Correlated Functional and Morphometric Study of Thyroid Hyperplasia Induced by Iodine Deficiency*

Denef, Jean‐François; Haumont, Stanislas; Cornette, C.; Beckers, Christian

doi:10.1210/endo-108-6-2352

Cited by 52 publications

(25 citation statements)

References 21 publications

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“…The temporal sequence of specific histological alterations was similar for thyroid glands of tadpoles treated with PER and ETU and included increased colloid resorption, follicular cell hypertrophy, thyroid hyperplasia, and goiter formation within 3, 5, 8, and 12 days of treatment, respectively. These findings in X. laevis correlate well with other reports on experimental induction of hyperplastic goiters in mammalian species (Denef et al, 1981;Wynford-Thomas et al, 1982b). However, thyroid histopathology also revealed that PER and ETU treatment cause goiters with strikingly different follicular morphologies.…”

Section: Discussionsupporting

confidence: 91%

“…The majority of the hyperplastic follicles in the PER treatment were characterized by narrow, slit-like or collapsed lumina. A similar histological appearance has been reported for thyroids of other species treated with PER (Stoker et al, 2006) or iodine-deficient diets (Denef et al, 1981). In sharp contrast, colloid depletion was accompanied by distension of follicular lumina in ETU-treated tadpoles.…”

Section: Discussionsupporting

confidence: 83%

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Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Opitz

Schmidt

Braunbeck

et al. 2009

Molecular and Cellular Endocrinology

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Despite evidence for a conserved role of thyroid-stimulating hormone (TSH) in regulating vertebrate thyroid function, molecular data on thyroid responses to TSH are mainly limited to mammalian species. In this study, we examined histological and molecular changes in the thyroid of Xenopus laevis tadpoles during a 12-day treatment with 20 mg/l perchlorate (PER) and 50 mg/l ethylenethiourea (ETU). Inhibition of thyroid hormone (TH) synthesis by PER and ETU was evident from developmental retardation, reduced expression of TH-regulated genes and up-regulation of tshb-A mRNA. Thyroid histopathology revealed goiters with strikingly different follicular morphologies following PER and ETU treatment. Using real-time PCR, we analyzed thyroids sampled on day 12 for differential expression of 60 candidate genes. Further temporal analyses were performed for a subset of 14 genes. Relative to the control, PER and ETU treatment modulated the expression of 51 and 49 transcripts, respectively. Particularly genes related to TH synthesis and protein metabolism were similarly affected by PER and ETU.However, several genes were differentially expressed in PER-and ETU-treated tadpoles.Specifically, goiter formation in the PER treatment was associated with low expression of genes related to DNA replication but high expression of negative growth regulators. Results from this work provide for the first time a characterization of gene expression profiles during goitrogenesis in a non-mammalian vertebrate model. Overall, our data suggest that, in addition to TSH over-stimulation, further mechanisms related to the mode of goitrogen action contribute to the regulation of thyroid gene expression.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 83%

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Opitz

Schmidt

Braunbeck

et al. 2009

Molecular and Cellular Endocrinology

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“…Two-month-old NMRI mice received a low-iodine diet (LID) (0.1 g iodine/day; Animalabo, Brussels, Belgium) supplemented with perchlorate in the drinking water (ClO 4 Ϫ , 1%) for 0, 1, 2, 3, 4, 6, 12, or 24 days where indicated. In addition to LID/ClO 4 Ϫ , animals were injected intraperitoneally with a saline solution of bevacizumab (10 mg/kg/6 days; Roche, Welwyn Garden City, UK) or with a solution of SU5416 (25 mg/kg/day; Sigma, St. Louis, MO) in dimethyl sulfoxide.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…In addition to LID/ClO 4 Ϫ , animals were injected intraperitoneally with a saline solution of bevacizumab (10 mg/kg/6 days; Roche, Welwyn Garden City, UK) or with a solution of SU5416 (25 mg/kg/day; Sigma, St. Louis, MO) in dimethyl sulfoxide. Control and perchlorate-treated animals were also injected with an equimolar solution of irrelevant human IgGs (bevacizumab control) or dimethyl sulfoxide (SU5416 control, 100 l i.p./day).…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Gérard

