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NORA Manufacturing Sector Strategic Goals

927ZGFT - Neuroinflammation, Glial Signaling and Neurotoxicity

Start Date: 10/1/2008
End Date: 9/30/2013

Principal Investigator (PI)
Name: James O'callaghan
Phone: 304-285-6079
Organization: NIOSH
Sub-Unit: HELD
Funded By: NIOSH

Primary Goal Addressed

Secondary Goal Addressed


Attributed to Manufacturing


Project Description

Short Summary

This laboratory-based research project will be conducted to characterize novel molecular changes associated with gliosis, a sensitive cellular index of neurotoxicity. A large number of workplace-related chemicals, and the physiological and environmental factors with which they interact, are associated with subtle neurological effects. Establishing the adverse (i.e. neurotoxicological) nature of these effects is hampered by the lack of available biomarkers of neurotoxicity. Anti-inflammatory and proinflammatory agents will be employed to validate the role of neuroinflammation in the induction of gliosis and neurotoxicity. These studies will evaluate the utility of neuroinflammatory mediators as early biomarkers of neurotoxicity in preclinical assessments, research that directly address the needs described under the neurological component of the Cancer, Reproductive and Cardiovascular Cross-Sector Goals and Health Hazard Evaluation Goals. NIOSH neurotoxicity assessment guidelines are expected outcome.


Glial activation represents a dominant cellular response to all types of damage to the central nervous system (CNS). The generality of the glial reaction to injury, despite the regional- and cell-type specific targets of individual neurotoxic insults, implies there are common signals underlying this cellular response. Discovery and characterization of these signals offer the potential for developing biomarkers of neurotoxicity that can be used as preclinical indicators of any workplace neurotoxic exposure. Signal transduction, especially in the CNS, rely on numerous messengers, receptors and protein phosphorylation cascades. Knowledge of protein phosphorylation sites on a given phosphoprotein permits the accurate prediction of the upstream effectors involved (the Greengardian Model). Previously, we used this approach to discover and characterize glial activation associated phosphorylation of signal transducer and activator of transcription 3 (STAT3). Known upstream effectors for STAT3 include proinflammatory cytokines and chemokines involved in inflammation in the periphery and that are suspected to be involved in "neuroinflammation" in diseases of the CNS. Using genomic and proteomic profiling and qrtPCR, we discovered a rapid and large induction in the expression of a variety of proinflammatory mediators was associated with phosphorylation of STAT3 and activation of both microglia and astroglia (gliosis). While our initial findings make it clear that gliosis and the attendant expression of proinflammatory mediators are associated with toxicant-induced damage to the CNS, it is by no means clear that a cause-and-effect relationship exists between the presence of a neuroinflammatory process and neural damage. For example, workplace related events, such as stress, anxiety, depression, obesity, systemic infections, autonomic dysfunction and disrupted sleep-wake cycles all are associated with changes in the expression of CNS cytokines and chemokines in the absence of evidence of neural damage. Thus, "neuroinflammation"-related events in the CNS must be carefully defined with respect to involvement in neurotoxic responses and not just as a reflection of altered neural physiological responses. This is not just an issue of semantics because a presumed role of inflammation can influence the course of research in an entire field and can consume enormous resources without having the benefit of sound and substantial scientific footing. Therefore, in this project we will use a variety of known neurotoxic agents to induce glial activation and the expression of proinflammatory mediators in the brains of experimental animals. Our preliminary data indicate that antinflammatory agents can suppress neural inflammatory events without affecting neurotoxicity and gliosis. Thus, to examine the linkage between "neuroinflammation" mediators, neural (neuronal or glial) damage and subsequent gliosis, we will examine the effects of anti- and proinflammatory agents on neuroinflammatory responses associated with glial activation and neurotoxicity. Thus, on the one hand, we will evaluate the effects of actue and chronic glucocoritoids on neuroinflammation and neurotoxicity endpoints. On the other hand we will evaluate the effects of acute and chronic lipopolysacharide, as a proinflammogen, on neuroinflammation and neurotoxicity. Finally, we will evaluate animal models of the workplace-related events listed above, either alone, or in combination with known neurotoxic exposures, to determine their influence on neuroinflammtory responses associated with neurotoxicty and subsequent gliosis. In aggregate, these studies will serve to determine if proinflammatory mediators can serve as potential early and sensitive biomarkers of neurotoxicity that ultimately can be applied in a risk assessment context relevant to adverse workplace exposures.


