Plasma Thyroid Hormone Levels Research Articles

Thermal manipulations during broiler embryogenesis improves post-hatch performance under hot conditions

Previous studies on broilers conducted in our laboratory showed that intermittent thermal manipulation (TM) of 39.5 °C every 12 h during embryonic days E7–E16 improved thermoregulative parameters in the embryo and post-hatch, as well as the broilers' ability to cope with heat challenge at marketing age. The aim of this study was to investigate the effect of intermittent TM of 39.5 °C (65% RH) for 12 h/d (12 H), during E7–E16, on post-hatch performance and thermoregulation under both optimal and hot conditions. Chicks from the control and TM treatments were raised under “regular” conditions until 21 d of age. Then, each treatment was divided into 2 sub-treatments (growth conditions) – optimal conditions (25 °C) and hot conditions of 32 °C for 12 h/d – until 35 d of age. Under optimal conditions, no difference in growth rates was found between TM and control throughout the growth period, but TM had significantly larger relative breast muscle weight, and on days 13, 25, and 35 breast muscle in the TM treatment contained a higher percentage of large-diameter fibers than controls. Consequently, average fiber diameter was significantly larger in TM than in control. Relative weight of the abdominal fat pad was significantly lower in the TM treatment than in control, under both environmental conditions. Hot conditions negatively affected growth rates of broilers in both treatments. The TM chickens showed no body-weight advantage over controls, nevertheless, feed conversion between days 21 and 35 was lower in the TM chickens of both sexes than in controls. This could be attributed to lower body temperature and lower plasma thyroid hormone levels found in the TM chickens, indicating lower heat production rates. Greater muscle growth and lower relative weight of abdominal fat pad were found in the TM chickens than in controls, under hot conditions. It can be concluded that TM during embryonic development improves performance as well as thermoregulation.

Variations in the Plasma Levels of Thyroid Hormones and Testicular Activity in the Male Air-breathing Catfish (Clarias gariepinus) over the Annual Cycle

The purpose of this study is to evaluate seasonal variations in thyroxine (T4) and triiodothyronine (T3) levels and testicular activity in the male air-breathing catfish Clarias gariepinus. Plasma T4 levels increased from March to a peak in July and then decreased throughout autumn, declining to their lowest level in January. Plasma T3 levels also varied seasonally, increasing from March to a peak in June. The increase in plasma levels of thyroid hormones coincided with an increase in the testicular activity of the fish. The gonadosomatic index (GSI) peaked in May and then declined slowly. In February and March, the testes were characterized by a new generation of spermatogenic cells. Mature spermatozoa appeared in April and became dominant in the testes during the summer months. Testicular activity decreased gradually with the gradual decrease in water temperature and day-length during the autumn season. Decreased testicular activity during the winter months was associated with low GSI values. The patterns of seasonal change in the levels of thyroid hormones as well as testicular activity were similar to those in water temperature and natural day-length.

Use of 82Br and 131I radionuclides in studies of goitrogenic effects of exogenous bromide

The interference of excessive bromide intake with iodine metabolism in the rat was studied using 82Br and 131I radionuclides. Mainly lactating rat dams and their pups were used, in addition to adult male rats, in the present studies. Particularly, the influence of high bromide intake in lactating rat dams on the transfer of iodine and bromide to suckling young through breast milk was evaluated. The induction of hypothyroid status in the pups by high bromide intake in the mothers was proved unambiguously. Excessive bromide in lactating rat dams caused a marked decrease in plasma levels of thyroid hormones both, in the mothers and in their sucklings. The effects of an enhanced bromide intake on the thyroid function in relation to iodine status in the animals were also followed. Marked goitrogenic and thyrotoxic effects of excessive bromide in adult rats were significantly enhanced under the conditions of simultaneous iodine deficiency in the experimental animals.

Biomarker responses associated with halogenated organic contaminants in northern fulmars (Fulmarus glacialis) breeding in the Canadian Arctic

We examined relationships between hepatic concentrations of halogenated organic contaminants and ethoxyresorufin O-deethylase (EROD) activity and retinoid (vitamin A) concentrations in livers, as well as retinol and thyroid hormone (TT3, TT4) levels in blood plasma, of northern fulmars at two breeding colonies in the Canadian High Arctic. Biomarker levels or responses did not differ significantly between males and females at either colony, nor was there any significant difference between colonies. No significant relationships were found between thyroid hormone or hepatic retinoid concentrations and any of the dioxin-like compounds or their Toxic Equivalents (TEQs) although significant positive correlations were found with plasma retinol (p < 0.03). EROD activity was significantly correlated with hepatic dioxin-like compounds and their TEQs (p < 0.001) as well as total PCBs (p < 0.01), which suggests that EROD induction occurs in northern fulmars at environmentally-relevant concentrations.

