Low-level toxicant perturbation of neural cell function

点击翻译按钮获取中文摘要

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.