2: fluoride, pineal, glutathione, liver, kidney: autism epidemiology

[Guest guest]

This series' initial post called attention to fluoride-accumulation within the

human pineal, stating:

" Since many autism-spectrum children (ASC) have impaired detoxification (as

documented by high levels of toxic metals excreted during chelation, as

reinforced by the traits-improvements many such children experience during and

after chelation), the question arises: Does an autism-spectrum child with

impaired detoxification accumulate excessive fluoride or fluoride-related

compounds. Relatedly, might the sleep problems common in ASC be -- in many such

kids -- a reflection of excessive accumulation of fluoride within the pineal

gland? " Several abstracts were presented " linking pineal and autism, pineal

and fluoride " -- along with a quote from fluoride researcher Ellen Connet.

Glutathione participates in immune processes and in detoxification of toxic

metals, thus a child low in GSH or having impaired GSH-transport might

accumulate excessive fluoride. One ramification of these relationships is that

studies about fluoride-effects in healthy human adults may have little

significance regarding adverse effects of fluoride accumulation in autistic

children or in infants and toddlers who would regress into the autism-spectrum.

1: Zhonghua Yu Fang Yi Xue Za Zhi 2000 May;34(3):134-135

[The effect of fluoride-arsenic exposure on the lipid peroxidation and

antioxidation of the offspring of rats] [Article in Chinese]

Zhang C, Liu J, Ling B, et Al.

OBJECTIVE: To provide information on the effects of the offspring of rats

exposed to fluoride-arsenic... CONCLUSION: Fluoride-arsenic exposure can cause

oxidative damage of the rat's offspring.

2. [renal damage, role of GSH]

Arch Toxicol 1999 Aug;73(6):346-51

Usefulness of the assessment of urinary enzyme leakage in monitoring acute

fluoride nephrotoxicity.

Usuda K, Kono K, Dote T, Nishiura H, Tagawa T.

A single oral dose of sodium fluoride (NaF) in aqueous solution was given to

male Wistar rats. Twenty-four-hour urine samples were collected and examined to

evaluate fluoride-induced acute renal damage. The following parameters were

measured in 24-h urine: urine volume and urinary excretion of fluoride,

N-acetyl-beta-d-glucosaminidase (NAG), alpha-glutathione-S-transferase

(alpha-GST), and creatinine (CR). Fluoride exposure produced specific,

dose-dependent changes of these parameters. Significant increases of fluoride

and fluoride-induced polyuria were observed. NAG as specific marker of proximal

convoluted tubule (PCT) function showed a significant increase when the lowest

dose of fluoride was administered. At this minimal dose, alpha-GST, a specific

marker for the S3 segment, did not show a significant increase but presented the

strongest relationship (r = 0. 83) to fluoride dose. No significant changes were

measured for CR excretion, which showed a low correlation coefficient (r = 0.36)

to administered fluoride. The specific differences in the increase pattern of

these parameters show that the PCT is more susceptible to damage by low-dose

fluoride than the S3 segment or the glomerulus. We concluded that both NAG and

alpha-GST are useful for the diagnosis of fluoride-induced acute nephrotoxicity.

Proper evaluation of these urinary indices may be of help to establish the site

and extent of kidney injury in acute fluoride toxicity.

3. [impaired detox was not a focus of this study, thus its findings are perhaps

magnified for fetuses, infants, and toddlers with impaired detox.]

Cell Biol Toxicol 1998 Dec;14(6):383-9

Cytotoxicity of sodium fluoride on human oral mucosal fibroblasts and its

mechanisms.

Jeng JH, Hsieh CC, Lan WH, Chang MC, Lin SK, Hahn LJ, Kuo MY.

School of Dentistry, College of Medicine, National Taiwan University, Taipei.

Because sodium fluoride (NaF) is widely used for prevention of dental caries,

pathobiological effects of NaF were investigated on human oral mucosal

fibroblasts... These results indicate that NaF can be toxic to oral mucosal

fibroblasts in vitro by its inhibition of protein synthesis, mitochondrial

function and depletion of cellular ATP. Because of repeated and long-term usage

of NaF, more detailed studies should be undertaken to understand its toxic

effects in vitro and in vivo. "

4. Brain Res Mol Brain Res 1998 Jan;53(1-2):196-205

Glutathione depletion exacerbates impairment by oxidative stress of

phosphoinositide hydrolysis, AP-1, and NF-kappaB activation by cholinergic

stimulation.

Li X, Song L, Jope RS.

University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.

Oxidative stress appears to contribute to neuronal dysfunction associated with

Alzheimer's disease and other CNS neurodegenerative disorders. This

investigation examined if oxidative stress might contribute to impairments in

cholinergic receptor-linked signaling systems and if intracellular glutathione

levels modulated responses to oxidative stress... These results demonstrate

that the vulnerability of signaling systems to oxidative stress is influenced by

intracellular glutathione levels, indicating that cell-selective susceptibility

to inhibition of signal transduction systems by oxidative stress can arise from

cellular variations in antioxidant capacity.

