Embryonic Arsenic Exposure Impacts Satellite Cells

胚胎砷暴露影响卫星细胞

• 批准号: 8822357
• 负责人: LISA J BAIN
• 金额: $ 7.1万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822357
• 关键词: Accounting; Actins; Adolescent; Adult; Age-Months; Animals; Arsenic; Arsenites; Cell physiology; Cleaved cell; Collagen; Cyprinodontidae; Data; Defect; Development; Direct Lytic Factors; Dose; Embryo; Embryonic Development; Exposure to; Fiber; Fishes; Food; Fundulus heteroclitus; Goals; Health; In Vitro; Injury; Insulin-Like Growth Factor I; Laboratories; Life; Link; Location; Low Birth Weight Infant; Modeling; Motor Activity; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle satellite cell; Myoblasts; Myogenin; Organism; Population; Prevalence; Process; Publishing; Recovery; Rice; Risk; Skeletal Muscle; Stem cells; Testing; Toxic effect; Toxicant exposure; Water; Weight; Weight Gain; Work; adverse outcome; caspase-3; drinking water; experience; macrophage; muscle form; muscle regeneration; offspring; public health relevance; satellite cell; skeletal muscle differentiation; transcription factor

DESCRIPTION (provided by applicant): Arsenic is found in drinking water and rice, resulting in exposure to millions of people throughout the world. Exposure to arsenic during embryogenesis is associated with low birth weight, altered locomotor activity, and reduced weight gain, likely because of reductions in the number of skeletal muscle progenitor cells. Indeed, our data indicate that arsenite exposure to stem cell-derived embryoid bodies reduces the expression of MyoD, Myf5, and myogenin, all transcription factors needed to differentiate stem cells into skeletal myocytes. We have also shown that arsenic impedes the ability of myocytes to differentiate into mature myotubes. Muscle progenitor cells, or satellite cells, arise during embryogenesis and are needed for new fiber formation later in life. We have been using the killifish as a model species to examine changes in muscle development following embryonic arsenic exposure. Our preliminary data indicates that arsenite exposure only during embryogenesis reduces weight gain in offspring even 4 months later. This reduced weight gain appears to be due to reductions in the total muscle fiber numbers, as embryonically-exposed fish have 15-20% less fibers than control fish at 4 months of age, even when accounting for difference in size. Thus, the goal of this application is to assess the mechanism by which arsenic reduces muscle fiber number by determining the number, location, and function of satellite or muscle stem cells. We will examine these processes from the juvenile period and into adulthood, and during both normal development and during recovery after an injury. In the first aim, we will determine whether exposure to low arsenite concentrations during embryogenesis reduces the number and/or localization of the satellite cells as the organism develops into an adult. These results will enable us to determine if the satellite cells are targeted, and also determine whether muscle mass is inhibited. The goal of the second aim is to determine whether organisms exposed embryonically to arsenic can recover from a muscle injury later in life, which will indicate whether arsenic exposure during embryogenesis has latent effects that only become apparent in adulthood. Our long-term objective is to understand why arsenic-exposed populations are at increased risk for defects in muscle development, and how this leads to functional changes such as reduced weight gain. It will also help to determine whether a standard for arsenic levels in food should be set - one that will be protective of embryonic health.

描述（由申请人提供）：在饮用水和大米中发现了砷，导致全世界数百万的人接触。胚胎发生过程中暴露于砷与低出生体重，运动活性改变和体重增加有关，这可能是由于骨骼肌祖细胞数量减少。实际上，我们的数据表明，砷暴露于干细胞衍生的胚胎体会降低MyOD，MyF5和肌蛋白的表达，将干细胞分化为骨骼肌细胞所需的所有转录因子。我们还表明，砷阻碍了肌细胞区分为成熟的肌管的能力。肌肉祖细胞或卫星细胞在胚胎发生过程中出现，生命后期需要新的纤维形成。我们一直在使用Killifish作为模型物种来检查胚胎砷暴露后肌肉发育的变化。我们的初步数据表明，仅在胚胎发生期间，仅在4个月后的后代中，砷的暴露才会减少后代的体重增加。减轻的体重增加似乎是由于总肌肉纤维数量减少，因为胚胎暴露的鱼的纤维比对照鱼在4个月大时的纤维少15-20％，即使在大小差异的情况下也是如此。因此，该应用的目的是评估砷通过确定卫星或肌肉干细胞的数量，位置和功能来减少肌肉纤维数的机制。我们将研究这些过程从少年时期到成年期，以及在正常发育期间和受伤后康复期间。在第一个目标中，我们将确定在胚胎发生过程中暴露于低砷浓度是否会随着生物体发展成成人的卫星细胞的数量和/或定位。这些结果将使我们能够确定是否靶向卫星细胞，并确定是否抑制肌肉质量。第二个目的的目的是确定胚胎暴露于砷的生物是否可以在以后的生活中从肌肉损伤中恢复，这将表明胚胎发生过程中的砷暴露是否具有潜在作用，而这种作用只有在成年后才会显而易见。我们的长期目标是了解为什么砷暴露的人群会增加肌肉发育中缺陷的风险，以及这如何导致功能变化，例如减轻体重增加。它还将有助于确定是否应该设定食物中的砷水平的标准 - 一种保护胚胎健康的标准。