Mitigating Developmental Neurotoxicity Through Maternal and Offspring Exercise

通过母亲和后代运动减轻发育神经毒性

• 批准号: 10725969
• 负责人: Christine Perdan Curran
• 金额: $ 14万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725969
• 关键词: Adverse effects; Aerobic Exercise; Affinity; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Behavior; Behavioral; Benzo(a)pyrene; Biochemical; Brain; Brain-Derived Neurotrophic Factor; CYP1A2 gene; Carcinogens; Chemicals; Child; Cognitive; Data; Development; Dopamine; Ensure; Exercise; Exhibits; Exposure to; Food; Gene Expression; General Population; Genetic; Genetic Predisposition to Disease; Genetic study; Goals; Government; Health; Hippocampus; Hormones; Human; Impairment; Intervention; Knock-out; Lead; Learning; Life; Literature; Memory; Memory impairment; Methods; Modification; Molecular; Moods; Mothers; Motor; Mus; Neurologic; Neurologic Deficit; Neurological outcome; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 2; Norepinephrine; Performance; Pilot Projects; Plasma; Population; Predisposition; Pregnancy; Regimen; Reporting; Risk; Running; Serotonin; Signal Transduction; Stress; Testing; Wildfire; anxiety reduction; anxiety-like behavior; brain health; cigarette smoke; developmental neurotoxicity; early life exposure; exercise intensity; exercise regimen; exposed human population; health of the mother; improved; knock-down; morris water maze; motor deficit; mouse model; offspring; pollutant; prenatal; prenatal stress; pup; receptor; relative effectiveness; traffic-related air pollution

Project Summary/Abstract Benzo[a]pyrene (BaP) is a known carcinogen and ranked 8th on the U.S. government’s Priority Pollutants List while the entire class of compounds (polycyclic aromatic hydrocarbons or PAHs) ranks 9th. Human exposures are widespread from traffic-related air pollution, wildfires, cigarette smoke, and grilled foods and nearly impossible to avoid. Recent human studies found strong correlations between prenatal PAH exposure and persistent cognitive and behavioral deficits in exposed children. We recently reported results from a mouse study demonstrating that genetic differences in the aryl hydrocarbon receptor (AHR) and CYP1A2 increase risk following developmental exposure to BaP. AhrbCyp1a2(-/-) mice with the high-affinity AHR and AhrdCyp1a2(-/-) mice with the poor-affinity receptor both had impaired performance in the Morris water maze test of spatial learning and memory. High-affinity Ahr knockouts also had motor deficits in Rotarod, and poor-affinity knockouts exhibited higher levels of anxiety-like behavior. The benefits of regular exercise on brain health are well established, but considerably less is known about the effects of exercise during pregnancy on the health of the mother and brain function in her offspring. The neurological benefits of exercise include increased levels of brain-derived neurotrophic factor (BDNF) and beneficial modifications of neurosignaling by serotonin, dopamine and noradrenaline. The mechanism of action for aerobic exercise benefits on hippocampal dependent learning and memory were directly tied to BDNF signaling. Both maternal and offspring exercise have been successful in reversing spatial learning and memory deficits induced by prenatal stress. Exercise during early life has additional benefits on improving mood and reducing levels of stress hormones whereas anxiety-like behavior is increased in mice with a knockdown of the BDNF receptor TrkB. We conducted pilot studies in C57BL/6J mice and found that both maternal and offspring voluntary wheel running increased circulating BDNF levels. Our proposed studies will use aerobic exercise to increase BDNF levels in offspring exposed to BaP during early brain development with the goal of rescuing the neurological deficits observed in our previous studies. First, we will compare the relative effectiveness of four different exercise treatments and ensure they do not cause harm to the dam or pups. Next, we will use the exercise regimen determined to be safe and most effective in an attempt to rescue learning and memory and motor deficits and to reduce anxiety-like behavior in our most susceptible mouse lines.The translational value of these studies is high, because we seek to identify the minimum level of exercise necessary to produce beneficial effects. This greatly increases the feasibility of compliance in the human population.

项目摘要/摘要 Benzo [A] Pyrene（BAP）是已知的致癌物，在美国政府的优先级排名第八 污染物列出了整个化合物（多环芳烃或PAHS）的整个类别排名第9。 人类的暴露与交通相关的空气污染，野火，香烟烟和烤食品广泛存在 几乎不可能避免。最近的人类研究发现产前PAH之间有很强的相关性 暴露和持续的认知和行为定义了暴露的儿童。我们最近报道了结果 从一项小鼠研究中表明，芳基烃受体（AHR）和 CYP1A2增加了BAP发育的风险。 AHRBCYP1A2（ - / - ）具有高亲和力的小鼠 AHR和AHRDCYP1A2（ - / - ）具有较差的亲密受体的小鼠都在莫里斯的表现受损 空间学习和记忆的水迷宫测试。高亲和力AHR淘汰也有电动机在rotarod中定义 较差的亲密敲除暴露于焦虑状的行为水平更高。定期锻炼的好处 大脑健康已经建立得很好，但对运动的影响少得多 怀孕对母亲的健康和后代的功能。运动的神经功效 包括脑衍生的神经营养因子（BDNF）的水平增加以及对 5-羟色胺，多巴胺和去甲肾上腺素的神经信号。有氧运动的作用机制 海马依赖学习和记忆的好处直接与BDNF信号联系在一起。两者都是母亲 后代练习已经成功地扭转了空间学习和记忆的定义 产前压力。早年的锻炼在改善情绪和降低水平方面还有其他好处 压力骑马，而击倒BDNF受体的小鼠中焦虑样行为则增加 trkb。我们在C57BL/6J小鼠中进行了试点研究，发现母乳和后代自愿车轮 运行增加了循环的BDNF水平。我们提出的研究将使用有氧运动来增加 在早期大脑发育期间，后代的BDNF水平，目的是营救 在我们以前的研究中观察到的神经缺陷。首先，我们将比较 四种不同的运动治疗，并确保它们不会对大坝或幼崽造成伤害。接下来，我们将使用 锻炼方案确定为安全，最有效，以挽救学习和记忆和记忆和 电动机定义并减少我们最易感的鼠标线中的动画样行为。翻译值 这些研究很高，因为我们试图确定生产所需的最低练习水平 有益的效果。这大大提高了遵守人口的可行性。