Anti-Thyroid Effect of High Aluminum Intake in Rats
Subgroup: Volume 2, Issue 1, Winter
Date: March 2004
Type: Original Article
Start Page: 41
End Page: 46
- Taheri M aDepartment of Histology, The Medical School, Ahwaz University of Medical Sciences, Ahwaz, IR Iran
- Zahedi-Asl S bEndocrine Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, and Departmen of Physiology, Ahwaz University of Medical Sciences, Ahwaz, IR Iran
- Ahangarpoor A aDepartment of Histology, The Medical School, Ahwaz University of Medical Sciences, Ahwaz, IR Iran
City, Province: Ahwaz,
Country: IR Iran
Patients with chronic renal failure have abnormal thyroid function and higher levels of serum aluminum. In recent years, the toxicity of Al in human and animals has been a matter of concern_ In this study the effect of high aluminum intake in the diet has been investigated in rats.
Materials and Methods: Aluminum (1620 mglkg of the diet as aluminum chloride) was added to the diet of Wistar rats for 40 days. At the end of this period serum aluminum, T4 and TSH concentrations were measured. Aluminum was determined by atomic absorption spectrometry and the hormones were assayed using commercially available kits.
Results: Serum aluminum concentration of the test rats (6.3±.1 pgIL) was not significantly different from controls (6.6±.4 pgIL). Serum T3 concentration in animals consuming a diet with high aluminum content (138±8 ngldL) was not significantly different from the control animals (146±7 ngldL). Serum T3, T4 concentration of the test animals (3.0±0.3 pgldL) was significantly lower than control animals (4.7±0.5 pgldL, p<0.05). Thyrotropin concentrations were not significantly different.
Conclusion: The results of this study indicate that high aluminum intake in rats can disturb thyroid function and possible adverse effect(s) of the element need to be considered and fully investigated in subjects in close contact with high amounts.
Keywords: Aluminum;Thyroid;Calcium Channel;Blocker;Rat
Aluminum (AI) is the most abundant element in the earth's crust, comprising about 8% of it. I Aluminum enters the body through different routes2 and its concentration in the serum of healthy subjects is very low.3 It is poorly absorbed through the gastrointestinal tract4 and the physiological role of the element has not yet been established.s In recent years toxicity of aluminum has been a matter of concern. Serum aluminum concentration in patients with chronic renal failure is high6 and some of the impairments in these patients h d ' . 6 . 78 . 9 suc as ementla, anemIa,' osteoporosIs, and abnormalities of thyroid function 10 have been related to high concentrations of the element.
Thyrotropin releasing hormone release, I 1 its effed 2 , 13 and effects of thyroid stimulating hormone on thyroid cells l4 are dependent on extracellular calcium concentration. On the other hand, the calcium channel blocking effect of aluminum has been well established.15-17 In this study the effect of chronic orally administered aluminum on thyroid function has been tested on rats.
Materials and Methods
The study was carried out on male N-MRI rats weighing 180-250 gr. The animals, obtained from the Razi institute, were kept under standard conditions (12: 12 hours cycle, Tem. 24±2 DC with free access to food and tap water). Animals in the control group (n = 12) consumed ordinary diets (purchased from a local producer, Shoshtar animal food production Co.), while animals in the test group (n =13) received similar food containing 1620 mg/kg of aluminum as aluminum chloride for 40 days.18 At the end of this period, animals were anesthetized with 50 mg/kg of sodium thiopental (Pharmacia, Sweden) and the abdomen was opened. Two 2.5 ml samples of blood were obtained through abdominal aorta and centrifuged; sera were separated and kept at _20DC until the time of the assay. Aluminum concentration of the serum samples was determined using flameless atomic absorption spectrometry (AAS, SEA, Carl Zaiss, Germany) with a recovery value of 93±8% and intra-assay coefficient variation of 9±2%. Detection limit for aluminum ass ay was 1 p,g/L. Serum total thyroxin (IT4), total tri-iodothyronin (IT3) and thyroid stimulating hormone (TSH) concentrations were assayed with radioimmunoassay kits purchased from local supplier (Kavoshiar Co.-Iran) each in a single batch assay. Sensitivities of the assays for TT4 , IT3 and TSH (IRMA) were 0.4 ug/dL, 5ng/dL and 0.02 mIU/L, respectively. Mean±SE of the data were compared using student t-test and P values less than 0.05 were considered significant.
