Vitamin A/Dopamine/Pesticides/dilated pupils/constipation

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STATEMENT ON VITAMIN A IN RELATION TO GULF WAR SYNDROME AND OTHER AUTOIMMUNE

DISEASESDear Listers,

Any of you who have children with constipation and diIated pupils, have a look

at this page which I just came across. It connects lack of Vitamin A to

pesticide poisoning.

Lack of Vitamin A leads to reduced dopamine receptors and this deficiency means

unopposed high acetylcholine which in turn means Sympathetic Nervous System in

overdrive. This manifests clinically constipation and dilated

pupils!!!!!!!!!!It would also explain reflux as this valve is a smooth muscle

and also the fequent urination as the inside valve in the bladder is also smooth

muscle. ( Smooth muscle is relaxed by acetylcholine)

Unless I am very mistaken I think I just found another cause of ADHD..PESTICIDE

POISONING! Any children with autism manifesting the above symptoms, maybe not a

bad idea to do a pesticide check.

Quote from text: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.

Certain researchers are very interested in the connection between GWS and

Autism and Alzheimers as all have high values of IAG in their urine. ( Please

look up " Autism Research Unit, Sunderland, Shattock " for more details on

this.) High IAGs are being found also in Dyslexia and M.E. I believe there is a

common link being pesticides.

Feel free to post further.

in Germany

VITAMIN A IN RELATION TO GULF WAR SYNDROME AND OTHER AUTOIMMUNE DISEASES

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Subject: VITAMIN A IN RELATION TO GULF WAR SYNDROME AND OTHER AUTOIMMUNE

DISEASES

Date: Sun, 19 May 2002 09:09:40 -0400

From: Tvedten <steve@...>

Organization: Get Set Inc. (www.getipm.com)

Helliker <phelliker@...>

Director, State of California, Department of Pesticide Regulation

cc: Whitman whitman.christine@...

Gentlemen, I have read your postings in my email file. I am a retired

insecticide toxicologist with similar interests. For your information I paste

below a statement I have prepared describing what I propose may be an important

mechanism in this area. Please let me know what you think. Bill Plapp

STATEMENT ON VITAMIN A IN RELATION TO GULF WAR SYNDROME AND OTHER AUTOIMMUNE

DISEASES Frederick W. Plapp, Jr. Ph.D.

Professor Emeritus of Insecticide Toxicology Texas A & M University

<fwplapp@...

INTRODUCTION 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.

SUMMARY 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.

REFERENCES

1.. McLaren DS. 1999, J Indian Med Assoc 97:320

2.. Semba RD et al. 1998, J Trop Pediatr 44:232

3.. PR et al. 1995, S Afr Med J 85:373

4.. Wiedermann U et al. 1996, Infect Immun 64:209

5.. Harbige LS. 1996, Nutr Health 10:285

6.. son CB. 2001, Annu Rev Nutr 21:167

7.. Comstock GW et al. 1997, Ann Rheum Dis 56:323

8.. Helgeland M et al. 2000, Clin Exp Rheumatol 18:637

9.. Cantorna MT, CE. 1996, J Infect Dis 174:747

10.. Krill D et al. 1997, Hum Biol 69:89

11.. Baena N et al. 2002, Eur J Clin Nutr 56:44

12.. un SY, Lotan R. 2002, Crit Rev Oncol Hematol 41:41

13.. Kafwembe EM et al. 2001, East Afr Med J 78:451

14.. Samad TA et al. 1997, Proc Natl Acad Sci 94:14349

15.. Wolf G. 1998, Nutr Rev 56:354

16.. Misner DL et al. 2001, Proc Natl Acad Sci 98:11714

17.. Etchamendy N et al. 2001, J Neurosci 21:6423

18.. Brouwer A, van den Berg KJ. 1986 Toxicol Appl Pharmacol 85:301

19.. Fletcher N et al 2001, 62:166

20.. Hallgren S et al. 2001, Arch Toxicol 75:200

21.. Haley RW et al. 1999, Toxicol Appl Pharmacol 157: 227

22.. Mackness B et al. 2002, Eur. J Clin Invest 32:259

23.. Furlong CE et al. 2000, Neurotoxicology 21:91

24.. Brophy VH et al. 2001, Pharmacogenetics 11:77

25.. Mackness B et al. 2000, Eur J Clin Invest 30:4

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