Sensitivity of thyroid gland growth to thyroid stimulating hormone (TSH) in rats treated with antithyroid drugs.

Antithyroid drugs and phenobarbital (PB) have been shown to promote thyroid tumors in rats. It has been proposed that increased thyroid-stimulating hormone (TSH) mediates the thyroid tumor-promoting effect of antithyroid drugs and PB, and is increased because of decreased thyroxine (T4) concentration. However, PB is much less effective than antithyroid drugs at increasing TSH. It has been proposed that small increases in serum TSH produced by PB treatment is sufficient to promote thyroid tumors. However, the level to which TSH must be increased to stimulate the thyroid gland has not been reported. Therefore, we have examined the effect of increasing serum TSH concentration on thyroid growth by measuring thyroid gland weight and thyroid follicular cell proliferation. Serum TSH concentrations were increased by feeding rats various concentrations of propylthiouracil (PTU) or methimazole (MMI) for 21 days. Serum total T4, free T4, total T3 (triiodothyronine), free T3, and TSH concentrations were measured by radioimmunoassay. Thyroid follicular cell proliferation was measured by autoradiography and expressed as a labeling index (LI). PTU and MMI treatments reduced total and free T4 more than 95% by day 21, whereas total and free T3 were reduced 60%. TSH, thyroid follicular cell proliferation and thyroid weight were increased 560%, 1400%, and 200%, respectively, by day 21. TSH was significantly correlated with thyroid weight and LI. Moderate increases in serum TSH of between 10 and 20 ng/ml increased the number of proliferating thyroid follicular cells, but had no effect on thyroid weight. These results support that small increases in serum TSH can be sufficient to stimulate thyroid follicular cell proliferation. Furthermore, thyroid follicular cell proliferation may be more useful than thyroid weight alone for assessing alterations in thyroid growth in rats treated with chemicals that produce only small to moderate increases in serum TSH.     

Neonatal hypothyroidism caused by maternal nicotine exposure is reversed by higher T3 transfer by milk after nicotine withdraw

Maternal nicotine exposure leads to neonatal hypothyroidism that can be returned to euthyroidism after nicotine withdrawal. Here, we examined the transfer of iodine through milk, deiodinase activities (D1 and D2), and serum T3, T4 and TSH in rat offspring after maternal exposure to nicotine. One day after birth, a minipump was implanted to dams releasing nicotine (NIC), 6 mg/kg/day for 13 days or vehicle saline. Animals were killed at the day 15 and 21 of lactation. At day 15, NIC-treated dams showed decreased T4 and mammary 2 h-radioiodine uptake (RAIU) and increase of TSH, thyroid 2 h-RAIU, liver D1 and mammary D2. At the cessation of NIC-exposure, pups displayed decreased T3, T4 and thyroid 2 h-RAIU and increased TSH. At weaning (21-postnatal day), NIC-treated dams recovered their T4 and TSH, but increased deiodinase level in the liver and mammary gland. Milk T3 content in NIC-treated dams was higher at both day 15 and 21, and thyroid function was recovered at the day 21. Thus, thyroid function was affected by nicotine in both mothers and pups, suggesting a primary hypothyroidism. After nicotine withdrawal, pups recovered thyroid function probably due to the increased lactational transfer of T3 in relation with increased mammary gland deiodinase activities.     

Subacute toxicity of p,p'-DDT on rat thyroid: Hormonal and histopathological changes

