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The Seaweed Gatherers, Paul Gaugin
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Iodine Research
Resource Network of The Iodine Movement
GOITROGENIC FOODS pg 2
(return to overview, pg 1)
DOERGE
Goitrogenic and estrogenic activity of soy isoflavones
Doerge DR, Sheehan DM.
Environ Health Perspect. 2002 Jun;110 Suppl 3:349-53. Review.
Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of
isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen
developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic
effect in women. We then focus on evidence from animal and human studies suggesting a link
between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency
greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy
effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats
consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced
dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro.
Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects
are clear and reproducible, other measures of thyroid function in vivo (serum levels of
triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid
histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid
toxicity. These clearly include iodine deficiency but may also include additional soy components, other
defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of
natural products, including soy products, is not required, the possibility that widely consumed soy
products may cause harm in the human population via either or both estrogenic and goitrogenic
activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the
best way to address these concerns. Similar studies in wildlife populations are also appropriate.
Inactivation of thyroid peroxidase by soy isoflavones, in vitro and in vivo
Doerge DR, Chang HC.
J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Sep 25;777(1-2):269-79. Review.
[abstract only
Soy-containing foods and dietary supplements are widely consumed for putative health benefits (e.g.
cancer chemoprevention, beneficial effects on serum lipids associated with cardiovascular health,
reduction of osteoporosis, relief of menopausal symptoms). However, studies of soy isoflavones in
experimental animals suggest possible adverse effects as well (e.g. enhancement of reproductive
organ cancer, modulation of endocrine function, anti-thyroid effects). This paper reviews the evidence
in humans and animals for anti-thyroid effects of soy and its principal isoflavones, genistein and
daidzein.
Mechanism for inhibition of thyroid peroxidase by leucomalachite green.
Doerge DR, Chang HC, Divi RL, Churchwell MI.
Chem Res Toxicol. 1998 Sep;11(9):1098-104.
[abstract only]
The triphenylmethane dye, malachite green (MG), is used to treat and prevent fungal and parasitic
infections in the aquaculture industry. It has been reported that the reduced metabolite of MG,
leucomalachite green (LMG), accumulates in the tissues of fish treated with MG. MG is structurally
related to other triphenylmethane dyes (e.g., gentian violet and pararosaniline) that are carcinogenic
in the liver, thyroid, and other organs of experimental animals. The ability of LMG to inhibit thyroid
peroxidase (TPO), the enzyme that catalyzes the iodination and coupling reactions required for thyroid
hormone synthesis, was determined in this study. LMG inhibited TPO-catalyzed tyrosine iodination
(half-maximal inhibition at ca. 10 microM). LMG also inhibited the TPO-catalyzed formation of thyroxine
in low-iodine human goiter thyroglobulin (half-maximal inhibition at ca. 10 microM) using a model
system that measures simultaneous iodination and coupling. Direct inhibition of the coupling reaction
by LMG was shown using a coupling-only system containing chemically preiodinated thyroglobulin as
the substrate. Incubation of LMG with TPO, iodide, and tyrosine in the presence of a H2O2-generating
system yielded oxidation products that were identified by using on-line LC/APCI-MS as desmethyl
LMG, 2desmethyl LMG, 3desmethyl LMG, MG, and MG N-oxide. Similar products from LMG were
observed in incubations with TPO and H2O2 alone. These findings suggest that the anti-thyroid
effects (increased serum thyroid-stimulating hormone and decreased serum thyroxine) observed in
rats treated with LMG result from blockade of hormone synthesis through alternate substrate inhibition
and that chronic exposure could cause thyroid follicular cell tumors through a hormonal mechanism.
The observed TPO-catalyzed oxidative demethylation of LMG to a primary arylamine also suggests a
genotoxic mechanism for tumor formation is possible.
Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action.
Divi RL, Chang HC, Doerge DR.
Biochem Pharmacol. 1997 Nov 15;54(10):1087-96.
[abstract only]
The soybean has been implicated in diet-induced goiter by many studies. The extensive consumption
of soy products in infant formulas and in vegetarian diets makes it essential to define the goitrogenic
potential. In this report, it was observed that an acidic methanolic extract of soybeans contains
compounds that inhibit thyroid peroxidase- (TPO) catalyzed reactions essential to thyroid hormone
synthesis. Analysis of the soybean extract using HPLC, UV-VIS spectrophotometry, and LC-MS led to
identification of the isoflavones genistein and daidzein as major components by direct comparison with
authentic standard reference isoflavones. HPLC fractionation and enzymatic assay of the soybean
extract showed that the components responsible for inhibition of TPO-catalyzed reactions coeluted
with daidzein and genistein. In the presence of iodide ion, genistein and daidzein blocked TPO-
catalyzed tyrosine iodination by acting as alternate substrates, yielding mono-, di-, and
triiodoisoflavones. Genistein also inhibited thyroxine synthesis using iodinated casein or human goiter
thyroglobulin as substrates for the coupling reaction. Incubation of either isoflavone with TPO in the
presence of H2O2 caused irreversible inactivation of the enzyme; however, the presence of iodide ion
in the incubations completely abolished the inactivation. The IC50 values for inhibition of TPO-
catalyzed reactions by genistein and daidzein were ca. 1-10 microM, concentrations that approach the
total isoflavone levels (ca. 1 microM) previously measured in plasma from humans consuming soy
products. Because inhibition of thyroid hormone synthesis can induce goiter and thyroid neoplasia in
rodents, delineation of anti-thyroid mechanisms for soy isoflavones may be important for extrapolating
goitrogenic hazards identified in chronic rodent bioassays to humans consuming soy products.
