Biomedical subjects
Publications and source records attributed to B M Stringer.
Rat thyroid follicular cells desensitized to the mitogenic action of TSH by prolonged stimulation retain the capacity to respond to the mitogenic stimulus of wounding. The implications for thyroid growth control and neoplasia are discussed.
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This study was designed to investigate the mitotic response to wounding in the rat thyroid. The spatial distribution of mitotic activity 48 hr after incision of the thyroid isthmus, or mere exposure of the gland (sham-operation), was assessed using a stathmokinetic technique. Incision resulted in a 66-fold increase over normal in metaphase index adjacent to the wound, falling over 2 mm to a stable 13-fold elevation. Sham-operation produced a smaller response with a complete return to normal levels over 1-1 X 5 mm. The results demonstrate that there is a dramatic localized mitotic response to wounding in the thyroid together with a smaller generalized response. Further, the response to sham-operation indicates that thyroid follicular cells respond to a diffusible 'wound hormone'. We suggest that this may be a major mechanism mediating reparative growth in this gland.
We have previously shown that the growth response of the rat thyroid to a sustained elevation of the serum level of TSH, induced by goitrogen administration, is self-limiting. This study investigated the possibility that this limitation of growth is due to the inhibitory action of a chalone secreted by the thyroid follicular cells, the serum concentration of which increases as the gland grows. Twenty-seven adult rats were treated with the goitrogen aminotriazole for 5 months to reach a 'plateau of growth'. One group of 9 rats was then subjected to hemithyroidectomy, another to a sham operation, while a third acted as unoperated controls. Four weeks later there was no significant difference between the groups in thyroid weight, follicular cell number or serum TSH. The absence of regeneration following hemithyroidectomy indicates that a systemically-circulating chalone does not play a role in the regulation of growth in the goitrous thyroid. Other mechanisms including the possible role of a 'local' chalone are briefly discussed.
A method is described for the rapid and accurate quantitation of tissue morphology using rat thyroid as a model. Perfused-fixed rat thyroid was diced into approximately thirty small pieces which were then randomly embedded in epon. Sections were taken at 500 micrometer intervals and stained with toluidine blue. Epithelial, follicular lumen and stromal components were quantified by a point counting technique. An analysis of variance was then performed on the data to determine whether there was any significant variation in the distribution of components between sections cut at different levels. No significant variation in any component was seen between sections for normal diced thyroid. This was also the case for diced thyroids of animals chronically treated with goitrogen to create a different physiological state. The method is therefore reliable even when marked changes in component distribution are induced. The physical randomization of tissue architecture by dicing, prior to embedding, greatly reduces the number of sections needed for the accurate morphometry of non-randomly distributed tissues.
Lack of species homology in radioimmunoassays can lead to serious errors. We have shown that a highly significant bias results from application of commercially available 'human' thyroxine and triiodothyronine assays to rat samples. This paper describes a simple modification whereby this source of error is overcome. Validation of the modified assays demonstrated their high degree of reliability.
This study was designed to provide a reliable quantitative assessment of the circadian rhythm of mitotic activity in the follicular cell population of the rat thyroid, and the effect on this rhythm of prolonged stimulation by a raised level of circulating TSH, induced by goitrogen administration. Mitotic activity in groups of control and goitrogen-treated rats was assessed by a stathmokinetic technique during four 4-h periods spaced equally through one 24-h cycle. Particular attention was paid to the method of sampling to eliminate systematic and minimise random errors, and to the assessment of rhythmicity which was carried out by an appropriate statistical method. A highly significant circadian rhythm was found in control animals with a daytime peak (12.00 to 16.00 h). Goitrogen treatment led to a 5- to 6-fold increase in the mean but a loss of detectable rhythmicity. The results show that the presence and timing of this circadian rhythm must be taken into account in future studied of thyroid growth, and they throw some light on the possible mechanisms of its control. Comparison of the rhythm with that of serum TSH reported previously raises the possibility of a dominant control by this hormone even in euthyroid animals and suggests that it may act on cells in the G2 and/or G1/G0 phases of the cell cycle.
This study was designed to investigate the changes in growth and function which occur in the rat thyroid during prolonged TSH stimulation. Animals maintained on the goitrogen aminotriazole were sacrificed together with controls at frequent intervals over a period of 5 months. The levels of serum T3 and T4 and TSH were measured by radioimmunoassay. Functional activity was assessed by measurement of the thyroid/serum iodide ratio (T/S) and growth by measurement of thyroid weight, follicular cell number and follicular cell mitotic activity. Serum T3 and T4 rapidly fell to undetectable levels within 2 weeks. The level of serum TSH rose to a stable 5-fold maximum after 4 weeks. The T/S ratio followed a closely similar pattern rising to a sustained 7-fold maximum. Thyroid weight and follicular cell number increased rapidly for the first few weeks but the growth rate declined progressively, falling almost to zero after 80 days. Mitotic activity rose dramatically to a 30-fold peak after 7 days but then declined almost to normal after 80 days, consistent with the observed change in cell number. The results thus demonstrate a clear dissociation between the functional and proliferative activity of the thyroid follicular cells during prolonged stimulation by a sustained elevation of serum TSH and point to the existence of specific growth regulating mechanisms which limit the mitotic response.
This paper describes the effect of long-term goitrogen-administration on the mast cell population of the rat thyroid. Animals were treated with the goitrogen aminotriazole at a dose sufficient to block thyroid hormone synthesis completely, and compared after 80 days with a control group. Serum TSH was measured by radioimmunoassay, and mast cell number quantified from specially-stained tissue sections using appropriate serological methods. Goitrogen treatment led to a 9-fold increase in serum TSH and an 8-fold increase in thyroid weight. Mast cell number per unit volume of thyroid decreased, but total numbers per gland increased 4 to 5 fold. There was a significant fall in mean mast cell size. The work demonstrates conclusively that mast cell hyperplasia occurs during goitre formation and provides a method for its quantitative assessment. The possible mechanisms and significance of thyroid mast cell proliferation are discussed.
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The expression of the known rat 5-HT receptor sub-types has been analyzed in a presumptive serotoninergic cell line derived from the rat raphé nuclei, using reverse transcription followed by polymerase chain reaction. By manipulating the activity of the oncogene (ts-SV40T) product used to immortalize the serotoninergic precursors, it has been possible to compare the expression of the 5-HT receptors in either replicative or differentiating cells. 5-HT1B, 5-HT1D, 5-HT3, 5-HT6 and 5-HT7 receptor gene expression were all observed in the replicating cells. However, under differentiation conditions, expression of all except the 5-HT1B receptor was lost. Only one novel amplification product appeared during early differentiation, in the 5-HT2B lane; its smaller than expected size was suggestive of a previously undescribed alternate splicing of the mRNA in brain. The curtailment of 5-HT receptor expression in differentiating neurones in vitro may reflect the normal ongoing restriction in the phenotypic potential during embryogenesis in vivo. The serotonin cells, therefore, constitute a pristine cell line in which to study the receptor pharmacology of one or more 5-HT receptor sub-types in isolation.