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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 GoitrogenesisGaitan 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 goitrogenesisGaitan 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 thyroidGaitan 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 suppliesGaitan 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."
Factors other than iodine deficiency in endemic goiter: goitrogens and protein-calorie malnutritionE Gaitan, RC Cooksey, RH Lindsay PCM, Bull, WHO, 502,28, 1986. (cited in Ermans AM, Antithyroid Sulfurated Compounds)
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."
Water-borne goitrogens and their role in the etiology of endemic goiter.Gaitan E World Rev Nutr Diet. 1973;17:53-90. Review [citation only]
Identification of a naturally occurring goitrogen in water.Gaitan E, Island DP, Liddle GW. Trans Assoc Am Physicians. 1969;82:141-52. [citation only]
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