5. [This study used healthy volunteers, thus has little relevance to fluoride

safety for fetuses, infants, and toddlers wherein impaired detoxification is

present.]

Anesthesiology 1998 Mar;88(3):601-10

Absence of biochemical evidence for renal and hepatic dysfunction after 8 hours

of 1.25 minimum alveolar concentration sevoflurane anesthesia in volunteers.

Ebert TJ, Frink EJ Jr, Kharasch ED.

Department of Anesthesiology, VA Medical Center, Milwaukee, Wisconsin 53295,

USA.

<tjebert@...>

BACKGROUND: Sevoflurane is degraded by carbon dioxide absorbents to a

difluorovinyl ether (compound A) that can cause renal and hepatic injury in

rats.... . METHODS: Thirteen healthy male volunteers provided informed consent

to undergo 8 h of 1.25 minimum alveolar concentration sevoflurane anesthesia

delivered with a fresh gas flow of 2 l/min... CONCLUSIONS: Prolonged (8 h), high

concentration (3%) sevoflurane anesthesia administered to volunteers in a fresh

gas flow of 2 l/min does not result in clinically significant changes in

biochemical markers of renal or hepatic dysfunction.

6. 12: FEBS Lett 1998 Jan 30;422(2):185-8

Activation by sodium fluoride of drug-metabolizing enzymes in rat

hepatoma-derived Fa32 cells.

Dierickx PJ. <p.dierickx@...>

Protection against xenobiotic insult, including cancer chemoprotection, can be

achieved by a variety of natural and synthetic compounds belonging to over 20

different classes of chemicals. They all induce or activate drug-metabolizing

enzymes. The discovery of a new class of activator is currently reported. Sodium

fluoride activated the phase I ethoxyresorufin-O-deethylase (to 240%) and

pentoxyresorufin-O-depentylase (to 156%), and the phase II glutathione

transferase to 120% of the basal activities in rat hepatoma-derived Fa32 cells.

It is, therefore, a bifunctional enzyme activator. A time- and

concentration-dependent activation was observed. A possible impact of the daily

fluoride uptake from drinking water is suggested.

7. [This study links sodium fluoride to kidney damage and shows a relationship

to a GSH-transferase. Acute toxicity in rats is not the same as chronic

toxicity in fetuses, infants, and toddlers wherein impaired detoxification is

present.]

Arch Toxicol 1998;72(2):104-9

Urinary biomarkers monitoring for experimental fluoride nephrotoxicity.

Usuda K, Kono K, Dote T, Nishiura K, Miyata K, Nishiura H, Shimahara M, Sugimoto

K.

Department of Hygiene and Public Health, Osaka Medical College, Takatsuki City,

Japan.

An excess of sodium fluoride (135 mg F/kg body weight) was given in a single

oral dose to male Wistar rats. Effects were investigated of fluoride-induced

acute kidney intoxication on the time-dependent variations of urine volume.

Also, of urinary fluoride ion (F-), alpha-glutathione-S-transferase (alpha-GST),

N-acetyl-beta-D-glucosaminidase (NAG), and creatinine (CR) concentrations.

Fluoride administration strongly affects these urinary biochemical indices. Of

the several biomarkers studied, alpha-GST is particularly useful as marker of S3

proximal tubule damage. We found that alpha-GST shows the strongest and more

durable changes as a result of the large dose of F- given to the experimental

animals. Our results suggest that the toxic effect of F- on the kidney may be

more pronounced in the proximal tubule than the glomeruli region, and that the

disorder of the proximal tubule is more serious in the S3 segment than S1 or S2

segment. Alpha-GST proved to be a useful marker for the early detection and

long-term observation of proximal renal tubular injury resulting from

F-intoxication. The animal model should help to establish guidelines for the

treatment of industrial workers suffering from acute renal failure resulting

from accidental exposure to fluoride.

8. [Low GSH exacerbates hepatic injury.]

Toxicol Appl Pharmacol 1995 Sep;134(1):175-81

Biotransformation and hepatotoxicity of HCFC-123 in the guinea pig: potentiation

of hepatic injury by prior glutathione depletion.

Lind RC, Gandolfi AJ, Hall PD.

The chlorofluorocarbon substitute 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123)

is a structural analog of halothane. Both are oxidatively metabolized by CYP2EI,

producing a reactive trifluoroacyl acid chloride intermediate and have been

shown to cause acute liver necrosis in the guinea pig. With halothane, liver

injury has been associated with the degree of reactive intermediate binding to

hepatic protein. This injury can be potentiated by prior glutathione (GSH)

depletion.... These findings demonstrate a role for hepatic GSH in helping to

prevent covalent binding by the trifluoroacyl acid chloride intermediate.

Inhalation of HCFC-123 can cause acute hepatic injury in the guinea pig that is

worsened by low hepatic GSH concentrations.

9. Bull Environ Contam Toxicol 2002 Apr;68(4):612-6

Lipid peroxidation and antioxidant defense systems in liver of rats in chronic

fluoride toxicity.

Shivashankara AR, Shivarajashankara YM, Bhat PG, Rao SH.