Inhibition of thyroid peroxidase by dietary flavonoids.
Divi RL, Doerge DR.
Chem Res Toxicol. 1996 Jan-Feb;9(1):16-23.
[abstract only]
Flavonoids are widely distributed in plant-derived foods and possess a variety of biological activities
including antithyroid effects in experimental animals and humans. A structure-activity study of 13
commonly consumed flavonoids was conducted to evaluate inhibition of thyroid peroxidase (TPO), the
enzyme that catalyzes thyroid hormone biosynthesis. Most flavonoids tested were potent inhibitors of
TPO, with IC50 values ranging from 0.6 to 41 microM. Inhibition by the more potent compounds,
fisetin, kaempferol, naringenin, and quercetin, which contain a resorcinol moiety, was consistent with
mechanism-based inactivation of TPO as previously observed for resorcinol and derivatives. Other
flavonoids inhibited TPO by different mechanisms, such as myricetin and naringin, showed
noncompetitive inhibition of tyrosine iodination with respect to iodine ion and linear mixed-type
inhibition with respect to hydrogen peroxide. In contrast, biochanin A was found to be an alternate
substrate for iodination. The major product, 6,8-diiodo-biochanin A, was characterized by electrospray
mass spectrometry and 1H-NMR. These inhibitory mechanisms for flavonoids are consistent with the
antithyroid effects observed in experimental animals and, further, predict differences in hazards for
antithyroid effects in humans consuming dietary flavonoids. In vivo, suicide substrate inhibition, which
could be reversed only by de novo protein synthesis, would be long-lasting. However, the effects of
reversible binding inhibitors and alternate substrates would be temporary due to attenuation by
metabolism and excretion. The central role of hormonal regulation in growth and proliferation of
thyroid tissue suggests that chronic consumption of flavonoids, especially suicide substrates, could
play a role in the etiology of thyroid cancer.
Inhibition of peroxidase-catalyzed reactions by arylamines: mechanism for the anti-thyroid action of
sulfamethazine.
Doerge DR, Decker CJ.
Chem Res Toxicol. 1994 Mar-Apr;7(2):164-9.
[abstract only]
Sulfonamide antibiotics, typified by sulfamethazine (SMZ), are widely used in veterinary practice.
Sulfonamide residues in milk and meat products are of regulatory concern since SMZ is a thyroid
carcinogen in rodents and sulfonamide-induced hypersensitivity reactions, including hypothyroidism,
have been reported in humans. SMZ and other primary arylamines inhibited iodination reactions
catalyzed by thyroid peroxidase (TPO) and the closely related lactoperoxidase (LPO). Inhibition of
LPO-catalyzed triiodide ion formation by SMZ and other primary arylamines was complex as both
apparent Km and Vmax values were affected, but consistent with a rapid equilibrium binding
mechanism. The apparent Ki for SMZ inhibition of TPO- and LPO-catalyzed iodide ion oxidation was
approximately 0.42 and 0.11 mM, respectively. The corresponding Ki values for a series of para-
substituted anilines correlated with the ease of one-electron N-oxidation as measured by ionization
potentials determined from semiempirical molecular orbital calculations. The aniline derivatives
containing electron-donating substituents (e.g., p-CH3, p-OEt, p-Cl) were converted by LPO to
colored products characteristic of one-electron oxidation. However, sulfonamides were not consumed
in such reactions nor were any N-oxygenated derivatives formed in the absence of ascorbate (e.g.,
hydroxylamino, nitroso, nitro, azoxy). These observations suggest that the primary mechanism for
sulfonamide-induced hypothyroidism is reversible inhibition of TPO-mediated thyroid hormone
synthesis and not the formation and covalent binding of reactive N-oxygenated metabolites. These
results are consistent with a hormonal mechanism for SMZ-induced thyroid carcinogenesis mediated
by thyroid-stimulating hormone (TSH). (ABSTRACT TRUNCATED AT 250 WORDS)
Mechanism-based inactivation of lactoperoxidase and thyroid peroxidase by resorcinol derivatives.
Divi RL, Doerge DR.
Biochemistry. 1994 Aug 16;33(32):9668-74.
