Mitigating Developmental Neurotoxicity Through Maternal and Offspring Exercise

项目概要/摘要 苯并[a]芘（BaP）是一种已知的致癌物质，在美国政府的优先级中排名第八 而整个化合物类别（多环芳烃或PAH）排名第9。 人类暴露于与交通有关的空气污染，野火，香烟烟雾和烧烤食品中 几乎不可能避免最近的人类研究发现，产前PAH与 暴露和持续的认知和行为缺陷暴露的儿童。我们最近报告了 一项小鼠研究表明，芳香烃受体（AHR）和 CYP 1A 2增加发育暴露于BaP后的风险。AhrbCyp 1a 2（-/-）小鼠与高亲和力 具有低亲和力受体的AHR和AhrdCyp 1a 2（-/-）小鼠在Morris中的表现都受损。 水迷宫空间学习记忆试验。高亲和力Ahr敲除在转棒中也有运动缺陷， 而亲和力差的敲除表现出更高水平的焦虑样行为。定期锻炼的好处 大脑健康已经得到了很好的建立，但对运动的影响知之甚少。 怀孕对母亲的健康和她后代的大脑功能的影响。运动对神经系统的益处 包括脑源性神经营养因子（BDNF）水平的增加和 由血清素、多巴胺和去甲肾上腺素传递的神经信号。有氧运动的作用机制 对海马依赖性学习和记忆的益处与BDNF信号直接相关。母体 和后代的运动已经成功地逆转了空间学习和记忆缺陷诱导的 产前压力在生命的早期进行锻炼对改善情绪和降低血糖水平有额外的好处。 而在BDNF受体敲低的小鼠中，焦虑样行为增加 TrkB。我们在C57 BL/6 J小鼠中进行了初步研究，发现母体和后代的自主轮 血液中的脑源性神经营养因子水平升高我们建议的研究将使用有氧运动来增加 在早期脑发育过程中暴露于BaP的后代的BDNF水平，目的是拯救 在我们之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 运动方案被确定为安全且最有效的，以试图挽救学习和记忆， 运动缺陷和减少焦虑样行为在我们最易感的小鼠品系。 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。 有益效果。这大大增加了人群依从性的可行性。

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.