STATEMENT ON VITAMIN A IN RELATION TO GULF WAR SYNDROME AND OTHER
Frederick W. Plapp, Jr. Ph.D.
Professor Emeritus of Insecticide Toxicology Texas A&M University
Vitamin A (retinol) and vitamin A hormone (retinoic acid, RA) comprise one of the major human hormone systems. The importance of this system in modulating vision as measured by both dark adaptation and photosensitivity has been known for many years.
Additional roles for RA have been recognized more recently. These include activation of
synthesis of immune system proteins, activation of enzyme synthesis relative to drug
detoxification, activation of protein synthesis related to neurotransmission, and
activation of protein synthesis relating to reproduction. These findings suggest that
changes in the vitamin A system may relate to health problems involving these areas.
Without normal levels of RA, these systems don't function as they should.
Variations in levels of vitamin A are known to occur in human populations and, as described below, deficiency in vitamin A may relate to increased frequencies of autoimmune diseases in the general population as well as sub-populations such as those who served in the 1990-1991 Persian Gulf War.
In addition, exposure of humans to various environmental chemicals such as pesticides and other endocrine disrupters may result in poisoning both the transport and synthesis of vitamin A and possibly other hormones. These chemically-caused deficiencies may produce effects similar to those associated with genetic deficiencies.
Based on these observations, it seems plausible that the vitamin A system may play a key role in many human illnesses including those associated with Gulf War Syndrome. Material in support of this hypothesis follows.
VITAMIN A AND HUMAN DISEASE
The occurrence of diseases associated with malnutrition/vitamin A deficiency is well established in developing countries. Vitamin A deficiency is clearly associated with blindness in children (xerophthalmia) (1).
Higher infant mortality rates (2) and morbidity and mortality associated with infectious diseases (3) have also been demonstrated.
Vitamin A deficiency is associated with a predisposition to Staphylococcus aureus infection in rats (4). The authors also reported that host defense mechanisms are "profoundly affected" by Vitamin A deficiency.
It is possible that vitamin A deficiency may play a role in both autoimmune and neurological diseases in humans. Vitamin A deficiency is "strongly associated" with impaired immunity and infectious disease (5).
Vitamin A deficiency impairs innate immunity and is also related to adaptive immunity (6).
Examples of autoimmune diseases associated with vitamin A deficiency include rheumatoid arthritis (7), juvenile arthritis (8), Lyme disease (9), systemic lupus (7), and insulin dependent diabetes mellitus (10, 11).
Evidence has been reported from several studies that low vitamin A levels occurred in affected individuals before they became ill. In other words, the lack of vitamin A is associated with development of the disease and is not a consequence of them.
Several human cancers have been reported to be associated with vitamin A deficiency (e.g. 12). Similarly, vitamin A levels are depleted in individuals with HIV/AIDS (13).
A number of neurological conditions may also relate to vitamin A deficiency.
Lack of retinoic acid depresses synthesis of dopamine D2 receptors in mice suggesting a key role for retinoic acid in CNS gene expression (14).
Further, a lack of retinoic acid induces a Parkinsonism-like condition in rats (15). The mouse hippocampus is a site of robust retinoid synthesis and retinoids are essential competence factors in the adult mouse brain (16).
Similarly, retinoids are required for normal brain signaling in aged mice (17), suggesting a role for retinoids in optimal brain functioning in older individuals.
As described above, a possible role of vitamin A deficiency seems well established for a number of human illnesses. To the best of my knowledge, there have not been studies directly investigating the relationships between vitamin A and any of the several Gulf War Illnesses. Similarly, there seem to be no studies involving vitamin A and more recently recognized conditions as chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity.
I propose such studies are badly needed. At the very least, the ideas presented here represent testable hypotheses and thus, are amenable to scientific study.
MECHANISMS CAUSING VITAMIN A DEFICIENCY
Deficiency of vitamin A frequently occurs in humans and wildlife exposed to a wide array of environmental chemicals. Two different processes appear to be involved. One is poisoning of transthyretin, the protein which transports thyroid hormones and the retinol-retinol binding protein complex from sites of synthesis to sites of action. Evidence for chemical poisoning of this process was first reported by Brouwer and Van Den Berg (18). The second process, poisoning of proteins involved in the synthesis of vitamin A, has not been systematically investigated. The apparent crucial step is inhibition of the esterases that hydrolyze fat-soluble retinyl esters such as retinyl acetate and retinyl palmitate. This hydrolysis converts the esters to retinol. Subsequent oxidations convert the alcohol first to retinaldehyde, and finally, to the cis and trans retinoic acids.