[abstract only]
Humans are exposed to resorcinol derivatives in the environment through ground water, foods, food
additives, drugs, and hair dyes. Epidemiological studies have linked human exposure to phenolic
compounds with the thyroid disorder, goiter. The results presented here demonstrate the suicide
(mechanism-based) inactivation of thyroid peroxidase (TPO) and the closely related lactoperoxidase
(LPO) by resorcinol derivatives. The evidence for this mechanism includes irreversible, hydrogen
peroxide-dependent loss of enzymatic activity by kinetics consistent with a suicide mechanism,
concomitant with changes in the visible spectrum of the prosthetic heme group and covalent binding of
resorcinol (ca. 10 mol/mol of lactoperoxidase inactivated). The inactivation was specific for thyroid
peroxidase and lactoperoxidase since the activity of horseradish peroxidase, myeloperoxidase,
chloroperoxidase, or the pseudoperoxidase, metmyoglobin, was unaffected by incubation with
resorcinol. The enzymatic oxidation of resorcinol by lactoperoxidase was linked to inactivation since
the same products were observed spectrally, albeit at a much lower level, as were observed with
horseradish peroxidase. The results are consistent with thyroid peroxidase- and lactoperoxidase-
catalyzed oxidation of resorcinol derivatives to reactive radical species that covalently bind to amino
acid residues unique to these two enzymes. The oxidation of thyroid peroxidase and lactoperoxidase
by hydrogen peroxide produces catalytic intermediates containing unpaired electron density on amino
acid residues similar to that seen with cytochrome c peroxidase. These results provide an explanation
for the potency of resorcinol derivatives in the inhibition of LPO and TPO and the goitrogenic
responses observed in humans and animals. The widespread occurrence of resorcinol derivatives in
the environment suggests that exposure to these compounds may cause thyroid dysfunction in
humans.
Mechanism of thyroid peroxidase inhibition by ethylenethiourea.
Doerge DR, Takazawa RS.
Chem Res Toxicol. 1990 Mar-Apr;3(2):98-101.
[abstract only]
Ethylenethiourea (ETU) is a thyroid carcinogen present in foods formed by degradation and
metabolism of ethylenebis[dithiocarbamate] fungicides. ETU inhibits thyroid peroxidase (TPX), the
enzyme that catalyzes synthesis of thyroid hormones. Inhibition of TPX-catalyzed reactions by ETU
occurs only in the presence of iodide ion with concomitant oxidative metabolism to imidazoline and
bisulfite ion. Inhibition ceases upon consumption of ETU with no loss of enzymatic activity and
negligible covalent binding of ETU to TPX. TPX inhibition by ETU is unlike that for derivatives of
imidazoline-2-thione, which cause suicide inactivation via covalent binding to the prosthetic heme
group. These results demonstrate a metabolic route for detoxication of ETU in the thyroid and suggest
that low-level or intermittent exposure to ETU would have minimal effects on thyroid hormone
production.
GAITAN
Flavonoids and the thyroid
Gaitan E.
Nutrition. 1996 Feb;12(2):127-9.
[citation only]
Antithyroid effects in vivo and in vitro of vitexin: a C-glucosylflavone in millet
Gaitan E, Cooksey RC, Legan J, Lindsay RH.
J Clin Endocrinol Metab. 1995 Apr;80(4):1144-7.
[abstract only]
Millet diets rich in C-glycosylflavones (C-GF) are goitrogenic, and its three most abundant C-GF inhibit
in vitro thyroid peroxidase, suggesting that these compounds are the goitrogens in millet. However,
proof of a cause and effect relationship between C-GF and goitrogenesis requires a demonstration of
in vivo antithyroid activity by the purified isolated compounds. Vitexin, one of the three major C-GF in
millet, was used to test this hypothesis. Twenty-four female Wistar rats, divided into groups of six rats
each and fed Purina iodine-rich diet (12 micrograms I-/day.rat), were administered acutely by
gastrointestinal tube goitrogen-free water (controls), methimazole (0.5 mumol), and vitexin (20 and 80
mumol). 125I (1 microCi) was injected ip 1 h later, and the rats were killed 2 h after the injection. The
thyroid glands were removed and analyzed for their content of total 125I and 125I-labeled compounds.
Rats given vitexin, in contrast to those receiving methimazole, did not show suppressed thyroid 125I
uptake. However, significant inhibition of the coupling mechanism (high 125I-labeled monoiodotyrosine
plus diiodotyrosine/125T3 plus T4 ratio and low 125T3 and T4 concentrations) did occur with the
highest dose of vitexin. These results provide direct evidence in vivo of C-GF antithyroid activity,
strongly supporting the concept that C-GF are the goitrogens in millet.
Antithyroid effects in vivo and in vitro of babassu and mandioca: a staple food in goiter areas of Brazil
Gaitan E, Cooksey RC, Legan J, Lindsay RH, Ingbar SH, Medeiros-Neto G.
Eur J Endocrinol. 1994 Aug;131(2):138-44.