The purpose of this study is to assess the effect of p,p'-DDT on thyroid activity of male Wistar rats. Pesticide was administered intraperitoneally (i.p.) for 10 consecutive days at doses of 50 and 100mg/kg/day. At the end of the treatment, the endpoints examined included serum total levels of triiodothyronine (T(3)), total thyroxine (T(4)), and thyroid stimulating hormone (TSH). Thyroid gland histopathology and tissue metabolism of thyroid hormone (T(4) UDP-glucuronyltransferase UDP-GT and 5'-deiodinases) were determined. DDT treatment altered thyroid function namely by increasing hepatic excretion of T(4) glucuronide. At the dose of 50mg/kg it decreased T(4) circulating levels and increased thyroid 5'-deiodinase type I (5'-D-I) and brown adipose tissue (BAT) 5'-deiodinase type II (5'-D-II) activities but it did not affect liver 5'-D-I activity which might contribute to the maintenance of the serum T(3) level. Treatment with 100mgDDT/kg decreased serum thyroid hormone concentration and tissue 5'-D-I activity without affecting BAT 5'-D-II activity. Gland histomorphological analysis showed hyperplasia and squamous metaplasia with abundant colloid. These observations associated to the elevated serum TSH levels and gland hypertrophy suggest that DDT exposure induced an hypothyroidism state with a colloid goiter in rats.     

Studies on the preventive action of neurotensin on dexamethasone-induced adrenocortical atrophy.

The effects of neurotensin (NT) and ACTH on the dexamethasone (Dx)-induced atrophy of the rat adrenal cortex (120 micrograms Dx/rat/day for 4 days) were investigated. NT at a dose of 8 micrograms/rat/day for 2 days prevented Dx-induced adrenal atrophy, and a similar effect was exerted by 10 micrograms/rat/day of ACTH for 2 days. Lower doses of NT were ineffective. ACTH markedly enhanced 3H-thymidine incorporation by adrenal slices, while NT did not. Neither ACTH nor NT had any effect on the number of metaphases per section of the adrenal gland. These findings indicate that NT, like ACTH, prevents Dx-induced adrenocortical atrophy, and that this effect does not depend, as does that of ACTH, upon the stimulation of proliferation of adrenocortical cells.     

Effects of phenobarbital, pregnenolone-16alpha-carbonitrile, and propylthiouracil on thyroid follicular cell proliferation.

Reduced thyroid hormone concentrations (T4 and/or T3) and increased thyroid-stimulating hormone (TSH) have been proposed to mediate the thyroid tumor promoting effects of hepatic microsomal enzyme inducers (MEI) and antithyroid drugs. TSH is known to stimulate thyroid gland function and growth, as well as neoplasia. Thyroid weight has been used as an indicator of thyroid gland growth in MEI studies, but little is known about the effects of these inducers on thyroid cell proliferation. Therefore, we determined the time-course of thyroid cell proliferation of rats treated with MEI, and with the antithyroid drug propylthiouracil (PTU). Male Sprague-Dawley rats were fed either a basal diet or a diet containing phenobarbitol (PB) (1200 ppm), PCN (500 ppm), or PTU (30 ppm) for 3, 7, 14, 21, 30, 45, 60, or 90 days. PB and PCN treatments did not affect T3, but PTU reduced T3 60%. PB and PCN treatments reduced T4 25%, whereas PTU treatment reduced T4 90%. PB and PCN treatments increased thyroid weight 80%, and PTU increased thyroid weight 500%. TSH was not appreciably altered in PB-treated rats, but was increased 75% and 830% in PCN- and PTU-treated rats, respectively. Thyroid cell proliferation was increased 260, 330, and 850% in rats treated with PB, PCN, or PTU, respectively, for 7 days, but returned to control levels by the 45th treatment day. In conclusion, treatment with MEI that produced mild increases in TSH resulted in dramatic increases in thyroid cell proliferation, which peaked after 7 days of treatment and then returned to control values. This result is similar to that of antithyroid drugs, which produce large increases in TSH. These findings may have important implications for the role thyroid follicular cell proliferation has in mediating the thyroid tumor promoting effects of MEI.     

