们能够在小鼠模型中完成整个 CYP1 家族的表征。目标 2：识别 与神经保护相关的肠道微生物组和下游代谢物的变化 神经炎症。在我们的初步研究中，我们能够对肠道微生物组进行探索性分析 在 BaP 处理和对照 Cyp1a1(+/+) 野生型和 Cyp1a1(-/-) 敲除母鼠和幼崽中。我们发现显着 BaP 暴露的基因敲除中 β 多样性的差异。使用靶向代谢组学方法，我们还发现 BaP 处理的 Cyp1a2(-/-) 敲除小鼠中色氨酸-犬尿氨酸途径存在显着差异。这些数据 最近的研究确定了 AHR 激活与 TRP-KYN 通路失调之间的联系，表明 神经毒性的潜在机制。作为 AREA-R15 应用程序，这将加强研究 北肯塔基大学的环境，该大学是大辛辛那提地区的一所以本科为主的机构 为大量多元化和弱势学生提供服务并支持早期研究者的区域 谁可以培训这些学生使用生物信息学技术。