Mechanisms of Methylmercury Toxicity in Neuromuscular Development

甲基汞对神经肌肉发育的毒性机制

• 批准号: 9275979
• 负责人: MATTHEW D RAND
• 金额: $ 34.64万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275979
• 关键词: Address; Adhesions; Adult; Advocate; Animal Model; Behavior; Behavioral; Biological Assay; Biological Models; Cell Adhesion Molecules; Cell Line; Cell Lineage; Cells; Child; Chimeric Proteins; Cognitive deficits; Consumption; Defect; Development; Diet; Drosophila genus; Eating; Embryo; Enhancers; Exhibits; Experimental Models; Fishes; Frequencies; Gene Activation; Gene Expression; Gene Targeting; Genes; Health; Health Priorities; In Vitro; Infant; Life; Mammals; Mediating; Mesoderm; Methylmercury Compounds; Molecular; Molecular Genetics; Morphogenesis; Motor; Motor Neurons; Mus; Muscle; Muscle Development; Muscle Fibers; Muscle function; Myoblasts; Myofibrils; Nervous system structure; Neurologic Deficit; Neurons; Nutrient; Outcome; Pathway interactions; Phenotype; Predisposition; Pregnant Women; Proteins; Resources; Risk; Role; Severities; Signal Pathway; Signal Transduction; Sum; System; Testing; Tissues; Toxic Environmental Substances; Toxic effect; Translating; adverse outcome; fetal; fly; genome wide association study; methylmercury exposure; motor deficit; motor neuron development; mouse model; myogenesis; neuromuscular; neurotoxicity; notch protein; novel; postnatal; prenatal; public health priorities; public health relevance; stem; toxicant

 DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a persistent environmental toxicant that has long been understood to target the developing nervous system. Understanding the risks of MeHg versus the benefits of essential nutrients that come with eating fish requires a greater understanding of the mechanisms by which MeHg induces neurological deficits during development. Fetal MeHg exposure can elicit both motor and cognitive deficits in infants and young children. Yet, the possibility that motor deficits stem from altered muscle development has been largely overlooked. In this proposal we will characterize an apparent role of embryonic muscle as a MeHg target, thereby extending the fundamental domain of MeHg neurotoxicity to the developing motor unit. This study is guided by our earlier discoveries in Drosophila that MeHg can activate developmental signaling through the Notch receptor pathway, specifically up-regulating the Notch target gene enhancer of split mDelta (E(spl)mδ). We also find that MeHg has a propensity to disrupt muscle development in the embryo in parallel with its effects on developing motor neurons. We now show that E(spl)mδ is intrinsically expressed in the embryonic mesoderm and myogenic lineages and that, akin to MeHg exposure, enhanced E(spl)mδ expression in the embryo induces a somatic muscle phenotype and corresponding defects in motor neuron outgrowth. Through a genome wide association analysis (GWA) we have uncovered numerous fundamental muscle development genes that associate with tolerance to MeHg, notably, the Kirre cell adhesion protein, a core component of myoblast fusion in myofibril formation. Thus, our overall hypothesis is that MeHg perturbation of myogenesis contributes to abnormal neuromuscular development leading to motor deficits. This hypothesis poses several fundamental questions that we will address through four Specific Aims. In Aim 1 we will determine the fundamental role of myogenesis as a MeHg target in neuromuscular development in the embryo. In Aim 2 we characterize further the role of Notch signaling as an adverse outcome pathway of MeHg toxicity in neuromuscular development. For Aim 3 we will interrogate the function of the myoblast fusion protein Kirre as moderator of MeHg effects on myoblast fusion in neuromuscular development. In Aim 4 we translate our findings to the mouse and investigate mammalian corollaries for muscle-intrinsic defects in cultured myoblasts and prenatally MeHg-exposed mice. In sum, this study will significantly advance the current understanding of how motor deficits are likely to arise from early life MeHg exposure and thereby inform both the experimental toxicologist and the clinician on the potential for a myopathic component of MeHg neurotoxicity.

 描述（由申请人提供）：甲基汞（MeHg）是一种持久性环境毒物，长期以来一直被认为针对发育中的神经系统。要了解甲基汞的风险与吃鱼带来的基本营养素的益处，就需要更好地了解甲基汞在发育过程中引起神经缺陷的机制。胎儿接触甲基汞可导致婴幼儿出现运动和认知缺陷。然而，运动缺陷源于肌肉发育改变的可能性在很大程度上被忽视了。在这项建议中，我们将描述一个明显的作用，胚胎肌肉作为一个甲基汞的目标，从而扩展的基本域甲基汞神经毒性的发展中的运动单位。这项研究是基于我们在果蝇中的早期发现，即甲基汞可以通过Notch受体途径激活发育信号，特别是上调Notch靶基因分裂mDelta增强子（E（spl）mδ）。我们还发现，甲基汞有一种倾向，破坏肌肉发育的胚胎在平行其对发展中的运动神经元的影响。我们现在发现，E（spl）mδ在胚胎中胚层和肌源性谱系中固有地表达，并且类似于甲基汞暴露，胚胎中增强的E（spl）mδ表达诱导体细胞肌肉表型和运动神经元生长的相应缺陷。通过全基因组关联分析（GWA），我们已经发现了许多基本的肌肉发育基因与耐受甲基汞，特别是Kirre细胞粘附蛋白，肌原纤维形成成肌细胞融合的核心组成部分。因此，我们的总体假设是，甲基汞扰动的肌肉有助于异常的神经肌肉发育，导致运动缺陷。这一假设提出了几个基本问题，我们将通过四个具体目标来解决这些问题。在目标1中，我们将确定作为甲基汞在胚胎神经肌肉发育中的目标的肌生成的基本作用。在目标2中，我们进一步表征Notch信号传导作为神经肌肉发育中甲基汞毒性的不良结局途径的作用。对于目标3，我们将询问成肌细胞融合蛋白Kirre的功能作为调节剂的甲基汞对成肌细胞融合的神经肌肉发育。在目标4中，我们将我们的发现转化为小鼠，并研究培养的成肌细胞和产前暴露于甲基汞的小鼠中肌肉内在缺陷的哺乳动物推论。总而言之，这项研究将显着推进目前对早期接触甲基汞可能如何引起运动缺陷的了解，从而让实验毒理学家和临床医生了解甲基汞神经毒性中肌病成分的可能性。