Induction of an autoimmune thyroid disease after subcutaneous or oral sodium silicate challenge/ Oral veya subkutan sodyum silikat yuklemesi sonrasi otoimmun tiroid hastaliginin induksiyonu.
Abstract: Thyroid gland is a target organ for the hazards of some drugs and toxins. The objective of this experimental study is to demonstrate whether the subcutaneous or oral sodium silicate will induce autoimmune thyroid disease. In this study, twelve Brown Norway rats were selected from my previous study (Almogairen et al, Lupus 2009 April). At 14th week post sodium silicate or normal saline exposure, the rats were sacrificed and then thyroidectomized. Histopathological studies were done in autoantibody-positive silicate group of six rats and were compared with the equal number of rats in autoantibody-negative control group. Thyroid gland in the sodium silicate group showed epithelial follicular proliferation in 5/6 (83.33%) compared with 2/6 (33.33%) of the corresponding control saline group, p=0.12, but the absolute difference in the percentage between the two groups was 50%; thyroid gland in the subcutaneous sodium silicate sub-group showed epithelial follicular proliferation in a relatively significant number (p=0.05). When correlating the above results with Serum ANA response of the same rats, it might be concluded that sodium silicate may play a role in inducing autoimmune thyroid disease in an immunosensitive rats.

Key words: Autoimmune, ANA, thyroid, silicate

Tiroid bezi bazi ilac ve toksinler icin hedef organdir. Bu deneysel calismanin amaci subkutan veya oral sodyum silikatin otoimmun tiroid hastaligini baslatip baslatmayacagini arastirmaktir. Bu calisma icin, daha onceki calismamdan (Almogairen et al., Lupus 2009 Nisan) 12 Norvec sicani secildi. Sodyum silikat verilen ve normal sodyum klorur verilen sicanlar 14 uncu haftada olduruldu ve tiroidektomi yapildi. Otoantikor pozitif olan silikat verilmis gruptaki alti sican uzerinde histopatolojik incelemeler yapildi ve otoantikor negatif olan kontrol grubundaki ayni sayidaki sicanlarla karsilastirildi. Sodyum silikat grubundaki sicanlarin 5/6 sinin tiroid bezinde (%83,33) epitelyal follikuler proliferasyon izlenirken bu oran kontrol sodyum klorur grubunda 2/6 (%33,33) idi (p=0,12). Ancak iki grup arasindaki kesin fark, oran olarak %50 idi; subkutan sodyum silikat alt grubunda, tiroid bezinde epitelyal follikuler proliferasyon gorulen sicanlarin sayisi digerlerine gore oldukca fazla idi (p=0,05). Yukaridaki sonuclar, ayni sicanlarin serum antinukleer antikor (ANA) cevabi ile iliskilendirildiginde, sodyum silikatin immunosensitif sicanlarda otoimmun tiroid hastaliginin induklenmesinde onemli rol oynayabilecegi sonucuna varilabilir.

Anahtar kelimeler: Otoimmun, ANA, tiroid, silikat
Article Type: Report
Subject: Thyroid diseases (Risk factors)
Thyroid diseases (Diagnosis)
Thyroid diseases (Research)
Antinuclear antibodies (Physiological aspects)
Antinuclear antibodies (Research)
Author: Mogairen, Sultan Al-
Pub Date: 12/01/2009
Publication: Name: Turkish Journal of Endocrinology and Metabolism Publisher: Galenos Yayincilik Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 Galenos Yayincilik ISSN: 1301-2193
Issue: Date: Dec, 2009
Topic: Event Code: 310 Science & research
Product: Product Code: 2819565 Sodium Silicate NAICS Code: 325188 All Other Basic Inorganic Chemical Manufacturing SIC Code: 2819 Industrial inorganic chemicals, not elsewhere classified
Geographic: Geographic Scope: Saudi Arabia Geographic Code: 7SAUD Saudi Arabia
Accession Number: 219520152
Full Text: Introduction

Silica exposure might be associated with autoimmune diseases such as scleroderma, systemic lupus erythematosus, and rheumatoid arthritis (1-3). Occupations having the potential for silica exposures include mining, quarrying, tunneling, glass manufacture, ceramics, pottery production, cement and concrete production (4-5). There are implants made of silicon for medical purposes such as cosmetic breast implants, cardiac valve replacement and joint implants (6-8). Thyroid gland is one of the targets to the hazards of toxins and drugs. These include amiodarone, lithium, cyclosporine, interleukin-2, interferon-alpha and propylthiouracil (PTU) (9-16). The main finding of PTU-induced hypothyroidism in rats was attenuation of c-cells activity with hypoactivity of follicular cells, confirmed by histologic and ultrastructural studies (12). Only five papers describe the pathological findings in amiodarone-induced hyper thyroidism and none in amiodarone-induced hypothyroidism (10). The aim of the present study is to investigate whether sodium silicate will induce autoimmune thyroid disease in immunosensitive rats. This study is an extension of a previous study (Almogairen et al, Lupus 2009 April) 17,but examines the correlation between the autoimmune response and the histopathological changes in the thyroid gland.

