During the development of the nervous system, the temporal and spatial regulation of gene expression is a critical component of neural and glial growth, development, and interactions. These critically timed events are assummed to be a major component in the differential susceptibility of the developing organism to environmental insult.This project examined chemical induced perturbations during development of the NS as indicated by alterations in the spatio-temporal expression of mRNA for various developmentally regulated proteins associated with distinct processes of development. We have shown by RNase protection assays that lead acetate alters developmentally regulated structural proteins for neurons and glia in the rat as well as an upregulation of apoptosis genes and brain derived neurotrophic factors. Early exposure to mercury vapors also elevate mRNA levels for apoptosis factors consistent with previous reports of mercury induced apoptosis in the brain.This technique is being expanded with the establishment of new probe sets to detect mRNA levels for proteins associated with the various cell types and stages of brain development. Future Research: The developmental related effects of chemicals which disrupt thyroid hormone levels,PTU and dioxin, will be examined to determine any relationship with structural alterations in the nervous system. Additional studies are based upon events associated with hypoxia-ischemia occurring at preterm birth. These studies will examine the acute toxicity of interleukin 6 on the early post-natal developing CNS and alteration in the normal ontogeny of molecular markers for cortical neuronal network development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021164-04
Application #
6432232
Study Section
(LT)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
McPherson, Christopher A; Zhang, Guozhu; Gilliam, Richard et al. (2018) An Evaluation of Neurotoxicity Following Fluoride Exposure from Gestational Through Adult Ages in Long-Evans Hooded Rats. Neurotox Res 34:781-798
Orihuela, Ruben; McPherson, Christopher A; Harry, Gaylia Jean (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649-65
Kraft, Andrew D; McPherson, Christopher A; Harry, G Jean (2016) Association Between Microglia, Inflammatory Factors, and Complement with Loss of Hippocampal Mossy Fiber Synapses Induced by Trimethyltin. Neurotox Res 30:53-66
Harry, G Jean (2013) Microglia during development and aging. Pharmacol Ther 139:313-26
Harry, G Jean; Kraft, Andrew D (2012) Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology 33:191-206
Kraft, Andrew D; Kaltenbach, Linda S; Lo, Donald C et al. (2012) Activated microglia proliferate at neurites of mutant huntingtin-expressing neurons. Neurobiol Aging 33:621.e17-33
Kraft, Andrew D; Harry, G Jean (2011) Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int J Environ Res Public Health 8:2980-3018
McPherson, C A; Aoyama, M; Harry, G J (2011) Interleukin (IL)-1 and IL-6 regulation of neural progenitor cell proliferation with hippocampal injury: differential regulatory pathways in the subgranular zone (SGZ) of the adolescent and mature mouse brain. Brain Behav Immun 25:850-62
Harry, Gaylia Jean; Kraft, Andrew D (2008) Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment. Expert Opin Drug Metab Toxicol 4:1265-77
Brock, Brian; Basha, Riyaz; DiPalma, Katie et al. (2008) Co-localization and distribution of cerebral APP and SP1 and its relationship to amyloidogenesis. J Alzheimers Dis 13:71-80

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