Mean the serum aluminum concentration of the test rats (6.3±0.1p,g/L) was not significantly different from that of the control animals (6.6±0.4 p,g/L) (Fig. 1). In animals consuming diets with high aluminum content, serum IT3 concentration (138±8 ng/dL) was not significantly lower than that of control animals (146±7 ng/dL). (Fig. 2)
Fig. 1. Serum aluminum concentration in controls (n= 12) and rats with high aluminum intake (n=13)
Fig. 2. Serum T3 concentration in controls (n=12) and rats with high aluminuim intake (n=13)
Mean serum TT4 concentrations of the test animals (3 .0±0.3 p,g/dL) was significantly lower than that of control animals (4.7±0.5 p,g/dL) (Fig. 3). Thyrotropin concentrations were not statistically different (Fig. 4).
Fig. 3. Serum T4 concentration in controls (n=12) and rats with high aluminum intake (n=13) * P<0.0S
Fig. 4. Serum TSH concentration in controls and rats with high aluminum intake
The weights of the animals in the groups were not significantly different at the beginning of the study and did not change insignificant until the end (225±5 for the controls versus 234±7 gr for the test animals).
The results of this study show that high oral aluminum intake induces hypothyroidism in Effect of high aluminum on thyroid 43 rats. Lack of similar studies on the effect of aluminum on thyroid makes it difficult to compare the results. However, the effects of calcium channel blockers have been investigated in vitro and in vivo. In a study on healthy human subjects, orally administered nifedipine did not alter thyroid function. 19 It should be noted that in the study mentioned, the blocker was administered only for one week and this period may not be sufficient to alter plasma TT3 and T4 concentration, In another study, it has been shown that TRH under normal physiological conditions, appears to cause mobilization of intracellular calcium and induces influx of extracellular Ca2 + on thyrotrope cells. Presence of the calcium channel blocker verapamil could reduce calcium influx in vitro.20 It has been suggested that TRH uses both intracellular calcium stores and extra cellular calcium through voltage-dependent calcium channels to increase intracellular calcium concentration causing TSH secretion.21 Release of TRH as a neurohormone, too, depends on extracellular ca1cium?2 Aluminum is a potent calcium channel b10cker15-17 and therefore it is expected to inhibit both TRH and TSH release. In fact, this effect has been reflected in this study as a low T 4 concentration (Fig. 1) and not increased TSH concentration (Fig. 2). This inhibitory effect of aluminum also shown in the rat, may explain at least in part the thyroid dysfunction seen in patients with chronic renal fai1ure. 23 These patients have high aluminum concentrations in their se- 24 rum.
Although TSH concentrations of the test animals did not change significantly, there was a general increase in the test animals (Fig. 4). Thyrotropin concentration in this study should be considered carefully because of the high variation of the hormone between individual samples. Also, it must be mentioned that the kit ' which was used in this study was for human TSH assay and the exact cross-reactivity of the kit was not determined. Comparing, however, the results of the assay for the control animals with those of another study/s it appears that the antibody of the kit has been able to recognize the hormone to a certain extent.
Plasma aluminum concentration did not increase in the test group despite high aluminum intake in the diet. This might be due to the fact that the element was added to the diet and naturally would be consumed gradually. The absorption of the element through gastrointestinal tract is poor3 and the changes of the serum aluminum concentration after oral administration of the element have been a matter of controversy. Some reports indicate that after oral administration, aluminum concentration in the serum increases significantly?2,23 However, it also has been suggested that when the renal function is normal, the element may not accumulate in the serum even when administered orally.24 A report states that the plasma concentrations of the aluminum-exposed workers hardly differ from those of the control group and they have concluded that aluminum in plasma could not be used as an indicator of daily exposure.26 The effect might be exerted through accumulation of the element in the thyroid and pituitary glands. Although there is evidence of different levels of uptake by different tissues,27,28 in this sues,27,28 in this study aluminum contents of the tissues from control and test animals were not compared.
