Low-level toxicant perturbation of neural cell function

描述(申请人提供)：这项研究的重点是了解非灾难性毒物暴露如何扰乱中枢神经系统的正常发育和功能。人们不断地确定，曾经被认为是安全的毒物浓度与各种疾病有关，再加上在我们的环境中发现了大量的毒物和潜在的毒物，这使得我们对这些物质如何扰乱正常细胞功能的理解变得非常重要。这项工作的一个中心目标是确定适用于理解大量毒物的一般原则。这一应用直接来自我们正在进行的研究，其基本原理/假设是，无论其其他活性如何，任何具有促氧化活性的毒物都将对前体细胞和分化细胞产生一系列高度可预测的影响。这些作用包括抑制前体细胞分裂和增强对分化诱导剂和细胞死亡的反应性。这一假设及其明确的机制预测，允许制定适用于环境中经常发生的浓度的广泛毒物暴露的发育神经毒理学的一般理论。此外，我们关于低剂量毒物暴露对其他潜在有害物质易感性的预测，可能会为不同个体对假定相同的生理应激源的反应存在巨大差异的原因提供新的理解。我们的初步体外实验为这一假设的正确性提供了强有力的支持，并证明了各种毒物对神经细胞功能的显著影响，包括显著增强对各种其他生理应激源的易感性。生化分析表明，尽管它们的化学成分不同，但所有被研究的毒物都集中在Fyn和Cbl的激活上，导致PDGFRA的降解增强。总之，这项研究计划将确定单一毒物的亚致死浓度对各种神经前体细胞的作用，确定毒物与其他生理应激源(包括其他毒物)的相互作用，特别是在协同毒性反应方面，将定义受毒物暴露调节的细胞调节系统，并将研究临床相关情况，在这些情况下，毒物负荷可以增强对损伤的反应，在这些情况下，在人类群体中的后续研究既特别重要，也相对简单。

DESCRIPTION (provided by applicant): This research is focused on understanding how non-catastrophic toxicant exposure disrupts normal development and function of the CNS. The continuing determination that concentrations of toxicants once thought to be safe are associated with a variety of maladies, combined with the large numbers of toxicants and potential toxicants found in our environment, make it of great importance to increase our understanding of how normal cellular function may be disrupted by such substances. A central goal of this effort is to identify general principles applicable to the understanding of large numbers of toxicants. The general principle/hypothesis that underlies this application, which emerges directly from our ongoing research, is that, regardless of its other activities, any toxicant that has pro-oxidant activity will have a highly predictable set of effects on both precursor cells and differentiated cells. These effects include inhibition of precursor cell division and enhancement of responsiveness to inducers of differentiation and cell death. This hypothesis, with its clear mechanistic predictions, allows the formulation of a general theory of developmental neurotoxicology applicable to exposure to a wide range of toxicants at concentrations that frequently occur in the environment. Moreover, the predictions of our hypothesis regarding the effects of low dose toxicant exposure on vulnerability to other potentially harmful agents may provide a new understanding of the reasons underlying the enormous variability seen in responsiveness of different individuals to putatively identical physiological stressors. Our in preliminary vitro experimentation provides strong support for the correctness of the hypothesis underlying this proposal, and has demonstrated marked effects of a variety of toxicants on neural cell function, including a striking enhancement of vulnerability to a variety of other physiological stressors. Biochemical analysis demonstrates that despite their different chemistries, all of the toxicants examined converge on Fyn and Cbl activation, leading to enhanced degradation of the PDGFRa. In sum, this research program will define the actions of sublethal concentrations of single toxicants on a variety of neural precursor cells, define the interactions of toxicants with other physiological stressors (including other toxicants) particularly in regards to synergistic toxicity reactions, will define cellular regulatory systems that are modulated by toxicant exposure, and will study clinically relevant situations in which toxicant load can enhance response to injury and in which follow on studies in human populations are both particularly important and comparatively straightforward to carry out.