10. [Note fluoride's effects upon phosphatidylethanolamine (PE),

phosphatidylcholine (PC) and phosphatidylserine (PS).]

Toxicology 2000 May 5;146(2-3):161-9

Effect of long term fluoride exposure on lipid composition in rat liver.

Wang YN, Xiao KQ, Liu JL, Dallner G, Guan ZZ.

Department of Scientific Research Administration, Guiyang Medical College,

Guiyang 550004, Guizhou, PR China.

Chronic fluorosis can severely damage many systems of human body, but its

pathogenesis is unclear. Normal composition and structure of cellular membrane

lipids are a basic factor to maintain cell function. In this investigation,

cellular membrane lipids of the liver were analysed after a long term fluoride

treatment for rats and the results are discussed in order to give an explanation

for the pathogenesis of this disease... Results showed that the total liver

phospholipid content decreased in the rats treated with high dose of fluoride

due to a lower content of phosphatidylethanolamine (PE), phosphatidylcholine

(PC) and phosphatidylserine (PS). Among the fatty acid compositions of PE and PC

in the livers of fluoride poisoned animals, the proportion of polyunsaturated

fatty acids (20:4 and 22:6) decreased, whereas saturated fatty acids (16:0 and

18:0) increased. No changes could be detected in the amounts of liver

cholesterol and dolichol. Total ubiquinone contents in rat liver were reduced by

11% in the group treated with 30 ppm fluoride and by 42% in the group treated

with 100 ppm fluoride. In the subclasses of ubiquinone, both ubiquinone-9 and

ubiquinoine-10 amounts decreased after fluoride treatment. These modifications

of membrane lipids might be induced by oxidative stress, which might be an

important factor in the pathogenesis of chronic fluorosis.

11. Arch Biochem Biophys 1992 Apr;294(1):238-43

A two-step mechanism of fluoride inhibition of rat liver inorganic

pyrophosphatase.

Baykov AA, androv AP, Smirnova IN.

Product formation curves for inorganic pyrophosphatase-catalyzed hydrolysis of

pyrophosphate in the presence of fluoride were analyzed in order to get insight

into the mechanism of its inhibitory action on this enzyme... Kinetic

parameters obtained in this work indicate that appreciable inactivation of

pyrophosphatase can occur at fluoride concentrations found in human plasma. This

effect may therefore be one of the major factors contributing to fluoride

toxicity.

12. Cell Signal 1991;3(6):599-606

Effect of fluoride, pertussis and cholera toxin on the release of arachidonic

acid and the formation of prostaglandin E2, D2, superoxide and inositol

phosphates in rat liver macrophages.

Schulze-Specking A, Duyster J, Gebicke-Haerter PJ, Wurster S, Dieter P.

Biochemisches Institut, Freiburg, Germany.

Fluoride elicited in liver macrophages a release of arachidonic acid and

prostaglandins but not formation of inositol phosphates or superoxide. The

effects of fluoride required extracellular calcium and were inhibited by

staurosporine and by phorbol ester treatment of the cells. Furthermore, fluoride

led to a translocation of protein kinase C from the cytosol to membranes. This

indicates that the calcium-dependent protein kinase C is involved in the action

of fluoride. Cholera toxin decreased the zymosan-induced release of arachidonic

acid and prostaglandins but not of inositol phosphates or superoxide. Pertussis

toxin ADP-ribosylated a 41,000 molecular weight membrane protein; enhanced

specifically the zymosan-induced formation of prostaglandin(PG)E2 but did not

affect the zymosan-induced release of arachidonic acid, PGD2, inositol

phosphates or superoxide. These data suggest that activation of phospholipase

(PL)A2, hosphoinositide (PI)-specific PLC and NADPH oxidase in liver macrophages

is most probably not mediated by activation of guanine nucleotide binding

(G)-proteins coupled directly to these enzymes.

13. [Mercury blood-levels]

Scand J Clin Lab Invest 1992 Jun;52(4):321-37

Reference intervals for trace elements in blood: significance of risk factors.

Grandjean P, Nielsen GD, nsen PJ, Horder M.

Institute of Community Health, Odense University, Denmark.

A random sample of 100 men and 100 women was examined for whole-blood

concentrations of mercury, lead, cadmium and selenium, and the serum

concentrations of selenium, nickel, fluoride, aluminium, zinc and copper. Major

predictors were sex, hormonal factors (pregnancy, menopause, use of oral

contraceptives), age, tobacco smoking and alcohol drinking. Among notable

associations, increased blood-mercury was related to the presence of more than

four amalgam fillings in the teeth. ...

14. Experientia 1981 Dec 15;37(12):1328-9

Zinc, copper and manganese levels in various tissues following fluoride

administration.

Kanwar KC, Singh M.

Distribution of zinc, copper and manganese has been studied in liver, kidney and

bone of rats subjected for 10 months to varied fluoride concentrations in

drinking-water. In the liver a significant fall in the levels of Mn, Cu and Zn

was registered. In the kidney, the Mn level fell whereas the zinc leve

increased. In the bone, the copper content fell, whereas the manganese content

increased.

eof