Low-level toxicant perturbation of neural cell function

描述（由申请人提供）：本研究的重点是了解非灾难性毒物暴露如何破坏中枢神经系统的正常发育和功能。曾经被认为是安全的有毒物质的浓度与各种疾病有关，再加上在我们的环境中发现的大量有毒物质和潜在有毒物质，这一持续的确定使得我们对这些物质如何破坏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了解大量毒物的一般原则。这一应用背后的一般原理/假设直接来自我们正在进行的研究，即无论其其他活性如何，任何具有促氧化活性的毒物都会对前体细胞和分化细胞产生高度可预测的影响。这些作用包括抑制前体细胞分裂和增强对诱导分化和细胞死亡的反应性。这一假设及其明确的机制预测，使发育神经毒理学的一般理论得以形成，适用于暴露于环境中经常出现的各种浓度的毒物。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影响的假设预测，可能为不同个体对假定相同的生理应激源的反应性存在巨大差异的原因提供了新的理解。我们的初步体外实验为这一提议背后的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，包括对各种其他生理应激源的脆弱性的显著增强。生化分析表明，尽管它们的化学性质不同，但所有检测的毒物都集中在Fyn和Cbl活化上，导致PDGFRa的降解增强。总之，本研究项目将确定亚致死浓度的单一毒物对多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，将确定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，对人群的后续研究特别重要，而且相对容易进行。

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.