Effects of dietary protein sources on feed intake, growth and plasma thyroid hormones levels of Japanese flounder (Paralichthys olivaceus)

An 8-week feeding trial was conducted to compare the effects of dietary protein sources on growth performance and plasma thyroid hormones levels of Japanese flounder Paralichthys olivaceus. Four isonitrogenous and isoenergetic diets were formulated to contain one of the followings as main protein source: fish meal (FM), fish protein concentrate (FPC), soy protein concentrate (SPC), and soy protein isolate (SPI). Each diet was randomly assigned to triplicate aquaria stocked with 25 fish each. The feed intake, specific growth rate, feed efficiency, and protein efficiency ratio in fish fed fish protein-based diets were significantly higher than those in fish fed soy protein-based diets. Feed intake and specific growth rate were significantly higher in FM treatment compared to FPC treatment and higher in SPI treatment compared to SPC treatment. The FM treatment had significantly higher levels of plasma cortisol, triiodothyronine, and thyroxin than the other treatments. These results indicate that high inclusion levels of soy protein in diets markedly inhibit the feeding rate and growth of P. olivaceus due to poor palatability caused by the removal of feeding stimulants and/or the incorporation of feeding deterrents. The reduced growth may be partly attributed to the amino acid imbalance, absence of small nitrogen compounds, and presence of antinutritional factors.

Salt sensitivity in experimental thyroid disorders in rats

This study assessed salt sensitivity, analyzing the effects of an increased saline intake on hemodynamic, morphological, and oxidative stress and renal variables in experimental thyroid disorders. Six groups of male Wistar rats were used: control, hypothyroid, hyperthyroid, and the same groups treated with salt (8% via food intake). Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 6 wk. Finally, BP and HR were recorded directly, and morphological, metabolic, plasma, and renal variables were measured. High-salt intake increased BP in thyroxine-treated rats but not in control or hypothyroid rats. High-salt intake increased cardiac mass in all groups, with a greater increase in hyperthyroid rats. Urinary isoprostanes and H(2)O(2) were higher in hyperthyroid rats and were augmented by high-salt intake in all groups, especially in hyperthyroid rats. High-salt intake reduced plasma thyroid hormone levels in hyperthyroid rats. Proteinuria was increased in hyperthyroid rats and aggravated by high-salt intake. Urinary levels of aminopeptidases (glutamyl-, alanyl-, aspartyl-, and cystinylaminopeptidase) were increased in hyperthyroid rats. All aminopeptidases were increased by salt intake in hyperthyroid rats but not in hypothyroid rats. In summary, hyperthyroid rats have enhanced salt sensitivity, and high-salt intake produces increased BP, cardiac hypertrophy, oxidative stress, and signs of renal injury. In contrast, hypothyroid rats are resistant to salt-induced BP elevation and renal injury signs. Urinary aminopeptidases are suitable biomarkers of renal injury.

Effects of Partial and Full Feed Restriction on the Plasma Levels of Thyroid Hormones and Testicular Activity in the Male Air-breathing Catfish, Clarias gariepinus during Different Phases of the Breeding Cycle

The effects of partial and full feed restriction on the plasma levels of thyroxine (T4), triiodothyronine (T3) andtesticular activity were studied in the male air-breathing catfish, Clarias gariepinus. Partial and full feedrestriction for 3 weeks significantly decreased the plasma T4 levels during the progressive and breeding phases,and decreased the plasma T3 levels only during the breeding phase. However, full feed restriction for 3 weeksincreased plasma T3 levels and T3/T4 ratio during the quiescent, progressive and regressive phases. Histologically,3 weeks of partial and full feed restriction markedly reduced the testicular activity during the progressive andbreeding phases. These results indicate that partial and full feed restriction adversely affects the thyroidhormonogenesis and testicular activity in a phase-dependent manner in C. gariepinus.