• Develop a comprehensive battery of neurotoxicity biomarkers, i.e. biomarkers applicable to the assessment of broad classes of known and suspected neurotoxic agents.

• Where specific ligands and receptors are implicated as neurotoxicity-related effectors, develop new PET ligands applicable to humans for assessing the onset, duration and functional outcome of potential human neurotoxic exposures.

• Detect and/or quantify evidence of the appearance of novel biomarkers in animal and human serum, during and after exposure to known or suspect neurotoxic agents.

Mission Relevance

A large number of workplace-related chemicals, and the physiological and environmental factors with which they interact, are associated with subtle neurological effects. Establishing the potential adverse (i.e. neurotoxicological) nature of these effects is hampered by the lack of neurotoxicity biomarkers. Microglia and astroglia, sub-types of central nervous system glia, have been shown to serve as microsensors of neurotoxic insult. Using tissue from experimental animals and humans, combined with the implementation of novel assay procedures, we have shown that enhanced expression of astrocytic and microglial genes, and their corresponding proteins, can be used to quantify toxicant-induced glial activation (glosis) resulting from dosages of a given agent below those that result in overt cytopathology or behavioral abnormalities. The generality of the glial reaction to injury that we observed, despite the target selectivity of specific neurotoxic insults, implied that there are common signals underlying this cellular reaction, signals that would serve as novel and early biomarkers of neurotoxicity. Cytokines, neurotrophins, neurohormones, and their down-stream signaling effector modules have been linked to toxicant-induced gliosis, as well as to neurological disease states such as Parkinson's and Alzheimer's disease. Consistent with these observations, we have discovered that a variety of proinflammatory cytokines and chemokines are associated with the early stages of exposure to a wide variety of known and suspected neurotoxicants, findings implicating these messenger molecules as early biomarkers of neurotoxicity. While it is becoming clear that activation of microglia and astroglia and the attendant expression of proinflammatory cytokines and chemokines often are associated with disease-, trauma- and, based on our findings, toxicant-induced damage to the CNS, it is by no means clear that a cause-and-effect relationship exists between the presence of a neuroinflammatory process and neural damage. Determining if the expression of specific neuroinflammation-related molecules in the brain is linked in a casual way to neural damage resulting from administration of a variety of known and suspected neurotoxic agents, will provide the information needed to move forward with further validation studies of these potentially sensitive and early biomarkers of neurotoxicity. In this project we will use experimental animals treated with known neurotoxicants and assess brain neuroinflammtory responses with and without pretreatment with anti-inflammatory agents. We then will determine if suppression of inflammation suppresses neurotoxicity using a variety of neuronal and glial biomarkers of neural injury previously established in this laboratory.

Workplace-related adverse effects on the nervous system continue to be of concern for most work sectors. A large number of workplace-related exposures, and the physiological and environmental factors with which they interact, are associated with subtle neurological effects. Establishing the potential adverse nature of these effects is hampered by the lack of biomarkers of neurotoxicity. Traditional morphological and/or behavioral indices of neurotoxicity have proven to lack sufficient sensitivity or specificity to define the neurotoxic condition. Thus, the success of this project, which is concerned with the development of specific and sensitive biomarkers of neurotoxicity, will have important implications for many of the NORA sector programs.

Thus, research results will directly address:

50% Manufacturing, 25% Ag, Forestry & Fishing, 25% Construction

Sector Program Goals:

Agriculture, Forestry and Fishing (25%), Strategic Goal 1 (09PPAFFSG1), Improve surveillance within the Agriculture, Forestry, and Fishing Sector to describe: the nature, extent, and economic burden of occupational illnesses, injuries, and fatalities; occupational hazards; and worker populations at risk for adverse health outcomes.

