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SUMMARY

Immune system dysfunction may be a cause of multiple human autoimmune diseases, ranging from rheumatoid arthritis to multiple chemical sensitivities and Gulf War Illness. A lack of vitamin A hormone (retinoic acid) appears to play a key role in autoimmune disease. The deficit may be the result of a genetic deficiency in synthesis of the hormone, of exposure to environmental chemicals which interfere with hormone synthesis, or of a combination of the two. Prevention may be achieved by the use of vitamin A-rich diets and/or by avoidance of exposures to appropriate environmental chemicals.

INTRODUCTION

Vitamin A (retinol) and vitamin A hormone (retinoic acid) comprise one of the major human hormone systems. The importance of vitamin A in regulating visual accommodation as measured by both dark adaptation and photosensitivity has been known for many years.

Additional roles for vitamin A/retinoic acid have been recognized more recently. These include activation of synthesis of immune system proteins, activation of enzyme synthesis relative to apoptosis (killing off old cells) and drug metabolism, activation of protein synthesis related to neurotransmission, and activation of protein synthesis relating to reproduction. These findings suggest that quantitative changes in the vitamin A system may relate to health problems involving these areas. Without normal levels of vitamin A hormone, these systems are not fully functional.

Variations between individuals 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 as compared to the general population. Sub-populations such as those who served in the 1990-1991 Persian Gulf War also seem to be at greater risk than the general population. 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. Individuals at greatest risk of autoimmune disease appear to be those who combine the genetic deficiency with chemical exposures. 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) (see ref. 1). Higher infant mortality rates (2) and morbidity and mortality associated with infectious diseases (3) have also been demonstrated in vitamin A deficient children.

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.

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 central nervous system 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 a dearth of 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.

CHEMICAL EXPOSURES CAUSING VITAMIN A DEFICIENCY

Deficiency of vitamin A occurs frequently in humans and wildlife exposed to a wide array of environmental chemicals. Several processes appear to be involved. One is the binding of environmental chemicals to transthyretin, the protein which transports thyroid hormones and the retinol-retinol binding protein complex from sites of synthesis to sites of action. Evidence for poisoning of this process by environmental chemicals 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 inhibition blocks the conversion of these esters to retinol.

The third process involves interference with the oxidation of retinol, the product of retinyl ester hydrolysis, to retinoic acid, the active hormone. Retinol is oxidized via a two step process. The first step converts retinol to retinaldehyde and the second step converts retinaldehyde to retinoic acid (19,20). This step is also subject to poisoning. The synthetic chemicals, formaldehyde and acetaldehyde, both used in resin components of building products such as plasterboard and carpeting, are oxidized by the same process that converts retinaldehyde to retinoic acid. The presence of these competitors blocks the final step in hormone production and may be responsible for the human illness known as Sick Building Syndrome.

Different types of chemicals are involved in the different poisoning processes. Chlorinated phenoxyphenyls such as tetrachlorodioxin (TCDD), the major chemical involved in Agent Orange poisoning in Viet Nam, and polychlorinated biphenyls (PCB), a widely used plasticizer, both bind to transferrin and are well known as causes of human health problems. Hepatic vitamin A depletion in TCDD-treated rodents is a sensitive marker of TCDD exposures (21). Similar findings have been reported with exposures to PCBs and polybrominated biphenyls (22). Several types of insecticides, notably diphenyl ethanes such as DDT, and the phenoxybenzyl chlorinated pyrethroids such as permethrin and cypermethrin are potential transferrin poisons, but 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 poisons of many esterases, blocking reactions ranging from hydrolysis of acetylcholine 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 to protect 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.

High rates of Gulf War illnesses occurred in rear area personnel such as nurses. Sanitation and regular clothing changes are necessary for hospital service and laundry treatment of uniforms with permethrin is a possible cause of their health problems (personal communications with Gulf War veterans).

Exposures to residues of insecticides applied to interior living and working areas, and to lawns and gardens have produced 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 in civilians 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 the esterase gene PON-1, also known as paraoxonase or paraoxonase-1, 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 (23) 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 (24). Evidence of mutations in promoter sequences has been reported (25) along with evidence the mutations can cause large changes in PON1 activity.

The natural function of the PON1 esterase 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 (26) and other evidence it may relate to coronary disease (27). Alternative functions such as hydrolyzing lipophilic hormone precursors, e.g. retinyl esters, seem not to have been considered. 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.

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(c) 2002 Frederick W. Plapp, Jr. Ph.D. Reprinted with permission from the author.