Poncin

Caetano

et al. 2008

The American Journal of Pathology

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Expansion of the thyroid microvasculature is the earliest event during goiter formation, always occurring before thyrocyte proliferation; however, the precise mechanisms governing this physiological angiogenesis are not well understood. Using reverse transcriptase-polymerase chain reaction and immunohistochemistry to measure gene expression and laser Doppler to measure blood flow in an animal model of goitrogenesis, we show that thyroid angiogenesis occurred into two successive phases. The first phase lasted a week and involved vascular activation; this process was thyroid-stimulating hormone (TSH)-independent and was directly triggered by expression of vascular endothelial growth factor (VEGF) by thyrocytes as soon as the intracellular iodine content decreased. This early reaction was followed by an increase in thyroid blood flow and endothelial cell proliferation, both of which were mediated by VEGF and inhibited by VEGF-blocking antibodies. The second, angiogenic, phase was TSH-dependent and was activated as TSH levels increased. This phase involved substantial up-regulation of the major proangiogenic factors VEGF-A, fibroblast growth factor-2, angiopoietin 1, and NG2 as well as their receptors Flk-1/VEGFR2, Flt-1/ VEGFR1, and Tie-2. In conclusion, goiter-associated angiogenesis promotes thyroid adaptation to iodine deficiency. Specifically, as soon as the iodine supply is limited, thyrocytes produce proangiogenic signals that elicit early TSH-independent microvascular activation; if iodine deficiency persists, TSH plasma levels increase, triggering the second angiogenic phase that supports thyrocyte proliferation.

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“…In our study, we are obviously confronted by the 'chicken and egg' conundrum, because our results do not permit discrimination between the cause and the consequence, and do not explain, for example, the absence of growth factors in poorly vascularised areas of non-dividing cells. We can only refer to previous experiments that demonstrated that the earliest tissue modification occurring during goitre formation involves the proliferation of endothelial cells that takes place just before the proliferation of epithelial cells (Denef et al 1981, Many et al 1984. It is therefore conceivable that endothelial cells are the first to be stimulated in the presence of trophic factors.…”

Section: (N=5) P<0·05mentioning

confidence: 99%

Relationships between cell division, expression of growth factors and microcirculation in the thyroids of Tg-A2aR transgenic mice and patients with Graves' disease

Gérard

Denef²,

Many³

et al. 2003

Journal of Endocrinology

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Tissue heterogeneity and nodule formation are hallmarks of thyroid growth. This is accounted for by the clonality theory that acknowledges different individual cellular abilities to respond to trophic stimuli. In order to test the hypothesis that functional and mitotic properties of thyrocytes could be influenced by paracrine interactions with neighbour endothelial cells, studies were conducted in both mouse and human goitre models. In the first part of the study, homogenous goitres in C57 black mice were compared with heterogeneous goitres in transgenic hyperthyroid mice expressing the A2 adenosine receptor (Tg-A2aR). The second part of the study concentrated on comparing human thyroid tissue of control individuals and of patients with Graves' disease. The rate of cell division was evaluated by immunohistochemical detection of cells positive for proliferating cell nuclear antigen (PCNA). Their spatial distribution was then correlated with immunohistochemical cellular expression of growth-and vasoactive-related factors (fibroblast growth factor-2, transforming growth factor-, endothelin-1, vascular endothelial growth factor, nitric oxide synthase III), and with microcirculation expansion. Observations were made on digitalised images of histological serial sections. The nearest-neighbour method was used to distinguish between random or clustered distribution. PCNA-positive cells were both randomly and uniformly distributed in homogenous goitres from C57 black mice, and were clustered in tissue areas identified as papillary and hyperplastic zones in heterogeneous goitres from Tg-A2aR mice. However, they were absent in the so-called compact cellular zones featuring resting cells. Moreover, whereas papillary and hyperplastic zones were highly vascularised, compact zones were nearly free of microvessels. Spatial distribution of dividing cells was positively correlated with the expression of growth-related factors. A similar pattern was observed in the thyroids of patients with Graves' disease. In accordance with the recent demonstration of the presence of angiofollicular units in the thyroid, these data strongly support the hypothesis that functional and mitotic properties of each single thyrocyte, likely to be responsible for growth heterogeneity of hyperplastic glands, may be adjusted at tissue level by specific interactions with neighbour endothelial cells that, in turn, could alter the mitotic rate of thyrocytes through paracrine signals.

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Correlated Functional and Morphometric Study of Thyroid Hyperplasia Induced by Iodine Deficiency*

Cited by 52 publications

References 21 publications

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

Iodine Deficiency Induces a Thyroid Stimulating Hormone-Independent Early Phase of Microvascular Reshaping in the Thyroid

Relationships between cell division, expression of growth factors and microcirculation in the thyroids of Tg-A2aR transgenic mice and patients with Graves' disease

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