Materials and Methods

Brown Norway rats (BN) (average weight of 157 g) were purchased from Charles Rivers Laboratories, Wilmington, U.S.A. They were kept in polycarbonate metrolon plastic cages covered with stainless steel cover in the animal house in the College of Medicine, King Saud University, Riyadh, Saudi Arabia. They were maintained under 12-hr dark: 12-hr light cycles and were kept under observation for three weeks. No evidence of sickness was observed. All rats were 8-11 weeks old at the onset of the experiment. There were a total number of twelve rats divided into two main groups: silicate and control normal saline groups. There were four sub-groups, the first and the second subgroups (six rats) were called subcutaneous silicate sub-group (three rats) and oral silicate sub-group (three rats). The third and the fourth sub-groups (six rats) were called subcutaneous normal saline control sub-group (three rats) and oral normal saline control sub-group (three rats).

All the above groups were selected for histological studies of the thyroid gland from my previous study, where the first and the second silicate sub-groups were autoantibody-positive for serum ANA, anti-dsDNA, anti-Smith, anti-SSA and anti-SSB. On the other hand, the third and the fourth control normal saline sub-groups were overall autoantibody-negative. The above selected subgroups after fourteen weeks of exposure to sodium silicate or normal saline were sacrificed and then thyroidectomized. The tissues taken from them were bisected and fixed in 10% buffered formalin for 24 hours. The tissues were then processed in the Tissue-Tek vacuum infiltration processor and stained using hematoxylin and eosin stain. The slides were examined blindly by histopathologist using light microscope.

Statistical Analysis

Statistical differences between silicate and the corresponding control groups were calculated using the Fisher's exact test.

Results

The maximum serum antibody titers in the selected rats from my previous study are shown in Table 1.

The histopathological results are shown in Table 2. The changes in the thyroid gland were considered as negative if all of the parameters shown in Table 2 were negative, otherwise, positive. The positive changes in the thyroid gland, depicted in Figure 1, were seen in 3/3 (p=0.05) of subcutaneous sodium silicate subgroup, on the other hand, p value was 0.8 in the oral sodium silicate sub-group. When comparing the whole silicate group, including the subcutaneous and the oral sub-groups (total number is 6), with the control normal saline group, including the subcutaneous and the oral subgroups (total number is 6), positive changes in the thyroid gland were seen in 5/6 (83.33%) of the silicate group. In contrast, the positive changes in the thyroid were observed in 2/6 (33.33%) of the control normal saline group (p=0.12). Figure 2 shows the normal histopathological features of the control group.

Discussion

Environmental crystalline silica exposure has been associated with formation of autoantibodies and development of systemic autoimmune diseases (1-3,18-21).

Occasionally, exposure to some drugs or toxins is associated with thyroid gland diseases.9-16 Experimental autoimmune thyroiditis is an organ-specific autoimmune disease that can be induced in genetically susceptible strains of mice by injection of thyroglobulin or IL2 (22).

In my previous study, only in the subcutaneous silicate sub-group there was an overall increase in the number of rats with positive titers of all autoantibodies tested post exposure to sodium silicate with significant p value (p<0.05) (17).

In the present study, the histopathological examination of the thyroid glands showed an epithelial follicular proliferation in all rats of the subcutaneous silicate sub-group, reaching a significant level of p value=0.05. Due to the constricted budget of the present study, the number of subjects in the sub-groups (oral or subcutaneous silicate groups) was limited to three. Therefore, we tried to augment the number of subjects by comparing the silicate group, including the subcutaneous and the oral sub-groups (total number is 6), with the control normal saline group, including the subcutaneous and the oral sub-groups (total number is 6). The absolute difference in the percentage between the two groups was equal to 50% (83.33%-33.33%), which is clinically useful, although, we did not achieve statistical significance (p=0.12).

The mechanism of these histopathological changes is probably due to disruption of one of the following physiological systems: the hypothalamic-pituitary-thyroid (HPT) axis, the calcium metabolism, and immunosuppression (23).

The significant serum autoimmune response, particularly with ANA, suggests that the autoimmunity probably has a contribution to the histopathological histological changes in the thyroid gland. There are a limited number of publications concerning the structure of thyroid gland following the exposure to some drugs and toxins (9,10,12-14, 22-23).

