The nigro-striatal dopamine system in the basal ganglia is highly sensitive to damage from environmental neurotoxins. Exposure to elevated levels of the essential element manganese (Mn) causes neuronal injury to this brain region, as well as cortical and subcortical structures. The results of this neurotoxicity represent a continuum of neurological effects ranging from cognitive and behavioral impairment in children exposed to Mn in drinking water, to Mn-induced parkinsonism (manganism) from high-dose occupational exposure in adults. However, it is not clear how early life exposures to Mn might increase susceptibility to other neurotoxic challenges throughout life. Pesticides such as rotenone that affect mitochondrial function are amongst the environmental neurotoxins thought to amplify the effects of heavy metals such as Mn to increase risk for neurodegenerative disease. The capacity of Mn to sensitize neural tissue to damage from pesticide exposure may involve persistent inflammatory changes in glial cells. Mn- induced expression of neuroinflammatory genes in glial cells is regulated by the transcription factor, Nuclear Factor Kappa B (NF-?B), which promotes neuronal injury. However, the signaling mechanisms between microglia and astrocytes that regulate this damaging glial phenotype are not well understood. Lack of this information hinders scientific and medical progress in understanding key signaling pathways that may render individuals more susceptible to neurological disease following combined exposures to environmental neurotoxins, including Mn and pesticides. To address this question, we postulate that Mn exposure during development stimulates NF-?B-dependent inflammatory signaling between microglia and astrocytes, resulting in persistent glial activation that enhances susceptibility to neurotoxic injury during aging. This hypothesis will tested in three Specific Aims that will 1) Determine how manganese exposure during juvenile development promotes inflammatory activation of glial cells and modulates the effects of rotenone on neuronal injury during aging, 2) Identify critical inflammatory signaling pathways in microglia that modulate the effects of manganese and rotenone on neurological injury, and 3) Characterize the intercellular signaling factors between microglia and astrocytes that mediate neuronal injury during exposure to manganese and rotenone. To accomplish these Specific Aims, we will use unique microglia-specific NF-?B knockout mice generated in our laboratory in a `two-hit' model to determine how juvenile exposure to Mn alters glial activation and susceptibility to neurotoxic injury during aging following exposure to the environmental pesticide, rotenone, a systemic mitochondrial complex I inhibitor. It is our expectation that use of this powerful transgenic model will enable the determination of specific molecular signaling events underlying NF-?B-dependent activation of neuroinflammatory genes in glial cells in response to developmental exposure to Mn that may increase susceptibility to neurotoxic insults during aging.

Public Health Relevance

Statement of Relevance to Public Health Children in the US and around the world are exposed to excessive levels of heavy metals such as manganese (Mn) and are also increasingly subjected to the risk of co-exposure to neurotoxic pesticides. Research in the Tjalkens laboratory has examined how developmental exposure to Mn can stimulate a persistent neuroinflammatory phenotype leading to neuronal injury and neurological dysfunction during development. The current proposal extends this work in an important new direction by investigating how exposure to Mn during juvenile development may sensitize glial cells to respond to later exposure to neurotoxic pesiticides during adulthood with a more robust inflammatory response that damages neurons. Understanding such mechanisms would add significantly to our knowledge of gene- environment interactions that could predispose susceptible individuals to neurological diseases.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Hollander, Jonathan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Colorado State University-Fort Collins
Public Health & Prev Medicine
Schools of Veterinary Medicine
Fort Collins
United States
Zip Code
Popichak, Katriana A; Afzali, Maryam F; Kirkley, Kelly S et al. (2018) Glial-neuronal signaling mechanisms underlying the neuroinflammatory effects of manganese. J Neuroinflammation 15:324
Afzali, Maryam F; Popichak, Katriana A; Burton, Lindsey H et al. (2018) A novel diindolylmethane analog, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane, inhibits the tumor necrosis factor-induced inflammatory response in primary murine synovial fibroblasts through a Nurr1-dependent mechanism. Mol Immunol 101:46-54
Hammond, Sean L; Popichak, Katriana A; Li, Xi et al. (2018) The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. J Pharmacol Exp Ther 365:636-651
Popichak, Katriana A; Hammond, Sean L; Moreno, Julie A et al. (2018) Compensatory Expression of Nur77 and Nurr1 Regulates NF-?B-Dependent Inflammatory Signaling in Astrocytes. Mol Pharmacol 94:1174-1186
Phillips, Aaron T; Rico, Amber B; Stauft, Charles B et al. (2016) Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection. J Virol 90:5785-96
Safe, Stephen; Jin, Un-Ho; Morpurgo, Benjamin et al. (2016) Nuclear receptor 4A (NR4A) family - orphans no more. J Steroid Biochem Mol Biol 157:48-60
Rico, Amber B; Phillips, Aaron T; Schountz, Tony et al. (2016) Venezuelan and western equine encephalitis virus E1 liposome antigen nucleic acid complexes protect mice from lethal challenge with multiple alphaviruses. Virology 499:30-39
Schilz, Jodi R; Reddy, K J; Nair, Sreejayan et al. (2015) Removal of Trace Elements by Cupric Oxide Nanoparticles from Uranium In Situ Recovery Bleed Water and Its Effect on Cell Viability. J Vis Exp :e52715
De Miranda, Briana R; Popichak, Katriana A; Hammond, Sean L et al. (2015) Novel para-phenyl substituted diindolylmethanes protect against MPTP neurotoxicity and suppress glial activation in a mouse model of Parkinson's disease. Toxicol Sci 143:360-73
Li, Wencheng; Liu, Jiao; Hammond, Sean L et al. (2015) Angiotensin II regulates brain (pro)renin receptor expression through activation of cAMP response element-binding protein. Am J Physiol Regul Integr Comp Physiol 309:R138-47

Showing the most recent 10 out of 17 publications