Embryonic Arsenic Exposure Impacts Satellite Cells

描述（由申请人提供）：砷在饮用水和大米中被发现，导致全世界数百万人接触到砷。胚胎发生期间接触砷与低出生体重、运动活动改变和体重增加减少有关，这可能是由于骨骼肌祖细胞数量减少所致。事实上，我们的数据表明，亚砷酸盐暴露于干细胞衍生的胚胎样体会降低MyoD、Myf5和肌原蛋白的表达，这些转录因子都是干细胞分化为骨骼肌细胞所需的。我们还表明，砷阻碍肌细胞分化成成熟肌管的能力。肌肉祖细胞或卫星细胞在胚胎形成过程中产生，并在生命后期形成新的纤维。我们一直在使用鳉鱼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，即使在4个月后，仅在胚胎发生期间接触亚砷酸盐也会减少后代的体重增加。体重增加的减少似乎是由于总肌纤维数量的减少，因为胚胎期接触的鱼在4个月大的时候比对照鱼的纤维少15-20%，即使考虑到尺寸的差异。因此，本应用的目的是通过确定卫星细胞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。我们将研究这些过程，从青少年时期到成年期，在正常发育和受伤后恢复期间。在第一个目标中，我们将确定胚胎发生期间暴露于低亚砷酸盐浓度是否会在生物体发育成成人时减少卫星细胞的数量和/或定位。这些结果将使我们能够确定卫星细胞是否成为目标，并确定肌肉质量是否受到抑制。第二个目标是确定胚胎期暴露于砷的生物体在以后的生命中是否可以从肌肉损伤中恢复过来，这将表明胚胎发生期间暴露于砷是否具有仅在成年期才显现的潜在影响。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制定食品中砷含量的标准——一个将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.