[abstract only]
Babassu (Orbignya phalerata), a palm-tree coconut fruit, mixed with mandioca (Manihot utilissima) is
the staple food of people living in the endemic goiter area of Maranhao in Brazil, where goiter
prevalence among schoolchildren was still 38% in 1986 despite an adequate iodine intake in most of
the population. Therefore, the question arose as to whether or not the ingestion of babassu alone or
mixed with mandioca contributed to the persistence of endemic goiter in this area of Brazil. In this
investigation we examined the potential antithyroid effects of babassu and mandioca by means of in
vivo studies in Sprague-Dawley rats, in vitro studies in porcine thyroid slices and using a purified
porcine thyroid peroxidase (TPO) system. Samples of various edible parts of babassu and mandioca
flour were homogenized and extracted in goitrogen-free water (GFW) for in vivo experiments, and in
methanol (100 g/l), GFW or 0.06 mol/l phosphate buffer (pH 7.0) for in vitro experiments. The edible
parts of babassu produced significant in vivo antithyroid effects (p < 0.05- < 0.001) in rats on a high
iodine intake (14 micrograms I- day-1.rat-1), as well as distinct and reproducible antithyroid and anti-
TPO activities in both in vitro systems, their action being similar to that of the thionamide-like
antithyroid drugs propylthiouracil and methimazole. (ABSTRACT TRUNCATED AT 250 WORDS)
Antithyroid and goitrogenic effects of coal-water extracts from iodine-sufficient goiter areas
Gaitan E, Cooksey RC, Legan J, Cruse JM, Lindsay RH, Hill J.
Thyroid. 1993 Spring;3(1):49-53.
[no abstract]
Goiter in iodine-sufficient areas has been linked to water-borne goitrogens in watersheds and aquifers
rich in coal and shale. In the present study, the potential antithyroid and goitrogenic effects of coal-
water extracts (CWE) were investigated in vivo in rats after chronic and acute oral administration of
CWE, and in vitro by a thyroid peroxidase (TPO) enzyme system. CWE was prepared by continuous
extraction of ground (40 mesh) Appalachian coal with goitrogen-free water (GFW). Female Buffalo
rats fed on Purina iodine-rich diet (12 micrograms I-/day/rat), were given ad lib CWE (50 mg/ml;
approximately 20 mL/day/rat) or GFW (controls) for 2 months. At the end of the experiment, 125I 1
microCi, was injected i.p. and 4 h later the thyroid glands were removed, weighed, and analyzed
histologically and for total 125I and 125I-labeled compounds. Rats on CWE had larger thyroid glands
[7.2 +/- 0.3 mg/100 g (mean +/- SE) vs 5.0 +/- 0.5 controls; p < 0.005] with distinct histological
changes of smaller thyroid follicles, some with columnar epithelium, and with more dense colloid than
in controls, and had significant inhibition of the coupling mechanism for production of thyroid
hormones [125MIT + DIT/125T3 + T4: 5.1 +/- 0.2 vs 3.9 +/- 0.1 controls, p < 0.005; and 125T3 + T4
(%): 10.6 +/- 0.3 vs 12.6 +/- 0.4 controls, p < 0.005]. Female Sprague-Dawley rats under the same
conditions as Buffalo rats were given acutely by GI tube 2 mL of CWE (5 g/mL) or GFW (controls).
(ABSTRACT TRUNCATED AT 250 WORDS)
Antithyroid effects of coal-derived pollutants
Lindsay RH, Hill JB, Gaitan E, Cooksey RC, Jolley RL.
J Toxicol Environ Health. 1992 Dec;37(4):467-81.
[abstract only]
Endemic goiter in iodide-sufficient areas of the United States and Colombia has been linked to
watersheds rich in coal and shale, which several reports suggest are the source of water-borne
goitrogens. In this report the potential antithyroid activities of aqueous coal and shale extracts and of
compounds identified in aqueous effluents from coal conversion processes were assayed in thyroid
peroxidase (TPO) and thyroid slice systems. Aqueous extracts of coal and black shale were potent
inhibitors of TPO or 125I organification by thyroid slices. The most abundant water-soluble
compounds derived from coal are dihydroxy-phenols, thiocyanate, disulfides, and hydroxypyridines.
The dihydroxyphenols resorcinol, 2-methylresorcinol, and 5-methylresorcinol (orcinol) were 26.7, 22.5,
and 7.2 times more potent, respectively, than the antithyroid drug 6-propylthiouracil (PTU). Other
dihydroxyphenols and thiocyanate were less potent but comparable in activity to PTU. All
dihydroxypyridines and 3-hydroxypyridine produced inhibitory effects comparable to PTU. None of the
disulfides inhibited TPO. The antiperoxidase effects of combinations of two dihydroxyphenols or one
dihydroxyphenol and SCN were additive, whereas the effects of a combination of four
dihydroxyphenols at threshold inhibitory concentrations were synergistic, resulting in net effects
equivalent to or greater than the sum of the individual effects. Thus, antithyroid effects may be greatly
amplified by exposure to multiple coal-derived goitrogens and could be many times that produced by
any one of the contributing pollutants. These results demonstrate that potent water-borne goitrogens
are derived from coal and shale and that their contamination of water supplies could pose a serious
threat of thyroid disorders.
