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Neuronal oxidative stress from mild carbon monoxide exposure

Institution: University of California, Los Angeles
Investigator(s): John Edmond, Ph.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14RT-0068 Award: $417,403
Subject Area: General Biomedical Science
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Our first publications on the impact of chronic mild CO exposure on the developing auditory system were published in December 2003. (J Neurosci Res 74: 644-675). These were the first studies where chronic mild carbon monoxide exposures in the range 12 to 25 parts per million (0.0012 and 0.0025% carbon monoxide in air) revealed physical and biochemical differences to cells in specialized regions involved in hearing function. The information was obtained from experiments with an animal model where the period of examination is over a vulnerable stage in central nervous system development and where neural regions and their functions seem to be highly susceptible to exposure to carbon monoxide. In a paper published this year we identify oxidative stress as the cellular injury caused by chronic mild carbon monoxide exposure. Accompanying conditions may include carbon monoxide acting as a rogue neuro-modulator perturbing carbon monoxide-like regulatory processes that are involved in cell signaling. Several neuroscientists have proposed that two gases produced by enzymes in nerve tissue, carbon monoxide and nitric oxide, act as cell signals in modulating events important to the cell’s integrity. Very recently we have obtained preliminary data that cells (neurons) within two discrete brain regions, the lateral and anterior/central hypothalamic regions, and the cerebellum show intense increases in the heat shock protein-32, (HSP-32). Heat shock proteins increase in amount to produce substances that are neuro-protective. HSP-32 is also known as heme oxygenase I, an enzyme that breaks down heme to heme products that are neuro-protective, and at the same time produce carbon monoxide and iron. From our recent studies we know that available iron is needed to create conditions of oxidative stress and the reactive oxygen substances that are detrimental to cell viability and cellular function. Recent information in the literature indicates that chronic exposure to nicotine in a primate model where the nicotine was at levels measured in blood of smokers, causes oxidative stress in fetal brain regions.

The hypothesis and objectives in our proposal are based on these findings, particularly the fact that chronic mild exposure to carbon monoxide results in a chronic state of oxidative stress. Extreme distress could cause neuronal loss (cell death). In addition, another consequence is that carbon monoxide-related regulatory signal systems may also be impacted and marginalized. Our proposed studies aim to sort out these issues by an examination of the conditions that exist in-vivo with chronic oxidative stress and determine if markers that relate to cell signal functions have deviated from normal. The studies are to be done at carbon monoxide exposure conditions from a low of 0.0006% up to 0.0025% carbon monoxide in air, an exposure we know neuronal competencies are diminished. In the cochlea of the peripheral auditory system, exposure to 0.0025% carbon monoxide results in damage to the neurons of the spiral ganglia and also to their nerve fibers that make contact with the inner hair cells; yet the inner hair cells appear normal. In addition to the consequences of oxidative stress, the expected neuronal properties are reduced or impaired because signal systems responsible for neurons to develop their functions are persistently sub-optimal. The outcome for the exposed individual is that auditory impairment can be permanent.