Evaluation of possible goitrogenic and anti-thyroidal effect of nitrate, a potential environmental pollutant

Nitrate is a wide spread contaminant of ground and surface water. The source of nitrate in the ground water may be from run off or seepage from fertilized soil, municipal or industrial waste water, land fills, septic system, urban drainage or decaying plants. Human and animal systems are affected severely on nitrate exposure. The study was to investigate the effect of dietary nitrate exposure on the thyroid status along with the state of iodine nutrition. Rats were fed diet containing 3% potassium nitrate (KNO3) for 4 weeks and then thyroid status was evaluated by thyroid gland weight, urinary iodine excretion pattern, thyroid peroxidase (TPO) activity, serum levels of total thyroxine (T4), triiodothyronine (T3) and thyroid stimulating hormone (TSH) concentrations. In nitrate treated animals, the weight of thyroid gland was increased significantly (P<0.001) while thyroid peroxidase activity (P<0.01), serum T4 (P<0.01) and serum T3 levels (P<0.001) were reduced; but serum TSH level was increased (P<0.001) along with slightly elevated iodine excretion level (P<0.001) in comparison to control animals. The overall results indicated the development of a relative state of functional hypothyroidism with enlarged thyroid after nitrate exposure. This study can explain a part for the persistence of residual goitre in the post-salt iodization phase.     

Detection of thyroid toxicants in a tier I screening battery and alterations in thyroid endpoints over 28 days of exposure.

Phenobarbital (PB), a thyroid hormone excretion enhancer, and propylthiouracil (PTU), a thyroid hormone-synthesis inhibitor, have been examined in a Tier I screening battery for detecting endocrine-active compounds (EACs). The Tier I battery incorporates two short-term in vivo tests (5-day ovariectomized female battery and 15-day intact male battery using Sprague-Dawley rats) and an in vitro yeast transactivation system (YTS). In addition to the Tier I battery, thyroid endpoints (serum hormone concentrations, liver and thyroid weights, thyroid histology, and UDP-glucuronyltransferase [UDP-GT] and 5'-deiodinase activities) have been evaluated in a 15-day dietary restriction experiment. The purpose was to assess possible confounding of results due to treatment-related decreases in body weight. Finally, several thyroid-related endpoints (serum hormone concentrations, hepatic UDP-GT activity, thyroid weights, thyroid follicular cell proliferation, and histopathology of the thyroid gland) have been evaluated for their utility in detecting thyroid-modulating effects after 1, 2, or 4 weeks of treatment with PB or PTU. In the female battery, changes in thyroid endpoints following PB administration, were limited to decreased serum tri-iodothyronine (T3) and thyroxine (T4) concentrations. There were no changes in thyroid stimulating hormone (TSH) concentrations or in thyroid gland histology. In the male battery, PB administration increased serum TSH and decreased T3 and T4 concentrations. The most sensitive indicator of PB-induced thyroid effects in the male battery was thyroid histology (pale staining and/or depleted colloid). In the female battery, PTU administration produced increases in TSH concentrations, decreases in T3 and T4 concentrations, and microscopic changes (hypertrophy/hyperplasia, colloid depletion) in the thyroid gland. In the male battery, PTU administration caused thyroid gland hypertrophy/hyperplasia and colloid depletion, and the expected thyroid hormonal alterations (increased TSH, and decreased serum T3 and T4 concentrations). The dietary restriction study demonstrated that possible confounding of the data can occur with the thyroid endpoints when body weight decrements are 15% or greater. In the thyroid time course experiment, PB produced increased UDP-GT activity (at all time points), increased serum TSH (4-week time point), decreased serum T3 (1-and 2-week time points) and T4 (all time points), increased relative thyroid weight (2- and 4-week time points), and increased thyroid follicular cell proliferation (1- and 2-week time points). Histological effects in PB-treated rats were limited to mild colloid depletion at the 2- and 4-week time points. At all three time points, PTU increased relative thyroid weight, increased serum TSH, decreased serum T3 and T4, increased thyroid follicular cell proliferation, and produced thyroid gland hyperplasia/hypertrophy. Thyroid gland histopathology, coupled with decreased serum T4 concentrations, has been proposed as the most useful criteria for identifying thyroid toxicants. These data suggest that thyroid gland weight, coupled with thyroid hormone analyses and thyroid histology, are the most reliable endpoints for identifying thyroid gland toxicants in a short-duration screening battery. The data further suggest that 2 weeks is the optimal time point for identifying thyroid toxicants based on the 9 endpoints examined. Hence, the 2-week male battery currently being validated as part of this report should be an effective screen for detecting both potent and weak thyroid toxicants.     