Goitrogens in food and water
Gaitan E.
Annu Rev Nutr. 1990;10:21-39. Review.
Epidemiologic and experimental evidence reviewed in this article emphasizes the complex and
multifactorial etiology of endemic goiter. The important role of iodine deficiency as an etiologic factor
in endemic goiter is firmly established, but there is evidence that other environmental factors can play
an equally important role in the pathogenesis of this condition. Chemical categories, sources, and
sites of action of the various classes of naturally occurring goitrogens and antithyroid agents are
reviewed in this article. Evidence of the presence of these compounds in foodstuffs and drinking water
is discussed. Bacterial contamination of water supplies also appears to be important in the
development of goiter. Microorganisms appear to intervene in the biosynthesis and degradation of
organic goitrogenic pollutants or may induce thyroid growth-promoting activity in the host, or both.
Malnutrition and poor socioeconomic conditions, as for iodine deficiency, enhance the action of
environmental goitrogens. Thus, a coordinated multidisciplinary approach is essential to solving this
public health problem.
General Concepts of Environmental Goitrogenesis
Gaitan E, Cooksey RC
Chapter 1 in Environmental Goitrogenesis by E Gaitan, 1989, pp 4 - 11.
Agents and pollutants that cause goiter--also known as environmental goitrogens--will be the focus of
this book. The study of environmental goitrogens, requires the understanding, interest, and
collaboration of multiple disciplines--some outside the confines of the Biological Sciences. The
difficulty in complying with this important requirement has fragmented our knowledge and prevented
the effective investigation of many questions that surround this important and controversial issue.
With the exception of iodine deficiency, the public health and socioeconomic impact of environmental
goitrogens are practically unknown.
[Contains a table of 38 environmental agents (chemicals) producing goitrogenic and/or antithyroid
effects]
Epidemiological aspects of environmental goitrogenesis
Gaitan E
Chapter 12 in Environmental Goitrogenesis by E Gaitan, 1989, pp 161 - 169.
Seaweeds of species of the general Laminaria have a high content of phloroglucinol and
polyhydroxyphenols, some in the form of phloroglucinol polymers (fucophloroethols). Phloroglucinol
and other polyhydroxyphenols, which are potent antithyroid compounds, may play an additional role to
that of iodine excess in the development of these goiters.
Millet and the thyroid ( no link available)
Gaitan E, Lindsay R, Cooksey RC
Chapter 14 in Environmental Goitrogenesis by E Gaitan, 1989, pp 195 - 204.
Conclusions. The studies described in this chapter provide evidence that Pennisetum millet exerts
antithyroid activity and is goitrogenic, supporting the original epidemiological and experimental
observations made by Osman and Fatah, and that these activities are not prevented by a high iodine
intake. Furthermore, the antithyroid and goitrogenic effects of millet diets are significantly correlated
with their concentration of C-GF. The isolated C-GF, glucosylvitexin, glucosylorientin, and vitexin,
which constitute the largest proportion of the phenolic compounds in millet, all possess antithyroid
activity and appear to be the goitrogens in millet.
Thiocyanate is also present in millet and its antithyroid effects are additive to those of the C-GF.
Indeed, the thiocyanate content of Pennisetum millet is similar to that present in cabbage (3.5
mg/100g), a vegetable of the Brassica genus that is a reputed goitrogen.
Studies also demonstrate that heat treatment and storage of millet markedly increases its antithyroid
effects, an unfortunate aspect for millions of people deriving most of their caloric intake from this
staple food.
We conclude that goitrogens in millet in the presence of dietary iodine deficiency and various degrees
of protein-calorie malnutrition, both of which are prevalent in the semiarid tropics, explain the very high
incidence of goiter and associated disorders in areas where millet is a staple food.
Goiter endemias attributed to chemical and bacterial pollution of water supplies (no link available)
Gaitan E, Lindsay R, Cooksey RC
Chapter 15 in Environmental Goitrogenesis by E Gaitan, 1989, pp 207 - 231.
For centuries, countless theories have been proposed to explain the etiology of endemic goiter.
However, only three are supported by experimental evidence. These are the theories that nutritional
iodine deficiency, goitrogens in foodstuff, and the quality of drinking water are causative factors in
goiter endemias.
It is noteworthy that, under the conditions of adequate iodine supplementation in which these studies
were made, a positive and significant correlation was found between goiter prevalence and urinary
[iodine] excretion. This was contrary to what has been observed in iodine-deficient areas.
These results wholly support the hypothesis that sedimentary rocks rich in organic matter, such as
coals and shales, are the main source of water-borne goitrogens.
These results suggest that the higher goiter prevalence associated with the overall concentration of
bacteria in the pipeline system and the lower prevalence associated with K. pneumoniae in the water
source may be natural examples of biomagnification and biodegradation of the organic pollutants that
produce goiter.