Intermediate Goal 1.1 (09PPAFFIG1.1), Improve national and state-level illness, injury, hazard, and exposure surveillance by utilizing existing data systems or creating new databases to identify injuries, illnesses, hazards, and exposures within the AgFF sector.

Activity/Output Goal 1.1.1 (09PPAFFAOG1.1.1), Assess the available surveillance for all sub-sectors of the AgFF sector and identify gaps in the existing systems.

Strategic Goal 5 (09PPAFFSG5), Improve the health and well-being of agricultural workers by reducing occupational causes or contributing factors to acute and chronic illness and disease.

Intermediate Goal 5.3 (09PPAFFIG5.3), Reduce acute and chronic illnesses associated with exposure to pesticides and other agrochemicals.

Activity/Output Goal 5.3.4 (09PPAFFAOG5.3.4): Conduct research to develop and improve (1) methods to assess exposures to pesticides, agrochemicals, and interactions of multiple chemicals in the workplace, and (2) biomonitoring methods and direct reading devices to assess exposures and evaluate health effects of exposures in workers and their families.

Activity/Output Goal 5.3.5 (09PPAFFAOG5.3.5): Conduct research to assess the effects of occupational exposures to pesticieds and other agrochemicals on the reproductive, neurological and neurobehavioral health of men, women, and children.

Construction (25%), Strategic Goal 14 (09PPCONSG14), Improve surveillance at the Federal, State, and private level to support the identification of hazards and associated llnesses and injuries; the evaluation of intervention and organizational program effectiveness; and the identification of emerging health and safety priorities in construction.

Intermediate Goal 14.2 (09PPCONIG14.2), Partner with professional associations, surveillance experts, insurance companies, regulatory and consultation organizations to explore, develop, and implement new types of construction-sector hazard, exposure, and performance indicators to supplement current surveillance approaches.

Manufacturing (50%), Strategic Goal 9 (09PPMNFSG9), Enhance the state of knowledge related to emerging risks to occupational safety and health in manufacturing.

More specifically, this research addresses the occupational neurologic disease component of:

Cross-Sector Health Outcome Program Goals:

Cancer, Reproductive, and Cardiovascular Diseases Strategic Goal 5 (09PPCRCSG5), Reduce the incidence and mortality of other chronic diseases, including (but not limited to), work-related neurologic (cerebrovascular) and renal disease.

Other Cross-Sector Program Goals:

Exposure Assessment (25%) Strategic Goal 2 (09PPEXASG2), Develop or improve specific methods and tools to assess worker exposures to critical occupational agents and stressors.

Intermediate Goal 2.3 (09PPESAIG2.3), Development and evaluate new or improved methods for assessing exposure to workplace chemicals and occupational health stressors either singly or as mixtures, including both prospective and retrospective methods.

Activity/Output Goal 2.3.1 (09PPEXAAOG2.3.1), Development of new or improved methods to measure chemicals or other occupational hazards in the work environment.

Activity/Output Goal 2.3.2 (09PPEXAAOG2.3.2), Validation of these methods to provide and characterize their performance (specificity, sensitivity, accuracy, etc.) including publication in the NIOSH Manual of Analytical Methods.

Activity/Output Goal 2.3.3 (09PPEXAAOG2.3.3), Application of these methods to evaluate occupational exposure.

Intermediate Goal 2.4 (09PPESAIG2.4), Develop biomonitoring methods including biomarkers that are useful for mixed exposures.

Activity/Output Goal 2.4.1 (09PPESAIG2.4.1), Development of new biomonitoring methods.

Intermediate Goal 2.8 (09PPESAIG2.8), Develop and incorporate data from toxicity studies (including the mechanism of action of chemical, physical, and biological agents, including mixed exposures) or epidemiologic studies into the evaluation and improvement of exposure assessment strategies for priority occupational hazards.

Activity/Output Goal 2.8.2 (09PPESAIG2.8.2), Initiation of new toxicity or health studies to fill gaps in knowledge so that better-designed exposure assessment strategies can be developed.