The pituitary–thyroid axis during the parr–smolt transformation of Coho salmon, Oncorhynchus kisutch: Quantification of TSH β mRNA, TSH, and thyroid hormones

The objective of this investigation was to quantify pituitary thyroid stimulating hormone (TSH) β mRNA, pituitary and plasma TSH and plasma thyroid hormone levels during the parr–smolt transformation of Coho salmon that occurs in spring from February to May. The status of the pituitary–thyroid axis was assessed using an RNase protection assay for pituitary TSH β mRNA and radioimmunoassays for salmon pituitary and plasma TSH and thyroid hormones. TSH β mRNA was highest during late winter (February) (4.9 pg/μg DNA) and gradually declined during spring (2.3 pg/μg DNA). In contrast, pituitary and plasma TSH levels showed a small, but statistically non-significant change during smoltification. Despite minimal change in plasma TSH levels, characteristically large increases in plasma T4 (January-3.3 ng/ml to April-10.2 ng/ml) and significant, but modest increases in plasma T3 (February-2.4 ng/ml to April-5.8 ng/ml) were observed. Regression analysis showed a significant positive relationship between plasma T4 and T3 and negative relationship between plasma T3 and pituitary TSH β mRNA. However, all other relations were not significant. These data suggest a significant role for peripheral regulation (i.e. T4–T3 conversion, change in tissue sensitivity, hormone degradation rate) as well as evidence of central regulation via negative feedback at the level of the pituitary gland in regulation of thyroid activity in salmon. Furthermore, the increased thyroid sensitivity to TSH (shown previously), in the face of relatively constant plasma TSH levels, may be the major factor responsible for the increased thyroid activity observed during smoltification.

Adaptive Diversity: Hormones and Metabolism in Freshwaters

Genes underlying the evolution of morphological traits have recently been identified in a number of model species. In the stickleback, the metabolic adaptations to a freshwater habitat have now been linked to a well-known hormonal system.

Effects of Clofibrate on Salt Loading‐Induced Hypertension in Rats

The effects of clofibrate on the hemodynamic and renal manifestations of increased saline intake were analyzed. Four groups of male Wistar rats were treated for five weeks: control, clofibrate (240 mg/kg/day), salt (2% via drinking water), and salt + clofibrate. Body weight, systolic blood pressure (SBP), and heart rate (HR) were recorded weekly. Finally, SBP, HR, and morphologic, metabolic, plasma, and renal variables were measured. Salt increased SBP, HR, urinary isoprostanes, NOx, ET, vasopressin and proteinuria and reduced plasma free T4 (FT4) and tissue FT4 and FT3 versus control rats. Clofibrate prevented the increase in SBP produced by salt administration, reduced the sodium balance, and further reduced plasma and tissue thyroid hormone levels. However, clofibrate did not modify the relative cardiac mass, NOx, urinary ET, and vasopressin of saline-loaded rats. In conclusion, chronic clofibrate administration prevented the blood pressure elevation of salt-loaded rats by decreasing sodium balance and reducing thyroid hormone levels.

The thyroid-disrupting effects of long-term perfluorononanoate exposure on zebrafish (Danio rerio)

Concentrations of perfluorononanoate (PFNA) suggest an obvious increase in the environment, wildlife, and humans. However, the potential toxicity of PFNA still remains to be fully elucidated. Our present work is directed toward evaluating specific thyroid endpoints, and studying the long-term and the trans-generational effects of PFNA on zebrafish. Zebrafish (Danio rerio) were exposed to different concentrations of PFNA (0, 0.05, 0.1, 0.5, and 1 mg/l) from their early life stages (F(0), 23 day post-fertilization dpf), and the exposure period lasted for 180 days. At the end of the exposure period, thyroid follicle histology and plasma thyroid hormone levels in male zebrafish were evaluated as direct endpoints for the specific thyroid toxicities, while gene expression relative to the hypothalamus-pituitary-thyroid axis was also investigated to study the underlying mechanisms. In addition, offspring embryos (F(1)) from the PFNA exposure parental zebrafish was reared in water either without PFNA or under continual exposure to PFNA for an additional 180 days to investigate effects of multi-generational exposures on the circulating T(3) levels and thyroid-associated gene expression. Our results demonstrate significantly elevated plasma T(3) levels were observed in both F(0) and F(1) adults, as well as PFNA-induced histological changes in the thyroid follicles of F(0) male zebrafish. In the liver, the abundance of gene transcript encoding the protein transthyretin (TTR) was significantly induced, while the expression of UDP-glucuronosyltransferases in F(0) adult males was inhibited. The induced thyroid-disrupting effects also demonstrated a trans-generational effect that was reflected by altered gene expression related to thyroid hormone (TH) synthesis and metabolism in F(1) larvae. Our results provide the first evidence for the thyroid-disrupting effects of long-term PFNA exposure in zebrafish.

