Embryonic Arsenic Exposure Impacts Satellite Cells

描述（由申请人提供）：砷存在于饮用水和大米中，导致全世界数百万人接触砷。在胚胎发育过程中暴露于砷与低出生体重，改变运动活动，减少体重增加，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，亚砷酸盐暴露于干细胞衍生的胚状体会降低MyoD、Myf 5和肌生成素的表达，这些都是干细胞分化为骨骼肌细胞所需的转录因子。我们还发现砷阻碍了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生期间出现，并且在以后的生活中需要新的纤维形成。我们一直在使用作为一个模式物种，以检查胚胎砷暴露后肌肉发育的变化？我们的初步数据表明，砷暴露仅在胚胎发育过程中减少体重增加的后代，甚至4个月后。这种体重增加的减少似乎是由于总肌纤维数量的减少，因为胚胎暴露的鱼在4个月大时比对照鱼少15 - 20%的纤维，即使考虑到大小的差异。因此，本申请的目的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纤维数量的机制。我们将研究从青少年时期到成年期，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，我们将确定是否暴露于低砷浓度在胚胎发育减少卫星细胞的数量和/或本地化的生物体发育成成人。这些结果将使我们能够确定卫星细胞是否被靶向，并确定肌肉质量是否受到抑制。第二个目标是确定胚胎暴露于砷的生物体是否可以在以后的生活中从肌肉损伤中恢复，这将表明胚胎发育期间的砷暴露是否具有仅在成年期才变得明显的潜在影响。我们的长期目标是了解为什么砷暴露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。这也将有助于确定是否应该制定一个食物中砷含量的标准--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.