Embryonic Arsenic Exposure Impacts Satellite Cells

描述(申请人提供)：在饮用水和大米中发现砷，导致世界各地数百万人接触到砷。在胚胎发育期间暴露于砷与低出生体重、运动活动改变和体重增加减少有关，这可能是因为骨骼肌祖细胞的数量减少。事实上，我们的数据表明，亚砷酸盐暴露在干细胞来源的类胚体中会降低MyoD、Myf5和Mygenin的表达，这些都是干细胞分化为骨骼肌细胞所需的转录因子。我们还表明，砷阻碍了心肌细胞分化为成熟肌管的能力。肌肉祖细胞或卫星细胞在胚胎发育过程中出现，并在以后的生命中需要新纤维的形成。我们一直以剑鱼为模式物种，研究胚胎砷暴露后肌肉发育的变化。我们的初步数据表明，只有在胚胎发育期间接触亚砷酸盐，即使在4个月后，子代的体重增加也会减少。体重增加的减少似乎是由于肌肉纤维总数的减少，因为胚胎暴露的鱼在4个月龄时的纤维比对照鱼少15%-20%，即使考虑到大小的差异。因此，这项应用的目标是通过确定卫星或肌肉干细胞的数量、位置和功能来评估砷减少肌肉纤维数量的机制。我们将研究从青少年时期到成年，以及在正常发育和受伤后恢复期间的这些过程。在第一个目标中，我们将确定在胚胎发育过程中暴露在低浓度亚砷酸盐下是否会减少有机体发育成成体后卫星细胞的数量和/或定位。这些结果将使我们能够确定卫星细胞是否成为靶点，并确定肌肉质量是否受到抑制。第二个目标是确定在胚胎阶段暴露于砷的生物是否能够在以后的生命中从肌肉损伤中恢复过来，这将表明胚胎发育期间暴露于砷的潜在影响是否只有在成年后才会显现出来。我们的长期目标是了解为什么接触砷的人群肌肉发育缺陷的风险增加，以及这如何导致功能变化，如体重增加减少。它还将有助于确定是否应该为食物中的砷水平设定一个标准--一个保护胚胎健康的标准。

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.