Goiter prevalence was indeed significantly lower among children of high socioeconomic class, even
though dietary iodine intakes and water supplies were the same for both groups. Thus, general
nutrition or dietary factors other than iodine intake appear, under thee circumstances, to affect the
prevalence of endemic goiter....
A poor-protein diet in rats impairs the thyroidal transport of iodine, decreases its concentration in the
thyroid, and is accompanied by an enlargement of the gland. Under these circumstances the
goitrogenic effect of antithyroid agents is enhanced. The administration of protein reverses these
alterations and decreases the action of such goitrogenic agents.
Results clearly demonstrate that these goiters are not due to iodine deficiency and that iodine
supplementation is not the primary environmental cause of AT [Autoimmune Thyroiditis]. Other region-
specific environmental (i.e., organic and microbial water pollutants) and immunogenetic factors may be
responsible for the significantly different prevalence rates in goiter, AT, and SH (Subclinical
Hypothyroidism) among nearby localities as well as between the North American and Colombian
populations.
The presence of the PAH [polycyclic aromatic hydrocarbons], methoxyanthracene, in drinking water
from the coal-rich Appalachian area of eastern Kentucky where goiter and AT are prevalent,
underlines the need to test the hypothesis that environmental pollutants operating in genetically
predisposed individuals may trigger the pathogenic mechanisms leading to goiter formation and AT.
Thus, it appears that resorcinol-related goitrogenic pollutants, precursors of antithyroid compounds
and potential "triggers" of AT, may be derived from coals and shales and, with bacterial
intermediation, may play an important role in the causation of goiter and AT in eastern Kentucky.
Antithyroid and goitrogenic effects of millet: role of C-glycosylflavones.
Gaitan E, Lindsay RH, Reichert RD, Ingbar SH, Cooksey RC, Legan J, Meydrech EF, Hill J, Kubota K.
J Clin Endocrinol Metab. 1989 Apr;68(4):707-14.
[abstract only]
Pearl millet [Pennisetum millet (L.) leeke] is the main source of food energy for the rural poor in many
areas of the semiarid tropics. Epidemiological evidence suggests that millet may play a role in the
genesis of endemic goiter in these areas, and sparse experimental data in rats support this suspicion.
This study was undertaken to determine in vivo in rats and in vitro using porcine thyroid slices and a
thyroid peroxidase (TPO) assay the goitrogenic and antithyroid effects of millet diets, extracts of millet,
and certain pure compounds contained therein. For use in these studies, whole grain millet was
progressively dehulled to yield successively four bran and four flour fractions in which direct analyses
revealed progressively lower concentrations of C-glycosylflavones. In vivo feeding of bran fraction 1,
that richest in C-glycosylflavones, led to a significant increase in thyroid weight and antithyroid effects.
Feeding of bran fraction 2, the next richest in C-glycosylflavones, produced similar, but less marked,
changes. In vitro studies of 125I metabolism using porcine thyroid slices indicated that extracts of bran
fractions 1 and 2 were most potent, producing changes similar to those produced by methimazole
(MMI). At a concentration of 60 mumol/L, glucosylvitexin, the major C-glycosylflavone present in millet,
had effects comparable to those of 1 mumol/L MMI. Similarly, in studies of porcine TPO, extracts of
bran fraction 1 caused pronounced (85%) inhibition of enzyme activity, and progressively less
inhibition was induced by extracts of bran fractions 2, 3, and 4. Overall, the TPO-inhibiting activities of
the various millet fractions closely correlated with their C-glycosylflavone concentrations. Three C-
glycosylflavones present concentrations. Three C-glycosylflavones present in millet, glucosylvitexin,
glycosylorientin, and vitexin, also inhibited TPO activity. Thus, in vivo and in vitro studies revealed that
millet diets rich in C-glycosylflavones produce goitrogenic and antithyroid effects similar to those of
certain other antithyroid agents and small doses of MMI. We conclude that in areas of iodine
deficiency in which millet is a major component of the diet, its ingestion may contribute to the genesis
of endemic goiter.
Goitrogens.
Gaitan E.
Baillieres Clin Endocrinol Metab. 1988 Aug;2(3):683-702. Review.
[abstract only]
A large number of agents in the environment and some medications are known to interfere with thyroid
gland function, posing the danger of thyroid disease. Pollutants that cause goitre are known as
environmental goitrogens which may cause the condition by acting directly on the thyroid gland but
also indirectly by altering its regulatory mechanisms and the peripheral metabolism and excretion of
thyroid hormones. However, the mechanism that induces the trophic changes leading to goitre
formation, and in some instances with hypothyroidism, is not well understood. Antithyroid compounds
may enter into the water, air and food exposure pathways, becoming an important environmental
goitrogenic factor in man and other animals. Naturally-occurring and anthropogenic agents may act as
goitrogens, as well as some drugs, which in the presence of dietary iodine deficiency may exaggerate
the goitre and associated disorders. In iodine-sufficient areas, these compounds may be responsible
for the development of some "sporadic' goitres or the persistence of the goitre endemia with its
associated disorders. At present, medical or surgical treatments for the individual, but not measures
for prevention and control at community level, are being applied in iodine-sufficient goitre areas.