Dietary calcium induced cytological and biochemical changes in thyroid

Certain epidemiological studies revealed correlation between hard water consumption (with high calcium) and thyroid size of the population, though the possible alterations in thyroid physiology upon calcium exposure are still inconclusive. Adult male Wistar strain rats were subjected to calcium treatment at the doses of 0.5g%, 1.0g% and 1.5g% calcium chloride (CaCl(2)) for 60 days. The parameters studied were - thyroid gland weight, histopathology, histomorphometry; thyroid peroxidase (TPO), 5'-deiodinase I (DI), sodium-potassium adenosine triphosphatase (Na(+)-K(+)-ATPase) activities; serum total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), thyroid stimulating hormone (TSH) levels. Enlargement of thyroid with hypertrophic and hyperplastic changes, retarded TPO and 5'-DI but enhanced Na(+)-K(+)-ATPase activities, augmented serum total and free T4 and TSH but decreased total and free T3 levels and low T3/T4 ratio (T3:T4) were observed in the treated groups. All these findings indicate development of goitrogenesis upon exposure to excessive dietary calcium.     

Induction of T(4) UDP-GT activity,serum thyroid stimulating hormone,and thyroid follicular cell proliferation in mice treated with microsomal enzyme inducers

The microsomal enzyme inducers phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are known to induce thyroxine (T(4)) glucuronidation and reduce serum T(4) concentrations in rats. Also, microsomal enzyme inducers that increase serum TSH (i.e., PB and PCN) also increase thyroid follicular cell proliferation in rats. Little is known about the effects of these microsomal enzyme inducers on T(4) glucuronidation, serum thyroid hormone concentrations, serum TSH, and thyroid gland growth in mice. Therefore, we tested the hypothesis that microsomal enzyme inducers induce T(4) UDP-GT activity, resulting in reduced serum T(4) concentrations, as well as increased serum TSH and thyroid follicular cell proliferation in mice. B6C3F male mice were fed a control diet or a diet containing PB (600, 1200, 1800, or 2400 ppm), PCN (250, 500, 1000, or 2000 ppm), 3MC (62.5, 125, 250, or 500 ppm), or PCB (10, 30, 100, or 300 ppm) for 21 days. All four inducers increased liver weight and hepatic microsomal UDP-GT activity toward chloramphenicol, alpha-naphthol, and T(4). PB and PCB decreased serum total T(4), but PCN and 3MC did not. Serum thyroid stimulating hormone was markedly increased by PCN and 3MC treatments, and slightly increased by PB and PCB treatments. All four microsomal enzyme inducers dramatically increased thyroid follicular cell proliferation in mice. The findings suggest that PB, PCN, 3MC, and PCB disrupt thyroid hormone homeostasis in mice.     

A mode of action for induction of thyroid gland tumors by Pyrethrins in the rat

Prolonged treatment with high doses of Pyrethrins results in thyroid gland tumors in the rat. To elucidate the mode of action for tumor formation, the effect of Pyrethrins on rat thyroid gland, thyroid hormone levels and hepatic thyroxine UDPglucuronosyltransferase activity was investigated. Male Sprague-Dawley CD rats were fed diets containing 0 (control) and 8000 ppm Pyrethrins and female rats diets containing 0, 100, 3000 and 8000 ppm Pyrethrins for periods of 7, 14 and 42 days and for 42 days followed by 42 days of reversal. As a positive control, rats were also fed diets containing 1200-1558 ppm sodium Phenobarbital (NaPB) for 7 and 14 days. The treatment of male rats with 8000 ppm Pyrethrins, female rats with 3000 and 8000 ppm Pyrethrins and both sexes with NaPB resulted in increased thyroid gland weights, which were associated with follicular cell hypertrophy. Thyroid follicular cell replicative DNA synthesis was increased by treatment with Pyrethrins and NaPB for 7 and/or 14 days. Treatment with Pyrethrins and NaPB increased hepatic microsomal thyroxine UDPglucuronosyltransferase activity and serum thyroid stimulating hormone levels (TSH), but reduced serum levels of either thyroxine (T4) and/or triiodothyronine (T3). The effects of Pyrethrins in female rats were dose-dependent, with 100 ppm being a no-effect level, and on cessation of treatment were essentially reversible in both sexes. The concordance between the effects of Pyrethrins and NaPB suggests that the mode of action for Pyrethrins-induced rat thyroid gland tumors is similar to that of some other non-genotoxic inducers of hepatic xenobiotic metabolism.     