Chronic Alcohol Intake Upregulates Hepatic Expression of Carotenoid Cleavage Enzymes and PPAR in Rats ,

Excessive and chronic alcohol intake leads to a lower hepatic vitamin A status by interfering with vitamin A metabolism. Dietary provitamin A carotenoids can be converted into vitamin A mainly by carotenoid 15,15’-monooxygenase 1 (CMO1) and, to a lesser degree, carotenoid 9′10’-monooxygenase 2 (CMO2). CMO1 has been shown to be regulated by several transcription factors, such as the PPAR, retinoid X receptor, and thyroid receptor (TR). The regulation of CMO2 has yet to be identified. The impact of chronic alcohol intake on hepatic expressions of CMO1 and CMO2 and their related transcription factors are unknown. In this study, Fischer 344 rats were pair-fed either a liquid ethanol Lieber-DeCarli diet (n = 10) or a control diet (n = 10) for 11 wk. Hepatic retinoid concentration and expressions of CMO1, CMO2, PPARγ, PPARα, and TRβ as well as plasma thyroid hormones levels were analyzed. We observed that administering alcohol decreased hepatic retinoid levels but increased mRNA concentrations of CMO1, CMO2, PPARγ, PPARα, and TRβ and upregulated protein levels of CMO2, PPARγ, and PPARα. There was a positive correlation of PPARγ with CMO1 (r = 0.89; P < 0.0001) and both PPARγ and PPARα with CMO2 (r = 0.72, P < 0.001 and r = 0.62, P < 0.01, respectively). Plasma thyroid hormone concentrations did not differ between the control rats and alcohol-fed rats. This study suggests that chronic alcohol intake significantly upregulates hepatic expression of CMO1 and, to a much lesser extent, CMO2. This process may be due to alcohol-induced PPARγ expression and lower vitamin A status in the liver.

Relationship between growth retardation and impaired glucose tolerance in hypothyroidal growth‐retarded (grt) mice

Growth-retarded (grt) mice exhibit congenital hypothyroidism and a characteristic growth pause followed by delayed onset of pubertal growth. This pattern of growth has never been reported in any other animal model exhibiting hypothyroidism; therefore, the growth retardation observed in grt mice is unlikely to be explained completely by the low plasma thyroid hormone levels. As growth is closely related to nutrient metabolism, we investigated the relationship between the appearance of growth retardation and glucose utilization, which is the main component of nutrient metabolism, in the peripubertal stage of grt mice. The relative weights of the organs involved in nutrient digestion and absorption were abnormal in grt mice. The intraperitoneal glucose tolerance test (IGTT) showed impaired glucose tolerance in grt mice. Moreover, this symptom appeared in parallel with the progression of growth retardation in grt mice. The impaired blood glucose levels on the IGTT in grt mice were considered to be attributable to decreased plasma insulin levels rather than to impaired insulin sensitivity. The pattern of anti-insulin antibody staining on sections of pancreatic islets from grt mice was almost the same as that in the corresponding sections from normal mice. Insulin treatment accelerated the growth of peripubertal grt mice. These findings suggest that the appearance of growth retardation in grt mice might be partially attributable to a reduction in glucose metabolism and impairment of insulin secretion during the early period of growth.

Influence of topical dexamethasone applications on insulin, glucose, thyroid hormone and cortisol levels in dogs

The influence of two topical dexamethasone applications (dermal and ototopical) on plasma insulin, glucose, thyroid hormone and cortisol levels was investigated in beagle dogs. Both treatments significantly decreased basal cortisol values, associated with exaggerated rise in insulin (∼50%), together with unchanged serum glucose levels. Dermal dexamethasone quickly decreased plasma thyroxin (T 4) levels; whereas dexamethasone in ear drops gradually inhibited time-dependently T 4 release (18–50%). Both formulations blunted plasma triiodothyronine (T 3) levels but the response induced by dermal dexamethasone was stronger than by dexamethasone ear drops. Upon drug withdrawal, insulin secretion returned to baseline a week after treatment cessation, while cortisol, T 4 and T 3 levels did not reach baseline values. These results suggest that topical glucocorticoids unexpectedly trigger secondary hypothyroidism with concomitant suppression of hypothalamic–pituitary–adrenal axis but sensitize the endocrine pancreas, thus, their application needs careful evaluation for surprisingly different effects on endocrine stress axis activity.