In vitro measurement of antithyroid compounds and environmental goitrogens
Gaitan E, Cooksey RC, Matthews D, Presson R.
J Clin Endocrinol Metab. 1983 Apr;56(4):767-73.
[abstract only]
A specific, sensitive, and reproducible in vitro assay for antithyroid compounds and environmental
goitrogens has been used to investigate antithyroid activity (AA) in small samples of water supplying
15 localities in endemic and nonendemic goiter areas of western Colombia. A significant positive
correlation was observed between goiter prevalence and AA in water collected from the pipelines of
these localities. Samples at the water source showed only borderline significance. No significant
correlation was observed in waters between AA and total hardness (ppm) or concentrations of Ca, Mg,
sulfates, chlorides, silicates, nitrates, and iodine. AA was also demonstrated by this in vitro assay in
well water previously shown experimentally to be goitrogenic and that supplied the endemic goiter
district of Candelaria town in western Colombia. In contrast, water from the well supplying the area of
lower endemicity was found to possess little AA. These results provide experimental support for
epidemiological observations that demonstrate a relationship between the sources of drinking water
and goiter prevalence rates, and are consistent with previous findings indicating that organic
antithyroid compounds contaminate water supplies in areas where goiter persists despite adequate
iodine supplementation.
Antigoitrogenic effect of casein
Gaitan E, Merino H.
Acta Endocrinol (Copenh). 1976 Dec;83(4):763-71.
[no abstract]
Epidemiological findings from the city of Cali, Colombia, support the hypothesis that water supply and
iodine intake are not the only dietary factors which influence the magnitude of the goitre endemia.
Experiments were conducted in rats to determine whether casein has a counteracting effect on the
goitrogenic and antithyroid activities of methimazole (MMI) and goitrogenic water extracts (GWE) from
the endemic area of the Cauca Valley. Female albino rats (Charles River, DC strain) 100-110 g initial
weight, receiving 12 mug of iodine daily, were divided into three groups annd put on special diets:
protein-free, 8 % casein, or 60 % casein, respectively. Each group (24 rats) was then divided into
three subgroups. Subgroup one received goitrogen-free water and was used as a control. Subgroup
two was administered MMI, 50 mug/day/rat. Subgroup three was given per animal a daily amount of
GWE equivalent in antithyroid potency to 50 mug of MMI. At 77 days, the thyroid glands were studied
for weight, 131I uptake, and 127I concentration. Animals on the protein-free diet showed significantly
(P less than 0.05 - less than 0.01) larger thyroid glands per 100 g body weight and lower thyroidal 4 h
131I uptake and 127I-concentrations than rats on casein diets. These differences were significantly
increased (P less than 0.01) by the administration of MMI and GWE. All the effects were completely
reversed by the 60 % casein diet showing no differences between control rats and those on MMI or
GWE. Rats on 8 % casein showed intermediate values between those of animals on protein-free and
60 % casein diets; differences were still present between the control as against the MMI or GWE
groups, The results indicate that under these experimental conditions, a poor-protein diet impairs the
thyroidal transport of iodine, decreases its concentration in the thyroid and is accompanied by an
enlargement of the gland. Under these circumstances, the action of thiourea-like antithyroid agents is
enhanced. The administration of protein reverses these alterations and decreases the action of such
antithyroid agents. Whether the changes observed are due to a direct action of casein on the thyroid
and/or to effects of malnutrition on the metabolism of antithyroid compounds remains to be determined.
SHOMON
Don't Like Certain Veggies? It May Be Your Thyroid Talking!
Shomon M
Glucosinolates are compounds that act as goitrogens and have an anti-thyroid effect by inhibiting the
gland's ability to absorb iodine. Iodine is needed by the thyroid as a building block for thyroid
hormone. It's thought that being able to detect -- and, due to an aversion, avoid -- glucosinolates
found naturally in food could provide a biological advantage to the more than 1 billion people
worldwide who have low iodine status, and face a risk of thyroid disease.
MASTERJOHN
Thyroid Toxins: The Double-Edged Swords of the Kingdom Plantae
Masterjohn, C
Cholesterol-And-Health.com Special Reports Volume 1 Issue 1, 2008.
Plants produce many toxic substances to defend themselves from insects and other herbivores.
Because some of these may be healthful to humans in small amounts by helping to rev up our
defenses against toxins, it is important to rely on human epidemiological evidence and
experimentation using whole foods in live animals rather than test tube science. Such research has
indicted several classes of foods that may exert a toxic effect on the thyroid gland and thyroid
hormone metabolism in humans; we call these foods goitrogenic and we call the chemicals responsible
for this effect goitrogens. Goitrogenic foods include soy, millet, cruciferous vegetables, cassava, lima
beans, flax seeds, almonds, and fruits and fruit seeds of the Rosacea family. Millet flavonoids are
more dangerous than others.