The herbicide metolachlor induces liver cytochrome P450s 2B1/2 and 3A1/2, but not thyroxine-uridine dinucleotide phosphate glucuronosyltransferase and associated thyroid gland activity

Metolachlor (2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide) is widely used internationally as a corn and cotton herbicide. The metolachlor effects noted in rats during testing for U.S. pesticide registration include increased liver weight and hepatocarcinogenicity associated with eosinophilic foci. These properties, plus nongenotoxicity, are also characteristic of the prototypical rat liver tumor promoter, phenobarbital. Phenobarbital induces hepatic cytochrome P450s CYP2B1/2 and CYP3A1/2 and thyroxine (T(4))-UDP-glucuronosyltransferase (T(4)-UGT), which enhances thyroxine clearance and thus indirectly increases thyroid gland activity. Because other chloroacetanilide herbicides are known to similarly affect rat thyroid gland, this study tested the hypothesis that metolachlor would have these additional phenobarbital-like effects on liver, especially that of T(4)-UGT induction with consequential stimulation of thyroid gland. Effects of metolachlor, fed to male Sprague-Dawley rats for 14 days at the carcinogenic dose of 3000 ppm, were compared to those of equimolar phenobarbital. Liver microsomal CYP2B1/2 and CYP3A1/2 were probed by immunoblotting and T(4)-UGT was measured enzymatically. Serum T(4), triiodothyronine (T(3)), and thyroid-stimulating hormone (TSH) and thyroid follicular epithelial cell morphology and proliferation were used to assess thyroid gland activity. Metolachlor induced CYP2B1/2 and CYP3A1/2 proteins, but unlike phenobarbital, did not affect T(4)-UGT activity. In agreement, serum T(4), T(3), or TSH were unaffected by metolachlor. Also, no significant effects of metolachlor on thyroid gland morphology or follicular epithelial cell height or proliferation were observed. These data demonstrate that metolachlor is an inducer of hepatic CYP2B1/2 activity. But unlike the prototypical CYP2B1/2 inducer phenobarbital, metolachlor does not cause an increase in T(4)-glucuronidation and thyroid gland activation.     

The effects of chronic ingestion of spironolactone on serum thyrotropin and thyroid hormones in the male rat

Male rats were fed spironolactone admixed with feed at doses of 6, 50, and 200 mg/kg/day for up to 13 weeks. After 13 weeks of treatment, there were dose-related increases in thyroid weight and follicular hypertrophy. Serum thyrotropin (TSH) concentrations were significantly increased throughout the treatment period. Serum thyroxine (T4) and triiodothyronine (T3) were significantly decreased at Weeks 2 and 4, but returned to control concentrations by Week 13. The TSH increase and transient T4 decrease suggested that the thyroid hypertrophy was a compensatory reaction to lowered thyroid hormone levels. To determine the effect of spironolactone ingestion on T4 synthesis and metabolism, male rats were fed spironolactone admixed with feed at 200 mg/kg for 2 weeks. The decrease in T4 was not due to decreased synthesis, since iodide uptake and organification were significantly increased by spironolactone treatment. Since uridine diphosphate glucuronosyl transferase activity was significantly increased by spironolactone treatment, it appears that, by increasing hepatic clearance of T4, spironolactone causes a decrease in the serum concentration of this hormone. The lower T4 level causes a release of feedback inhibition and an increase in TSH resulting in the increase in thyroid gland size and activity.     