Altered Thyroid Hormones and Behavioural Change in a Sub‐Population of Rats Following Chronic Constriction Injury

Hypothyroidism is associated with a disturbance of behaviour and mood. There are also individuals, not classified as hypothyroid, with low to 'low normal' thyroid hormone levels and normal thyroid-stimulating hormone (TSH) levels who have mood and behavioural changes. As the peripheral thyroid hormones decrease, TSH is expected to increase. However, there are a number of physiological mechanisms known to suppress TSH. In the present study, we report on thyroid hormone regulation in a rat model of neuropathic pain and altered social behaviour that is usually transient, but is persistent in a sub-group of the population. Following ligation of the sciatic nerve, male Sprague-Dawley rats were assessed for social dominance towards an intruder: 20% showed persistently decreased social dominance. Plasma levels of thyroid hormones, TSH and corticosterone were measured before and on days 2, 3, 4, 5 and 6 after injury in 21 rats. The mean plasma thyroxine (T4), free thyroxine (fT4) and triiodothyronine (T3) levels decreased significantly post-injury in rats with persistently changed behaviour compared to rats with unchanged behaviour (P < or = 0.002). There was no significant difference between groups for mean change in free triiodothyronine (fT3) or TSH. There was a correlation between decreased dominance behaviour and decrease in both T4 (r = 0.62, P = 0.009) and fT4 (r = 0.71, P = 0.001), but no correlation with TSH. In a sub-population of rats, decreased thyroid hormones did not result in the expected increased levels of TSH to restore pre-injury levels, nor did they show increased hypothalamic thyrotrophin-releasing hormone mRNA expression, indicating altered hypothalamic-pituitary-thyroid axis regulation. Because T3 availability to the brain is dependent on both circulating T3 and T4, decreased peripheral thyroid hormones may result in changed neural function, as expressed in altered complex behaviours in this sub-population of rats.

Increasing levels of free thyroxine as a risk factor for a first venous thrombosis: a case-control study

AbstractA hypercoagulable state exists in hyperthyroidism, but the association with venous thrombosis (VT) is not fully explored. We aimed to investigate VT risk for different plasma levels of thyroid hormones and thyroid antibodies. We used a case-control study on leg vein thrombosis conducted between September 1999 and August 2006 at the Academic Medical Center, Amsterdam, The Netherlands. Parameters of thyroid function were assessed in 190 cases (mean age, 57 years; range, 19-90 years) and 379 sex-matched controls (mean age, 56 years; range, 18-93 years). Odds ratios (ORs) and 95% confidence intervals (CIs) for VT risk were estimated according to several cutoff levels derived from plasma levels observed in controls. We found the risk of VT to gradually rise with increasing levels of free thyroxine (FT4). In the absence of traditional acquired risk factors, FT4 levels above 17 pmol/L yielded a sex- and age-adjusted OR of 2.2 (95% CI, 1.2-4.2) for deep VT, which further increased up to an OR of 13.0 (95% CI, 1.1-154.1) for FT4 levels above reference range. Our data suggest increasing levels of FT4 to be a risk factor for VT and may have implications for both the prevention and management of this disease.

Partial pressure of carbon dioxide in the venous blood of young birds as a predictor of ascites susceptibility in broiler chickens

In order to investigate the relationship between carbon dioxide tensions in the venous blood of young chickens and ascites susceptibility, one hundred day-old chickens from two pure broiler breeder lines differing in susceptibility to ascites syndrome were obtained and reared at low environmental temperature. Weekly, blood samples were taken for the determination of blood gas parameters and plasma thyroid hormone levels. Dead birds were examined for lesions of ascites daily and all survived birds were autopsied at the end of the trials. In cold conditioning, the cumulative incidence of right ventricular hypertrophy (RVH) and ascites was 78% (39/50) in fast-growing (line A) and 50% (25/50) in slow-growing (line B) chickens, confirming that line A chickens had higher susceptibility to ascites than line B chickens. At 12 days of age, the mean pCO(2) tension was significantly (P < 0.01) higher in the venous blood of line A than line B chickens. During the experiment, the majority of line A and line B chickens showing RVH and ascites exhibited pCO(2) tensions equal to, or exceeding 50 mmHg at 12 days of age. Additionally, fast-growing chickens showed significantly lower plasma T3 and T4 concentrations than slow-growing chickens. In conclusion, our data indicate that carbon dioxide pressure in the venous blood of early postnatal broiler chickens could be used as a valuable predictor in the selection of birds susceptible to pulmonary hypertension and ascites. The function of thyroid hormones should also be taken into consideration in further selection procedures for meat-type chickens.

