Mitigating Developmental Neurotoxicity Through Maternal and Offspring Exercise

项目摘要/摘要 苯并[a]芘(BaP)是一种已知的致癌物质，在美国政府的优先事项中排名第八 污染物排行榜，而整个类别的化合物(多环芳烃或多环芳烃)排在第9位。 与交通有关的空气污染、野火、香烟烟雾和烧烤食品是人类广泛接触的来源。 而且几乎是无法避免的。最近的人体研究发现，产前PAH与 暴露与暴露儿童持续的认知和行为缺陷。我们最近公布了结果 从一项小鼠研究中发现，芳香烃受体(AHR)和 CYP1A2增加了发育过程中暴露于BaP的风险。AhrbCyp1a2(-/-)小鼠具有高亲和力 具有低亲和力受体的AHR和AhrdCyp1a2(-/-)小鼠在Morris中的表现都受到损害 水迷宫空间学习记忆测试。高亲和力的AhR基因敲除者在旋转棒中也有运动缺陷， 亲和力差的基因敲除者表现出更高水平的焦虑样行为。经常锻炼身体的好处 大脑健康是众所周知的，但人们对运动的影响知之甚少。 怀孕对母亲的健康和后代的大脑功能都有影响。运动对神经系统的益处 包括脑源性神经营养因子(BDNF)水平的提高和有益的修改 通过5-羟色胺、多巴胺和去甲肾上腺素传递神经信号。有氧运动的作用机制 对海马区依赖学习和记忆的益处直接与BDNF信号联系在一起。都是母性的 和后代锻炼成功地逆转了空间学习和记忆障碍 产前压力。早年锻炼对改善情绪和降低体重指数有额外好处。 应激激素而焦虑样行为在BDNF受体被敲除的小鼠中增加 TrkB。我们在C57BL/6J小鼠身上进行了初步研究，发现母鼠和子鼠的自愿轮 跑步增加了循环中的BDNF水平。我们提议的研究将使用有氧运动来增加 在大脑发育早期暴露于BaP的子代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，我们将比较两种方法的相对有效性。 四种不同的运动疗法，并确保它们不会对水坝或幼崽造成伤害。接下来，我们将使用 被确定为安全和最有效的运动养生法，试图挽救学习和记忆 运动缺陷和减少我们最敏感的小鼠品系中的焦虑样行为。 这些研究的比例很高，因为我们试图确定产生 有益的影响。这大大增加了在人类人口中遵守的可行性。

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.