Carbon monoxide and the brain growth spurt
Abstracts
Initial Award Abstract |
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The studies proposed in this grant are designed to examine the influence of exposure to carbon monoxide (CO) at a critical period of growth in the brain. This period is the brain growth spurt which coincides with the start of myelin (white matter) formation. During this crucial stage the brain undergoes cell division and the development of an intricate multi-cellular organization, particularly that of the myelin-forming cells. The growth of these cells require the production of lipids (fats). At this time, metabolic activity and energy needs are dynamic. It is believed that anything that would cause a delay in these growth events would cause damage to the brain. Prior research has clearly demonstrated that pregnant women exposed to tobacco smoke, either directly or second-hand, give birth to children with lower birth weights. However, in these previous studies it was not possible to analyze for deficiencies in brain size or function. This deficit in general fetal growth takes place during the critical time for brain development. For the human infant this critical time spans the third trimester of pregnancy into the first 6 months after birth. Our hypothesis states that these growth deficiencies are a result of exposure to CO from tobacco smoke. To examine the effect directly on brain, we plan to use the artificially-reared rat pup which is our animal model. In the rat pup, unlike the human baby, the important stage for the brain growth spurt and onset of myelin formation takes place after birth when the pups are fed milk. The artificially-reared rat pups are fed rat milk substitutes under carefully controlled conditions. To test our hypothesis these rat pups will be exposed to CO in amounts found in tobacco smoke to find out if the brain is compromised at this vulnerable age. Tobacco smoke contains more than 3000 active compounds and it is known that the two most common are nicotine and CO. One cigarette can yield from 0.003 to 0.05 gram CO and one cigar up to 0.8 gram CO. Nonsmokers can be exposed to significant amounts of CO because it has been shown the air can contain up to 4000 parts per million CO from tobacco smoke. Carbon monoxide is a general poison. CO inhaled with air decreases the oxygen carrying capacity of red blood cells and this can reduce the availability of oxygen to organs. In addition, CO is known to block the energy production centers within cells. Our research project seeks to address how CO influences brain growth and function from several perspectives; (1) by examining cognitive function through standard behavioral tests in a collaboration with Dr David Hovda, a Clinical Psychologist at UCLA; (2) by monitoring the cellular infrastructure of the brain; and (3) by examining the lipid composition, and capacity of developing brain to produce its major lipids. Preliminary data from our milk fed rat pup model shows that exposure to tobacco smoke causes a statistically significant reduction in brain weight with a modest, but insignificant reduction in body weight. This means that tobacco smoke and thus CO may influence developmental milestones in brain which may never be recouped at later stages in development. The two key considerations are that lipid production requires energy and that the brain is independent and produces greater than 90% of the major lipids it needs, since most lipids cannot be imported from the blood. This research is expected to advance our understanding of the seriousness of second hand cigarette smoke on early brain development. |
Final Report |
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Carbon monoxide (CO) is produced and accumulates as the result of incomplete combustion, from burning tobacco, vehicle exhaust, and other heat producing systems. CO is particularly dangerous in closed and poorly ventilated environments. Inhaled CO can bind to hemoglobin in red blood cells and decreases their oxygen carrying capacity. CO is known to block respiration within cells. It is produced naturally in mammals and may be a distinctive messenger for nerve cells. Our studies were designed to examine the consequences of exposure to CO during a critical period of growth in the brain when it undergoes profound cell division and the development of an intricate multi-cellular organization. To test our hypothesis that exposure to CO causes developmental impairments in brain, we are examining exposure to CO using our animal model, the artificially reared rat pup. An important age for brain growth and onset of myelin formation takes place after birth within the milk-feeding period for the rat. We have developed controlled conditions to examine the specific consequences of mild CO exposure, rather than examine the gross pervasive damage that can be expected from overdosing with CO. We have discovered that CO at 25 ppm and less in air causes significant auditory deficits. The culmination of our studies indicates there are no differences in the data for many measures we have made in test and control conditions. However, we have identified the auditory brain stem as one region that can be compromised by exposure to 12.5 and 25 ppm CO in air. The most distinctive functional impairment to the auditory system is a significant attenuation of the amplitude of the eighth cranial nerve’s action potential. Studies at the cellular level, by histological and immunochemical methods, demonstrate that several components of the auditory system are affected by mild CO exposure. The somata of several neurons in the spiral ganglia in the CO exposed animals are distorted in shape and size. The central process of the eighth nerve exhibits some myelin disorganization. Analysis of the cochlea of CO exposed animals demonstrates a marked decrease of cytochrome oxidase, calcium ATPase, NADPH diaphorase and neurofilament immunoreactivity when compared with controls. In the inferior colliculus, the basal c-Fos immunoreactive cells (most likely neurons) are decreased significantly in number in the CO exposed animals. Our studies indicate that several critical components of the auditory pathway are selectively affected by very mild CO exposure. We believe our studies are significant and can be related to human conditions where there is mild exposure to CO in the air. Attenuation of the amplitude of the eighth cranial nerve’s action potential in children, similar to what we find in our rat pup model, might be a link to the disorder auditory neuropathy, in which children have normal otoacoustic emissions but a very poor, or absent, eighth nerve action potentials. These children have auditory processing disorders but often have normal hearing "sensitivity" with pure tone testing. Also they show language delays, because they cannot understand words that are spoken. These children are typically identified as "impaired" later in childhood. |