Some studies have shown that in those patients who receive aluminum hydroxide as antiacid and levothyroxine simultaneously, levothyroxine absorption is significantly decreased while serum TSH concentration increases significantly.29-3o Although similar studies have not been carried out in rats, one can assume that high aluminum in the diet may interfere with the enterohepatic cycle of the thyroid hormones. This possible effect remains to be clarified.
The present results cannot be explained with general toxic effect of aluminum because firstly, the administered amount is far less than the toxic level,28 and secondly, the weight of the animals demonstrate their well being during the test period.
From the results of this study it is possible to conclude that exposure to aluminum can disturb pituitary-thyroid function in rats. Possible adverse effects of the element on neuroendocrine systems need further investigation and studies.
- Klein GL.The aluminum content of parenteral solutions: current status. Nutr Rev. 1991 Mar;49(3):74-9.
- Flaten TP, Alfrey AC, Birchall JD, Savory J, Yokel RA. Status and future concerns of clinical and environmental aluminum toxicology. J Toxicol Environ Health. 1996 Aug 30;48(6):527-41.
- Lin JL, Lim PS, Leu ML. Relationship of body iron status and serum aluminum in chronic renal insufficiency patients not taking any aluminum-containing drugs. Am J Nephrol. 1995; 15(2): 118-22.
- Powell JJ, Thompson RP. The chemistry of aluminium in the gastrointestinal lumen and its uptake and absorption. Proc Nutr Soc. 1993 Feb;52(1 ):241-53.
- Yokel RA, Allen DD, Meyer JJ. Studies of aluminum neurobehavioral toxicity in the intact mammal. Cell Mol Neurobiol. 1994 Dec; 14(6):791-808.
- Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med. 1976 Jan 22;294(4):184-8.
- Abreo K, Brown ST, Sella M. Correction of microcytosis following elimination of an occult source of aluminum contamination of dialysate. Am J Kidney Dis. 1989 Jun; 13( 6) :465-8.
- Rosenlof K, Fyhrquist F, Tenhunen R. Erythropoietin, aluminium, and anaemia in patients on haemodialysis. Lancet. 1990 Feb 3 ;335(8684):247 -9.
- Ward MK, Feest TG, Ellis HA, Parkinson is, Kerr DN. Osteomalacic dialysis osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminium. Lancet. 1978 Apr 22; 1(8069):841-5.
- Loudes C, Faivre-Bauman A, Patte C, TixierVidal A. Involvement of DHP voltagesensitive calcium channels and protein kinase C in thyroliberin (TRH) release by developing hypothalamic neurons in culture. Brain Res. 1988 Jul 26;456(2):324-32.
- Lackoff A, Jackson 1M. Calcium dependency of potassium-stimulated hyroh'opin-releasing hormone secretion from rat neurohypophysis III vitro. Neurosci Lett. 1981 Dec 11 ;27(2): 177-81.
- Gershengorn MC, Geras E, Purrello VS, Rebecchi MJ. Inositol trisphosphate mediates thyrotropin-releasing hormone mobilization of nonmitochondrial calcium in rat mammotropic pituitary cells. J Bioi Chern. 1984 Sep 10;259(17): 10675-81.
- Geras E, Rebecchi MJ, Gershengorn Me. Evidence that stimulation of thyrotropin and prolactin secretion by thyrotropin-releasing hormone occur via different calcium-mediated mechanisms: studies with verapamil. Endocrinology. 1982 Mar;110(3):901-6.
- Metcalfe RA, Findlay C, Robertson WR, Weetman AP, Mac Neil S. Differential effect of thyroid-stimulating hormone (TSH) on intracellular free calcium and cAMP in cells transfected with the human TSH receptor. J Endocrinol. 1998 Jun;157(3):415-24.