[FIGURE 1 OMITTED]

To my knowledge, this is the first study showing the correlation between the histological changes in the thyroid gland secondary to silicate exposure and the serum autoimmune response.

In conclusion, silica exposure is probably one of the risk factors inducing autoimmune thyroid disease in immunosensitive rats.

Acknowledgement

The study was supported by a grant from Research Center, College of Medicine, King Saud University. The author is grateful to Dr. Sufia Husain, FRC Path for reporting histology. The author is also grateful for the following: Dr. B. Al-Mohaimeed, Dr. N. Khalil, Mr. M. Marzook, and Mr. S. Abu-al-Ghaith, S. Seno, Mitzi Guinto for their cooperation, and the Research Ethic Committee, College of Medicine for the approval of this study.

[FIGURE 2 OMITTED]

Recevied: 18.01.2010 Accepted: 26.01.2010

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Address for Correspondence: Sultan Al-Mogairen, MD, Department of Medicine, Faculty of Medicine, King Saud University, Saudi Arabia E-mail: almogairin@hotmail.com-salmogairin@ksu.edu.sa

Sultan Al-Mogairen

King Saud University, Medicine, Riyadh, Saudi Arabia
Table 1. Maximum serum antibody titres of the rast
in which histopathology was performed

RATS            ANA ([less       Anti-dsDNA
               than or equal   ([greater than or
                 to] 1/10)      equal to] 0.08)
                significant       significant

Silicate SC1        1/80              -ve
Silicate SC2        1/80             #NAME?
Silicate SC3        1/80              -ve
Silicate PO1        1/20              -ve
Silicate PO2        -ve               -ve
Silicate PO3        -ve               0.08
Control SC1         -ve               -ve
Control SC2         -ve               -ve
Control SC3         -ve               -ve
Control PO1         -ve               -ve
Control PO2         -ve               0.88
Control PO3         -ve               -ve

RATS              Anti-Smith            Anti-SSA
                ([greater than       ([greater than]
               or equal to] 0.06)   or equal to] 0.12)
                  significant          significant

Silicate SC1         0.152                 -ve
Silicate SC2          -ve                  -ve
Silicate SC3          -ve                  -ve
Silicate PO1          0.06                0.109
Silicate PO2          -ve                 0.24
Silicate PO3          0.06                0.16
Control SC1           0.06                 -ve
Control SC2           -ve                  -ve
Control SC3           -ve                  -ve
Control PO1           -ve                  -ve
Control PO2           -ve                  -ve
Control PO3           -ve                  -ve

RATS               Anti-SSB
               ([greater than
               or equal to] 0.05)
                  significant

Silicate SC1          -ve
Silicate SC2          -ve
Silicate SC3          -ve
Silicate PO1          -ve
Silicate PO2          -ve
Silicate PO3          1.7
Control SC1           -ve
Control SC2           -ve
Control SC3           -ve
Control PO1           -ve
Control PO2           -ve
Control PO3           -ve

SC: Subcutaneous

PO: Per oral

-ve: Negative

Table 2. Histopathological features of silicate-tested&control groups

Thyroid of the   Inflammation   Autoimmune    Granuloma
following rast                  thyroiditis

Silicate SC1         -ve            -ve          -ve
Silicate SC2         -ve            -ve          -ve
Silicate SC3         -ve            -ve          -ve
Silicate PO1         -ve            -ve          -ve
Silicate PO2         -ve            -ve          -ve
Silicate PO3         -ve            -ve          -ve
Control SC1          -ve            -ve          -ve
Control SC2          -ve            -ve          -ve
Control SC3          -ve            -ve          -ve
Control PO1          -ve            -ve          -ve
Control PO2          -ve            -ve          -ve
Control PO3          -ve            -ve          -ve

Thyroid of the   Epithelial follicular   Hurthle cell
following rast       proliferation

Silicate SC1               +                 -ve
Silicate SC2               +                 -ve
Silicate SC3               +                 -ve
Silicate PO1               +                 -ve
Silicate PO2               +                 -ve
Silicate PO3              -ve                -ve
Control SC1               -ve                -ve
Control SC2               -ve                -ve
Control SC3               -ve                -ve
Control PO1               -ve                -ve
Control PO2                +                 -ve
Control PO3                +                 -ve

Thyroid of the   Neoplastic change
following rast

Silicate SC1            -ve
Silicate SC2            -ve
Silicate SC3            -ve
Silicate PO1            -ve
Silicate PO2            -ve
Silicate PO3            -ve
Control SC1             -ve
Control SC2             -ve
Control SC3             -ve
Control PO1             -ve
Control PO2             -ve
Control PO3             -ve

-ve = 0 = negative
+ = 1 = mild
++= 2 = moderate
+++ = 3 = severe
SC: subcutaneous
PO: per oral
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