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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要苯并[a]芘 (BaP) 是一种已知的致癌物质，在美国政府优先考虑的物质中排名第八污染物列表中，整类化合物（多环芳烃或 PAH）排名第九。与交通相关的空气污染、野火、香烟烟雾和烧烤食品广泛导致人类暴露最近的人类研究发现，产前 PAH 之间存在很强的相关性。我们最近报告了暴露儿童的暴露情况以及持续的认知和行为缺陷。一项小鼠研究表明芳烃受体 (AHR) 和 CYP1A2 在发育过程中接触具有高亲和力的 AhrbCyp1a2(-/-) 小鼠后风险增加。具有亲和力差受体的 AHR 和 AhrdCyp1a2(-/-) 小鼠均在 Morris 中表现受损空间学习和记忆的水迷宫测试高亲和力 Ahr 基因敲除也有 Rotarod 的运动缺陷，和亲和力差的淘汰赛表现出更高水平的焦虑样行为。大脑健康已广为人知，但人们对运动对大脑健康的影响知之甚少。怀孕对母亲的健康及其后代的大脑功能运动的神经学益处。包括增加脑源性神经营养因子（BDNF）水平和有益的修饰血清素、多巴胺和去甲肾上腺素的神经信号传导有氧运动的作用机制。海马依赖性学习和记忆的益处与 BDNF 信号直接相关。和后代的运动已成功扭转由运动引起的空间学习和记忆缺陷生命早期的锻炼对于改善情绪和降低压力水平还有额外的好处。 BDNF 受体敲低的小鼠中，应激激素增加，而焦虑样行为增加 TrkB。我们在 C57BL/6J 小鼠中进行了初步研究，发现母体和后代都有自主轮。增加跑步循环 BDNF 水平。我们提出的研究将使用有氧运动来增加。在早期大脑发育过程中暴露于 BaP 的后代的 BDNF 水平，目的是拯救首先，我们将比较我们之前研究中观察到的神经功能缺陷的相对有效性。四种不同的运动疗法，并确保它们不会对母鼠或幼崽造成伤害接下来，我们将使用被确定为安全且最有效的锻炼方案，旨在挽救学习和记忆以及运动缺陷并减少我们最易受影响的小鼠系的焦虑样行为。转化价值这些研究的比例很高，因为我们试图确定产生所需的最低运动水平这大大增加了人群遵守的可行性。