Effects of oral erythrosine (2',4',5',7'-tetraiodofluorescein) on the pituitary-thyroid axis in rats

Erythrosine (FD&C Red Dye No.3) is a tetraiodinated derivative of fluorescein. Rats fed a 4% erythrosine diet for 30 months beginning in utero have an increased incidence of thyroid adenomas and adenocarcinomas. These tumors may be secondary to increased stimulation of the thyroid gland by TSH. This study was undertaken to determine if dietary erythrosine disrupts the pituitary-thyroid axis thereby altering serum thyroid hormone levels. TSH levels, or the pituitary's response to TRH. Rats were fed diets containing erythrosine (0.5, 1.0, 4.0%), sodium iodide (0.16%), or fluorescein (1.6%) for 3 weeks after which TRH testing was performed in vivo. Erythrosine produced a dose-dependent increase in serum T4 levels. With the 4% erythrosine diet, serum T4 and T3 levels and the free-T4 index were significantly increased, whereas the free-T3 index were significantly increased, whereas the free-T3 index was unchanged. Rats fed the 4.0% erythrosine diet had an exaggerated TSH response to TRH; 10 min after the TRH injection, serum TSH levels were 80% greater than TSH levels of control rats. Short-term administration of erythrosine to rats decreased hepatic T3 production by decreasing its conversion of T4 to T3, indicating that erythrosine decreases hepatic 5'-deiodinase activity. These data demonstrate that dietary ingestion of 4% erythrosine disrupts the pituitary-thyroid axis as evidenced by an increased TSH response to TRH. This effect is mediated by erythrosine or an iodinated metabolite, since ingestion of its fluorescein nucleus had no effect. Erythrosine's effects were not likely mediated by iodide, because serum T4 and T3 levels were elevated and iodide administration did not increase the TSH response to TRH. These data suggest that erythrosine increases the pituitary's TSH response to TRH by altering thyrotroph cell conversion of T4 to T3. Chronic erythrosine ingestion may promote thyroid tumor formation in rats via chronic stimulation of the thyroid by TSH.     

Effects of carbendazim on rat thyroid,parathyroid, pituitary and adrenal glands and their hormones

The purpose of this study is to determine the effects of low and high dose of carbendazim on the level of certain hormones and endocrine glands (thyroid, parathyroid, adrenal and pituitary glands) of male rats. Carbendazim is a systemic fungicide with activity against a number of plant pathogens. In this study, daily doses of 0, 150, 300 and 600 mg/kg per day carbendazim were applied to male rats by gavage for 15 weeks. At the end of the experiment, T3, T4, TSH, ACTH and GH levels in rat serum were analysed. Thyroid, parathyroid, adrenal and pituitary glands of rats were taken. A significant increase was observed in serum T3 levels of the rats, which were exposed to 300 mg/kg per day carbendazim doses, compared to the serum T3 levels of the control group. There were no differences between the control and carbendazim-treated group of rats regarding serum TSH, T4, ACTH and growth hormone levels. This showed us that carbendazim caused histopathological damages in thyroid, parathyroid and adrenal glands of rats. No changes were observed in pituitary glands of treated rats. These results suggest that a high quantity of subchronic carbendazim exposure affects thyroid, parathyroid and adrenal glands.     