We propose four aims to examine our core hypothesis that chronic oxidative stress is caused by chronic mild exposure to carbon monoxide or nicotine, or both, and each aim contains specific objectives. All aims use our animal model, the gastrostomy-reared rat, for early postnatal studies. Aims I and II deal with the impact of chronic mild carbon monoxide exposure on three well defined brain regions, the cerebellum, the lateral and anterior/central hypothalamic regions, and the inferior colliculus. Aim I examines, by a variety of techniques, the components and cellular outcome from oxidative stress as well as the expression of signal enzymes that relate to carbon monoxide as a neuro-modulator. In this aim the carbon monoxide exposure is to be 25 ppm (0.0025% in air). In aim II it is our plan to breach one more regulatory boundary by examining mild chronic exposure to carbon monoxide at 6 ppm, an exposure value well within the existing National Ambient Air Quality Standard’s upper limit of 9 ppm for ambient air as established by the EPA for air quality management. In this aim, the same brain regions as identified for aim I are to be examined and the most appropriate methods from the experience and data from aim I applied to aim II. By examining conditions at the very lowest CO exposure we can reliably perform, we hope to distinguish which brain region is most sensitive to chronic mild CO exposure and which cellular process is most sensitive to disruption. Our studies already published were principally done at carbon monoxide concentrations 12 to 50 ppm, within the acceptable concentrations ranges specified by the FAA, (up to 50 ppm); OSHA, (up to 35 ppm); and CalOSHA, (up to 25 ppm). Finding an effect at a common exposure in everyday air in some communities and particularly within a poorly ventilated home environment, (0.0006% carbon monoxide in air:- 6 ppm) presses the point that exposure to second hand tobacco smoke is a serious issue. Aim III is designed to show that the dynamics of carbon monoxide in the blood/body from very mild but chronic exposures is as unsafe as exposures at much higher concentrations, because the water solubility of carbon monoxide facilitates its distribution to vulnerable brain regions. Gas chromatography is to be used to examine the distribution of carbon monoxide in solution and bound to hemoglobin in blood after very mild chronic carbon monoxide exposures. Methods to make these measurements have been developed by others. Our objective is to show that very mild chronic carbon monoxide exposure is hazardous because the carbon monoxide is primarily in solution, available to tissues, rather than primarily bound and protectively sequestered in red cell hemoglobin. Another component of our hypothesis is that carbon monoxide and nicotine, the dominant by-products in tobacco smoke act synchronously to impact neurons of the developing auditory system. Both impair neurons when tested alone in animal models, but have never been studied in combination as the only two variables. In aim IV we propose to determine if there is a synchronized interaction that magnifies their impact on neurons as they develop in the auditory system and in the cerebellum and the lateral and anterior/central hypothalamic regions. This objective is more significant today for our proposal because evidence has been published that nicotine, in addition to other already known influences on nervous center regions, causes conditions of oxidative stress. In this aim, techniques and markers shown to be useful and relevant to the study of chronic oxidative stress from chronic mild carbon monoxide exposure in aims I and II are to be used to compare neural regions in animals exposed to carbon monoxide alone, or nicotine alone, or to carbon monoxide in combination with nicotine, and contrasted to controls not exposed to either substance. The evidence we expect to uncover from these studies with our animal model will show that neurons of highly susceptible nervous system regions are dysfunctional because of a persistent oxidative stress where cellular damage and neuronal loss are possible. We believe our studies (with Ivan Lopez) on the auditory system may be related to the adverse auditory development of humans, particularly children who have, or develop auditory neuropathies. The hypothalamic regions are intimately involved in homeostasis, in the integration of physiological stimulation from all 5 senses, taste, smell, sight, sound, and touch. The neurons in the hypothalamus produce a number of neurotransmitters which relay information and instruction to all parts of the brain and body. When the hypothalamus is perturbed, incorrect neuro-signals are generated and erroneous neuro-signals are received, resulting in an inaccurate integration of all sensory input, leading to subtle faulty perceptions. Dysfunction of the hypothalamus often leads to depression, hyperactivity, abnormal responses to stress, and disturbances within the emotional centers of the brain. The cerebellum is responsible for the regulation of body and limb movement, motor learning and motor function. The cells most critical to the function of the cerebellum are the Purkinje neurons and there is research in the literature that indicates oxidative stress can be associated with their loss.

Our studies identify oxidative stress as the cellular injury caused by exposure to carbon monoxide in air. Oxidative stress is a known condition in many disorders, including Alzheimer’s, Parkinson’s, multiple sclerosis, Lou Gherig’s disease and cardiovascular disease. Tobacco smoke, which contains carbon monoxide and nicotine, aggravates many of these diseases. We expect the outcome of our studies at the lowest carbon monoxide concentrations in air, at 6 ppm or less, to signal a significant health warning for children who are exposed to second hand tobacco smoke.
Publications

Nestin is increased in progenitor cells of the mouse cerebella following prental chronic mild carbon monoxide exposure.
Periodical: Journal of Neurochemistry Index Medicus:
Authors: Edmond J, Acuna D, Ngan A, Lopez IA ABS
Yr: 2009 Vol: 108 Nbr: 1 Abs: PTW01-05 Pg: 122

Evidence for oxidative stress in the developing cerebellum of the rat after chronic mild carbon monoxide exposure(0.0025% in air).
Periodical: BMC Neuroscience Index Medicus:
Authors: Lopez IA, Acuna D, Beltran-Parrazal L, Lopez E, Amarnani A, Cortes M, Edmond J ART
Yr: 2009 Vol: 10 Nbr: 53 Abs: Pg: 1471-2202