Effect of selenium on hypothyroidism induced by methimazole (MMI) in lactating rats and their pups

The present study was undertaken to assess the effect of selenium (Se) on hypothyroidism induced by methimazole (MMI) in lactating rats and their pups. Rats were randomly divided into four groups of six each: group I served as a negative control which received standard diet; group II received orally MMI (250 mg L -1 ); group II received both MMI (250 mg L -1 , orally) and Se (0.5 mg/kg of diet); group IV served as a positive control and received Se (0.5 mg Na 2 SeO 3 /kg of diet). Treatments were started from the 14th day of pregnancy until postnatal day 14. In the MMI-exposed group, the body weight of 14-day-old pups diminished compared to controls; besides, a hypertrophy of the thyroid glands was observed. Co-administration of Se through the diet restored these parameters to near normal values. In the MMI-treated group, thyroid iodine contents and plasma thyroid hormone levels significantly decreased, while plasma TSH levels increased in pups and their mothers. These biochemical modifications corresponded histologically to closed follicles, increased vascularity and a reduction in colloid volume. Co-treatment with Se ameliorated these parameters. We concluded that the supplementation of Se in diet had beneficial effects on hypothyroidism during a critical period of life.

5'-Deiodinase type 1 activity in liver and brain of the thyroxine-treated dystrophic hamster.

Dystrophic hamsters (DH), as well as dystrophic patients, exhibit alveolar hypoventilation (AH) and low plasma thyroid hormone levels. Thyroxine (T4) treatment of young DH retards AH development, and improves respiratory function and contractility of skeletal muscles. However, the mechanism responsible for the hypothyroidism in DH is not known. One possible cause of the hypothyroidism is reduced activity of the 5'-deiodinase enzyme system, which converts T4 to the more active triiodothyronine (T3). This study tested the above hypothesis by measuring the serum T3 and T4 levels and the activity of the enzyme type 1 5'-deiodinase (D1) in the liver and brain of normal and dystrophic hamsters before, and 8 weeks after, placebo or T4 treatment. There was no significant difference in T4 level between normal and dystrophic hamsters before or after treatment. However, the T4 level was lower in DH before treatment and 8 weeks after placebo and T4 treatment. Both in the liver and brain, D1 activity in DH was depressed compared with normal hamsters. In the liver, T4 supplementation restored enzyme activity to normal level, while in the brain there was no significant difference. The data indicate that the hypothyroidism in DH may be, in part, due to reduced activity of D1 enzyme, which could be partially reversed by T4 treatment.

Thyroid Hormone Beta Receptor Mutation Causes Renal Dysfunction and Impairment of ClC-2 Chloride Channel Expression in Mouse Kidney

Background/Aims: Mutations in the thyroid hormone receptor β (TR-β) gene result in resistance to thyroid hormone (RTH). Mutation Δ337T in the TR-β gene has been shown to have the characteristics of RTH syndrome in mice. The aim of this work was to study the possible involvement of TR-β receptor in thyroid modulation of ClC-2 in mouse kidney. Methods: Expression of mouse (Δ337T and normal C57BL/6) renal RNA and protein expression were studied by reverse transcriptase-polymerase chain reaction and Western blot, respectively, in mice with hyper- or hypothyroidism. Renal function was studied by analysis of urinary electrolyte excretion. Studies of the ClC-2 promoter region were performed in immortalized renal proximal tubule (IRPT) cells. Results: In RTH syndrome mice (Δ337T), renal dysfunction was found to be associated with changes in the fractional excretion of sodium (FE_Na) and chloride (FE_Cl). ClC-2 chloride channel mRNA and protein expression were found to be decreased by 40% in heterozygous and homozygous mutant mouse kidneys and high levels of plasma thyroid hormone were detected in both groups. Hypothyroidism induced by methimazole decreased the renal expression of ClC-2 in normal mice but not in Δ337T mutant mice. In in vitro studies performed on IRPT cells subjected to thyroid hormone treatment, the promoter region of the ClC-2 chloride channel was stimulated in a dose-dependent manner. Conclusions: This work emphasizes the importance of thyroid hormone in electrolyte handling along the nephron and suggests its participation in renal ClC-2 gene transcription via the TR-β receptor pathway.