Effects of 900 MHz electromagnetic field on TSH and thyroid hormones in rats

In this study, the effects of exposure to a 900 megahertz (MHz) electromagnetic field (EMF) on serum thyroid stimulating hormone (TSH) and triiodothronine-thyroxin (T3-T4) hormones levels of adult male Sprague-Dawley rats were studied. Thirty rats were used in three independent groups, 10 of which were control (without stress and EMF), 10 of which were exposed to 900 MHz EMF and 10 of which were sham-exposed. The exposures were performed 30 min/day, for 5 days/week for 4 weeks to 900 MHz EMF. Sham-exposed animals were kept under the same environmental conditions as the study groups except with no EMF exposure. The concentration of TSH and T3-T4 hormones in the rat serum was measured by using an immunoradiometric assay (IRMA) method for TSH and a radio-immunoassay (RIA) method for T3 and T4 hormones. TSH values and T3-T4 at the 900 MHz EMF group were significantly lower than the sham-exposed group (p<0.01). There were no statistically significant differences in serum TSH values and T3-T4 hormone concentrations between the control and the sham-exposed group (p>0.05). These results indicate that 900 MHz EMF emitted by cellular telephones decrease serum TSH and T3-T4 levels.     

A study of pituitary-thyroid function during exercise in man

Exercise induced modulations in circulatory T4, T3 and TSH were monitored in 14 healthy euthyroid male volunteers undergoing exercise on a bicycle ergometer at 750 KPM for 20 minutes. TSH response to 100 micrograms TRH was also studied in 4 exercising and 4 resting subjects. Serial blood samples were obtained before, during and after the exercise. Serum T4 exhibited a significant decrease (P less than 0.05) from 9.6 +/- 0.49 microgram/dl (mean +/- SE) to 8.3 +/- 0.47 microgram/dl at 20 min after the termination of the exercise, whereas a significant decrease (P less than 0.01) in T3 levels from 158 +/- 9 ng/dl to 144 +/- 8.2 ng/dl was recorded at 40 min after the termination of the exercise. The basal TSH levels as well as the sensitivity of the pituitary thyroid axis, monitored as overall TSH response, reflected by the sum of TSH values at different time intervals and the maximum rise over the basal levels (delta TSH) remained unaltered after exercise. These observations suggest that hormone secretion by the thyroid and its responsiveness to endogenous TSH are maintained after exercise. The decrease in circulatory T4 and T3 could be due to an increase in degradation of the hormones or may reflect a generalized adaptation phenomenon. The exact mechanism and significance of these alterations remains to be elucidated.     

Unusual characteristics of the dose-dependent uptake of propylthiouracil by thyroid gland in vivo. Effects of thyrotropin, iodide or phenobarbital pretreatment.

Dose dependency of propylthiouracil (PTU) uptake by the thyroid gland was investigated in intact, adult male rats after a single intraperitoneal dose of PTU. PTU pharmacokinetics in rat serum, liver and lung were independent of the size of this single dose of PTU. However, in the thyroid gland, PTU concentrations corrected for dose were disproportionately high at low doses. At low PTU doses, a transport mechanism contributes substantially to thyroidal PTU uptake, but at high PTU doses this transport system becomes saturated. Thus, at serum PTU concentrations of 5 μg/ml or above, thyroid to serum (T/S) PTU ratios are independent of PTU dose and serum concentration. Alteration in the functional status of the thyroid changed the relationship between serum and thyroidal PTU concentrations. Thyroxine administration prior to an intraperitoneal PTU dose of 5 mg/kg reduced ratios of T/S PTU concentrations. However, thyrotropic hormone (TSH) preadministration had little effect on early thyroidal PTU concentration, but appeared to exert an effect at later times. Chronic administration of either potassium iodide or phenobarbital prior to PTU increased T/S PTU ratios, again suggesting an effect of TSH on PTU metabolism in the thyroid.     

A 90-day drinking water toxicity study in rats of the environmental contaminant ammonium perchlorate.

