Effects of aluminum on the thyroid

Aluminum (Al) is a ubiquitous element widely distributed in the environment. The expanding use of Al in industrial and domestic applications has led to high human exposure to its toxicity. Al can accumulate in vulnerable regions of the brain and has been strongly associated with a range of neurodegenerative diseases (dialysis encephalopathy, amyotrophic lateral sclerosis, Parkinson's and Alzheimer's diseases) [1].

A role for Al as a disruptor of certain endocrine systems has recently emerged. For example, it is well established that Al can be classified as a metalloestrogen [2,3].

It was reported that in a group of 227 individuals with occupational aluminum exposure, thyroid-stimulating hormone (thyrotropin, TSH) values were reduced after 1 year of work and further decreased 6 months later [4]. This finding suggests that Al may alter pituitary endocrine regulation of the thyroid gland.

The aim of the present work was to elucidate whether Al can be considered a thyroid disruptor in adult rats. Referred to animal models, the basic areas of chemical interference in thyroid metabolism are: inhibition of iodide uptake at the thyrocyte cell membrane via blockade of the NIS transporter; inhibition of synthesis via thyroperoxidase; binding of the TTR transport protein in the bloodstream; altered hepatic phase II catabolism by glucuronosyltransferase and sulfotransferase metabolism of T3 and T4; alteration of T4 metabolism regulated by deiodinase; and alterations of transport across cell membranes and alteration of TH receptors in target cells [8,20]. In particular for Al, some of the main mechanisms were analyzed here.

The main finding was that circulating levels of free T4 and TSH, the most sensitive markers of mammalian thyroid function [21], were unaffected by Al, regardless of observed effects on iodide uptake. According to our results, the accumulation of radiolabeled iodide by the thyroid was decreased in Al-treated rats (Fig. 1A). Although Al cannot act as a direct competitor of iodine [6], it could nevertheless indirectly alter the function of the sodium-iodide symporter (NIS). This transport system moves iodide ions from the bloodstream into the epithelial cell of the thyroid follicles, and works synchronously with the Na/K-ATPase which expels the two sodium ions loaded along with iodine, in order to maintain the electrochemical balance of the cell.

It has been shown that Al inhibits Na/K-ATPase in cerebral cortex synaptosomes and renal homogenates from Al-exposed rats. Inhibition of Na/K-ATPase activity occurred, preceding possible alterations in catalytic subunit expression, cellular energy depletion, and disturbances in cell membrane integrity. The decreased total Na/K-ATPase activity was ensured by partial inhibition of isoenzymes containing α1-, α2- and α3 subunits [22,23]. Since the energy required to produce the Na gradient, which serves as the driving force for iodide ion transport by NIS, is provided by Na/K-ATPase [5], a failure of this enzyme can lead to decreased iodine uptake by thyrocytes. Furthermore, the increased thyroidal TBARS level in the Al-treated group (Fig. 2) would indicate some degree of oxidative stress in the thyroid tissue, which may contribute to impairing NIS activity due to implicated cell membrane disorganization [17,24]. Although a small amount of Al was found in the thyroid tissue of the Al-treated group, it is not possible to know its internal distribution: inside or outside the follicles (parafollicular tissue). Even the latter, Al can still exert its action on the basal membrane of thyrocytes.

The lower availability of iodine within thyrocytes may alone explain the fall in total serum T3 and T4 levels, although an effect on hormone secretion across the basal membrane into the bloodstream, as suggested by the decreased slope of 125I-releases from the thyroid gland in Al-treated rats, cannot be ruled out. However, the mechanisms of HT secretion at the basolateral membrane and the channel(s) involved have not been characterized [5].

Nevertheless, the overall impact of this reduction in total circulating HT levels produced by Al on the thyroid endocrine regulatory system appears to be insignificant, as the TSH level remained unchanged.

Circulating TH levels are maintained within a relatively narrow range largely by a negative feedback relationship between circulating TH levels and those of TSH [7,25]. THs appear to exert this effect by acting on a subtype of the TH receptor (TRβ2), which is expressed in the pituitary gland and the hypothalamic paraventricular nucleus, and appears to be the predominant mediator of the negative feedback action of THs on TSH. Thus, environmental chemicals that interact with TRs will affect this negative feedback system if, and only if, they interact with the TRβ2 isoform [26]. There is no evidence that Al is capable of such an interaction.

An important issue to consider in explaining this lack of response of the hypothalamus-pituitary-thyroid (HPT) axis in Al-treated rats is that, although circulating TH levels are generally maintained within a narrow range, the range is much narrower for an individual than for the population, and individual genetics is a major contributor to defining the set point around which the HPT axis is regulated [26]. Thus, the observed variability in total HT measurements between the Al-treated and control groups would be relativized.

The scenario presented by our results is a reduction in total HTs without variation in serum free T4 and TSH levels in the Al-treated group. To find a possible explanation, we need to analyze the factors that regulate the serum half-life of THs.

The long serum half-life of T4, when compared to other hormones, is largely the result of strong non-covalent binding to three main binding proteins: TBG, TTR, and albumin [7,8]. Bound T4 is in rapid equilibrium with unbound or free T4, which is available for cellular uptake. As T4 is more avidly bound to these proteins, it has a much longer half-life than T3. Chemicals that can displace THs from these binding proteins can cause a very rapid decline (within a period of minutes) in serum hormone levels (bound and free), in combination with their ability to increase biliary clearance by inducing phase I-III enzymes [27]. The main pathway for HT clearance from serum is by conjugation with glucuronic acid or sulfate [8]. The constitutive androstane receptor and the pregnane X receptor play central roles in xenobiotic-induced clearance of T3 and T4 and the subsequent ability of environmental chemicals to reduce serum concentrations of these hormones [26]. In the case of Al, a displacement effect of THs from their binding proteins seems unlikely, since the reduction of total THs was not as striking, and furthermore, free T4 was not altered; related to this, the biliary excretion rate of 125I−, used as an index of hepatic HT catabolism, was not modified by Al. Therefore, Al would not substantially alter the half-life of THs.

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