- Platt B, Busselberg D. Actions of aluminum on voltage-activated calcium channel currents. Cell Mol Neurobiol. 1994 Dec;14(6):819-29.
- Busselberg D, Platt B, Michael D, Carpenter DO, Haas HL. Mammalian voltage-activated calcium channel currents are blocked by Pb2+, Zn2+, and A13+. J Neurophysiol. 1994 Apr;71 (4): 1491-7.
- Busselberg D, Platt B, Haas HL, Carpenter DO. Voltage gated calcium channel currents of rat dorsal root ganglion (DRG) cells .are blocked by A13+. Brain Res. 1993 Sep 17;622(1-2): 163-8.
- Shahraki MR. The effect of peripheral and central aluminum administration on the male rats reproduction factors. [dissertation]. Ahwaz University of Medical Scinces, pp: 34-49; 1999.
- Zofkova I, Neradilova M, Kimlova I, Starka L, Reisenauer R. Effect of nifedipine on the adrenocortical and somatotrophic secretory reserve and TSH and thyroid hormone plasma levels. Exp Clin Endocrinol. 1983 Jul;82(1 ):97-1 00.
- Utas C, Taskapan H, Oymak 0, Akpolat T, Arinsoy T, Kelestimur F. Improvement of thyroid hormone profile and thyrotrophin (TSH) surge alterations in hemodialysis patients on erythropoietin treatment. Clin Nephrol. 2001 Jun;55(6):4 71-6.
- Cannata-Andia JB, Fernandez-Martin JL. The clinical impact of aluminium overload in renal failure. Nephrol Dial Transplant. 2002; 17 SuppI2:9-12.
- Allain P, Mauras Y, Krari N, Duchier J, Cournot A, Larcheveque J. Plasma and urine aluminium concentrations in healthy subjects after administration of sucralfate. Br J Clin Pharmacol. 1990 Apr;29( 4):391-5.
- Fernanez Martin JL, Macho M, Gomez Granda E, Diaz Lopez B, Sanz Medel A, Cannata JB. Serum aluminum and normal kidney function: effect of age and environmental exposure to aluminum. Rev Clin Esp. 1989 Nov; 185(8):388-90. (Spanish).
- Kinoshita H, Kumaki K, Nakano H, Tsuyama K, Nagashima R, Okada M, et al. Plasma Aluminum levels of patients on long term sucralfate therapy. Res Commun Chern Pathol Pharmacol. 1982 Mar;35(3): 515-8.
- Peng KL, Jiang Y, Zhao SL, Zhang YR, Lu CR, Peng DH, et al. Toxic effects of ammonium perchlorate on thyroid of rats. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2003 Dec;21(6):404-7. (Chinese).
- Mussi I, Calzaferri G, Buratti M, Alessio L. Behaviour of plasma and urinary aluminium levels in occupationally exposed subjects. Int Arch Occup Environ Health. 1984;54(2): 155- 61.
- Walker VR, Sutton RA, Meirav 0, Sossi V, Johnson R, Klein J, et al. Tissue disposition of 26aluminum in rats measured by accelerator mass spectrometry. Clin Invest Med. 1994 Oct; 17(5):420-5.
- Hicks JS, Hackett DS, Sprague GL. Toxicity and aluminium concentration in bone following dietary administration of two sodium alu-minium phosphate formulations in rats. Food Chern Toxico!. 1987 Jul;25(7):533-8.
- Sperber AD, Liel Y. Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. Arch Intern Med. 1992 Jan;152(1):183-4.
- Liel Y, Sperber AD, Shany S. Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide. Am J Med. 1994 Oct;97(4):363-5 .
- Mersebach H, Rasmussen AK, Kirkegaard L, Feldt-Rasmussen U. Intestinal adsorption of levothyroxine by antacids and laxatives: case stories and in vitro experiments. Pharmacol Toxico!. 1999 Mar;84(3):107-9.