Perchlorate (ClO(4)(-)), the dissociated anion of perchlorate salts such as ammonium, potassium, and sodium perchlorate, has been recently recognized as a persistent and pervasive contaminant of drinking water supplies in a number of metropolitan areas. Perchlorate is of concern because of uncertainties in the toxicological database available to address the potential human health effects of low-level exposure. The purpose of this study was to evaluate the subchronic toxicity of perchlorate when administered to Sprague-Dawley rats as ammonium perchlorate (AP) for 14 or 90 days. The study consisted of an untreated control group and five treatment groups that received continuous exposure to AP via the drinking water at dosage levels of 0.01, 0.05, 0.2, 1.0, and 10.0 mg/kg/day. The study design included a nontreatment recovery period of 30 days to evaluate the reversibility of any AP-induced effects at the 0.05, 1.0, and 10.0 mg/kg/day levels. The study also investigated the potential effects of AP on male sperm parameters, female estrous cyclicity, bone marrow micronucleus formation, and serum hormone levels, i.e., triiodothyronine (T(3)), thyroxine (T(4)), and thyroid stimulating hormone (TSH). No toxicologically meaningful differences were observed between the control and AP-treated groups with respect to survival, clinical observations, body weights, food consumption, water consumption, ophthalmology, hematology, clinical chemistry, estrous cycling, sperm parameters, or bone marrow micronucleus formation. A target organ effect was produced by AP in the thyroids of male and female rats at the 10 mg/kg/day level after 14 and 90 days of exposure. The effect was characterized by significantly increased thyroid weights and thyroid histopathology consisting primarily of follicular cell hypertrophy with microfollicle formation and colloid depletion. These changes were reversible after a nontreatment recovery period of 30 days. Statistically significant changes in TSH and thyroid hormones were observed at all AP dosage levels tested; however, no thyroid organ weight or histopathological effects were observed at AP dosage levels < or = 1.0 mg/kg/day. In the absence of thyroid organ weight and histopathological effects, the toxicological significance of TSH and thyroid hormone changes at AP dosage levels < or = 1.0 mg/kg/day remains to be determined.     

Increase in thyroid follicular cell tumors in nelfinavir-treated rats observed in a 2-year carcinogenicity study is consistent with a rat-specific mechanism of thyroid neoplasia

The carcinogenic potential of nelfinavir mesylate (nelfinavir) was evaluated in a 2-year oral (gavage) study on Sprague-Dawley rats at dose levels of 0 (control), 0 (vehicle control), 100, 300 and 1000 mg/kg per day. At the end of the treatment, increased incidences of thyroid follicular cell hyperplasia and neoplasms were observed at 300 (males) and 1000 mg/kg per day (both sexes). There were no other treatment-related effects and no tumors at other sites. Results from previous studies indicated a number of effects in the liver and thyroid, as well as metabolic profiles that suggested nelfinavir might cause thyroid hyperplasia/neoplasia secondary to hormone imbalance by altering thyroid hormone disposition. To investigate this hypothesis, the effects of nelfinavir on gene expression in rat hepatocytes and liver slices (in vitro), thyroxine plasma clearance, and thyroid gland function were evaluated. Compared to controls, gene expression analyses demonstrated an increased expression of glucuronyltransferase (UDPGT) and CYP450 3A1 in nelfinavir-treated rat hepatocytes and liver slices. In rats treated with nelfinavir (1000 mg/kg per day) for 4 weeks, liver weights and centrilobular hepatocellular hypertrophy were increased and minimal to mild diffuse thyroid follicular cell hypertrophy and follicular cell hyperplasia were evident in the thyroid gland. Thyroid-stimulating hormone (TSH) levels were significantly increased (three-fold), while tri-iodothyronine (T3)/tetra-iodothyronine (T4) and reverse T3(rT3) levels were unchanged, indicating that a compensated state to maintain homeostasis of T3/T4 had been achieved. Plasma 125I-thyroxine clearance was increased and the plasma thyroxine AUC0-48 was decreased (24%) compared to control. In conclusion, these data indicate that thyroid neoplasms observed in the nelfinavir-treated rats were secondary to thyroid hormone imbalance. Increased thyroxine clearance contributes to the effects of nelfinavir on thyroid gland function and is probably a result of UDPGT induction that leads to elevated TSH levels in the rat and eventual thyroid neoplasia. These results are consistent with a well-recognized rat-specific mechanism for thyroid neoplasms.