Cooking and fermenting do not destroy millet or soy goitrogens; in fact, they make these foods more
goitrogenic. Millet goitrogens are present in both the bran and the endosperm. Traditionally prepared
millet that is dehulled, fermented and cooked into a porridge is associated with goiter in humans.
Microwaving crucifers reduces the average isothiocyanate yield to one-half; steaming them reduces
this yield to one-third; boiling them for a half hour and dumping out the water almost entirely eliminates
this yield. The effect of microwaving and steaming is dependent on the individual's intestinal flora and
is thus highly variable, whereas the effect of boiling is more reliable and constant. Fermentation
makes crucifers more goitrogenic. The most effective way of removing cyanogenic glycosides is by
crushing the tubers and leaching them in running water for several days, and by blanching and boiling
the leaves. Dietary iodine is able to overcome the effect of cyanogenic glycosides, moderate amounts
of crucifers, and is probably able to overcome the effect of soy flavonoids. It is not able to overcome
large amounts of crucifers or any amount of millet.
People who have resilient health while eating these foods should continue to eat them with impunity.
However, people who have thyroid problems or other problems associated with iodine deficiency or
cyanide exposure should consider experimenting with the following dietary restrictions: 1) eliminate
millet; 2) moderate soy and only consume it with additional sources of iodine; 3) limit crucifer intake to
five servings per week, only eat more than this if ti is boiled, and match one's crucifer intake with extra
iodine; 4)avoid foods with cyanogenic glycosides unless they are extensively boiled or crushed and
leached in running water for several days, and match one's cyanogen intake with extra iodine and
vitamin B12-containing foods or supplements (but not cyanocobalamin). These foods are not
inherently unhealthy but simply contain chemicals that have the capacity to harm the health of some
people under some circumstances; this is true of all foods. Experience always trumps theory, so the
individual should use this information as but one tool with which she or he can experiment to find the
most appropriate diet for herself or himself.
ELNOUR
Endemic goiter with iodine sufficiency: a possible role for the consumption of pearl millet in the etiology
of endemic goiter.
Elnour A, Hambraeus L, Eltom M, Dramaix M, Bourdoux P.
Am J Clin Nutr. 2000 Jan;71(1):59-66.
BACKGROUND: Deficiencies of iodine, iron, and vitamin A are the 3 most common micronutrient
deficiencies in developing countries, although control programs, when properly implemented, can be
effective. OBJECTIVE: We investigated these deficiencies and their possible interaction in preschool
children in the southern Blue Nile area of Sudan. DESIGN: Goiter, signs of vitamin A deficiency, and
biochemical markers of thyroid, vitamin A, and iron status were assessed in 984 children aged 1-6 y.
RESULTS: The goiter rate was 22. 3%. The median urinary iodine concentration was 0.79 micromol/L
and 19.3% of the children had a concentration >1.57 micromol/L. Although serum thyroxine and
triiodothyronine concentrations were within reference ranges, the median thyrotropin concentration
was 3.78 mIU/L and 44% of the children had thyrotropin concentrations above normal. The mean
urinary thiocyanate concentration was high (259 +/- 121 micromol/L). The prevalences of Bitot spots
and night blindness were 2.94% and 2.64%, respectively, and 32% of the subjects had serum retinol
binding protein concentrations <15 mg/L. A significant positive correlation was observed between
thyrotropin and retinol binding protein. Whereas 88% of the children had hemoglobin concentrations
<1.86 mmol/L, only 13.5% had serum ferritin concentrations below the cutoff of 12 microg/L and 95%
had serum transferrin concentrations above the cutoff of 2.50 g/L. CONCLUSIONS: Our results
indicate that goiter is endemic in this region of Sudan despite iodine sufficiency and that both anemia
and vitamin A deficiency are health problems in the area. Moreover, consumption of millet, vitamin A
deficiency, and protein-energy malnutrition are possible etiologic factors in this endemic area.
KAPLAN
Hypothyroidism in Green Iguanas
Kaplan M
Unfortunately, some plants contain goitrogens - compounds that bind the iodine in food, preventing
the body from utilizing it. This is easily dealt with by simply not feeding your iguana a lot of those
vegetables: broccoli, cabbage, cauliflower, bok choy, Brussels sprouts, kale, soy (tofu), and grains.
Some of the chemicals found naturally occurring in plants that are known to bind iodine include:
- anthocyanin
- benzyl-thiocyanate (a possible goitrogen)
- goitrin
- phloroglucinol
- vitexin
very small amounts, while others have higher amounts. If you feed your iguana plants that are high in
goitrogens, and feed them regularly and in quantity, your iguana's thyroid gland will not be able to get
the iodine it needs and so will start to suffer a decline, not putting out the various hormones and
chemicals your body needs.
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