Different types of chemicals are involved in the two processes. Planer diphenyl, phenoxyphenyl, and dioxin-type molecules, often halogenated versions such as tetrachlorodioxin (TCDD) the major chemical involved in Agent Orange poisoning in Viet Nam, and polychlorinated biphenyls (PCB)
are well known as causes of both physical and mental health problems. Hepatic vitamin A depletion in TCDD-treated rodents is a sensitive marker of TCDD exposures (19). Similar findings have been reported with exposures to PCBs and polybrominated biphenyls (20). Several types of insecticides, notably bis-diphenyl ethanes such as DDT, and the phenoxybenzyl chlorinated pyrethroids such as permethrin and cypermethrin are potential inhibitors of hormone binding to transthyretin, but to date have not apparently been evaluated in this regard.
The second process, inhibition of retinyl ester hydrolysis by chemicals used in the Persian Gulf, has not been evaluated. It is well known that organophosphate and carbamate insecticides are potent inhibitors of a wide array of esterases, blocking reactions ranging from hydrolysis of simple aliphatic esters to hydrolysis of long chain fatty acid esters. Pyrethroid insecticides are known as substrates for multiple esterases and may reduce esterase activity via competition for active sites.
Human exposure to subacute doses of esterase inhibitors is widespread in both military and civilian populations. Permethrin aerosol formulations were routinely made available to personnel in the Persian Gulf for self treatment of uniforms in the name of protection against biting and disease carrying insects. I have not been able to determine if pretreated uniforms were issued to personnel in the Gulf or if uniforms were retreated with these chemicals at military laundry facilities in the Gulf. However, it is well established that the military has been developing the use of permethrin for treatment of uniforms since the early 1980s.
Exposures to residues of insecticides applied to interior living and w orking areas, and to lawns and gardens in the name of pest control can produce similar responses in civilians (numerous personal communications).
Based on my knowledge of the action of potential esterase inhibitors in combination with low dose exposures to chemical toxicants, these residue treatments offer a plausible explanation for health problems similar to those seen in Persian Gulf veterans.
PON1 AND VITAMIN A: IS THERE A RELATIONSHIP?
The only biochemical variations clearly shown to relate to Gulf War Illness are the several mutations in the sequence of PON1, also known as paraoxonase or paraoxonase1, as well as mutations in upstream promoter regions. PON1 is an esterase capable of metabolizing paraoxon, the active form of the organophosphate insecticide parathion, as well as oxon forms of other phosphorothionate insecticides. Sick Gulf War veterans from a small test population were shown to have lower levels of PON1 activity than their healthy peers (21) and also to have a greater frequency of the less frequent R allele as compared to the Q allele than healthy veterans. Low PON1 activity is also characteristic of individuals with type 1 diabetes (22).
Evidence of mutations in promoter sequences has been reported (23) along with evidence the mutations can cause large changes in PON1 activity.
The natural function of the PON1 gene is not known. The idea it evolved in order to react with insecticides developed in the 20th century is not evolutionarily sound. There are suggestions that PON1 functions to protect against oxidative damage associated with high and low density lipoproteins (24) and other evidence it may relate to coronary disease (25).
Alternative functions such as hydrolyzing lipophilic hormone precursors, e.g.. retinyl esters, seem not to have been evaluated. It may be worthwhile to determine if competition between endogenous hormone-related chemicals and xenobiotics could increase our knowledge of the esterase and its possible role in Gulf War Syndrome and other autoimmune diseases.
The materials covered in this statement provide abundant evidence for the importance of immune system dysfunction as a cause of multiple human diseases. It also suggests that a lack of vitamin A, either as the result of a genetic deficiency, or as the result of poisoning by pesticides and/or other environmental contaminants, may play a central role in health problems that share immune dysfunction as a common factor. The possible importance of such a common mechanism is certainly worthy of study in relation to Gulf War Syndrome and the multiple additional health conditions that may be associated with autoimmunity.
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25. Mackness B et al. 2000, Eur J Clin Invest 30:4 [Non-text portions of this message have been removed] _________________________________________________________________