Effects of phytate on thyroid gland of rats intoxicated with cadmium.

Cadmium (Cd) is one of the most dangerous occupational and environmental toxins. The objective of the present study is to examine the potential prophylactic effects of phytic acid (PA) on thyroid hormones of male rats intoxicated with Cd. The male albino rats were divided into five groups: group I (control) was fed with the basal diet, group II was intoxicated with Cd in drinking water, groups III, IV, and V were intoxicated with Cd in drinking water and fed with the diet containing 3.5, 7, and 10 g of PA/kg, respectively. The results indicated that the serum calcium, iron (Fe), and total Fe binding capacity levels and serum T3 and T4 in Cd-treated rats of group II were decreased when compared with the control group, while PA-administered groups with Cd showed a significant improvement when compared with the Cd-treated rats only. Serum thyroid stimulating hormone (TSH) level was significantly increased in Cd-treated rats compared with the control group, while the addition of PA in diet decreased the high levels of TSH. These results indicated a prophylactic effect of PA against Cd-induced toxicity in rats.

Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants.

BACKGROUND: Observational studies have shown an association between transiently low thyroid hormone levels in preterm infants in the first weeks of life (transient hypothyroxinaemia) and abnormal neurodevelopmental outcome. Thyroid hormone replacement might prevent this. OBJECTIVES: To determine whether prophylactic thyroid hormones given to preterm infants without congenital hypothyroidism result in clinically important changes in neonatal and long term outcomes. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), EMBASE, PREMEDLINE, and searches of abstracts of conference proceedings, citations of published articles and expert informants. SELECTION CRITERIA: All trials using random or quasi-random patient allocation in which prophylactic thyroid hormone treatment was compared to control in premature infants. DATA COLLECTION AND ANALYSIS: Assessment of trial quality, data extraction and synthesis of data, using relative risk (RR) and weighted mean difference (WMD), were performed using standard methods of the Cochrane Collaboration and its Neonatal Review Group. MAIN RESULTS: Four studies enrolling 318 infants were included. All studies enrolled preterm infants on the basis of gestational age criteria. All studies commenced treatment in the first 48 hours, but used different regimens, dose and durations of treatment. All four studies used thyroxine (T4). Valerio 2004 incorporated one arm with an early short course of T3, then T4 for 6 weeks. Only two studies with neurodevelopmental follow-up were of good methodology (van Wassenaer 1997; Vanhole 1997). All studies were small with the largest (van Wassenaer 1997) enrolling 200 infants.No significant difference was found in neonatal morbidity, mortality or neurodevelopmental outcome in infants who received thyroid hormones compared to control. van Wassenaer 1997 reported no significant difference in abnormal mental development at 6, 12, 24 months (RR 0.67, 95% CI 0.28, 1.56) or five years (RR 0.66, 95% CI 0.22, 1.99) or cerebral palsy assessed at five years (RR 0.72, 95% CI 0.28, 1.84). Meta-analysis of two studies (van Wassenaer 1997, Vanhole 1997) found no significant difference in the Bayley MDI (WMD -1.14, 95% CI -5.46, 3.19) and PDI (WMD 0.22, 95% CI -4.80, 5.24) at 7 - 12 months. van Wassenaer 1997 reported no significant difference in the Bayley MDI (MD -3.50, 95% CI -11.21, 4.21) and PDI (MD 3.10, 95% CI -3.31, 9.51) at 24 months, IQ scores at 5 years (MD -2.10, 95% CI -7.91, 3.71) and children in special schooling at 10 years (RR 0.88, 95% CI 0.43, 1.83). Meta-analysis of all four trials found no significant difference in mortality to discharge (typical RR 0.76, 95% CI 0.46 to 1.24). van Wassenaer 1997 reported no significant difference in death or cerebral palsy at five years (RR 0.70, 95% CI 0.43 to 1.14). No significant differences were reported for neonatal morbidities, including the need for mechanical ventilation, duration of mechanical ventilation, air leak, CLD in survivors at 28 days or 36 weeks, intraventricular haemorrhage, severe intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus, sepsis, necrotising enterocolitis or retinopathy of prematurity. AUTHORS' CONCLUSIONS: This review does not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality, neonatal morbidity or improve neurodevelopmental outcomes. An adequately powered clinical trial of thyroid hormone supplementation with the goal of preventing the postnatal nadir of thyroid hormone levels seen in very preterm infants is required.

[Thyroid hormones and lipid metabolism].

Thyroid hormone (T3) and its receptor (TR) have the diverse effects on the lipid metabolism and hypothyroidism causes hypercholesterolaemia characterized by increased levels of low-density ripoproteins (LDL). There are multiple TR isoforms such as TRalpha1, TRbeta1 and TRbeta2, of which expressions are known to be tissue-specific. For example, TRbeta1 is the major TR in the liver while T3 action is mediated via TRalpha1 in the heart. The X-ray crystallography of the ligand-binding domain of TRs enabled the development of TRbeta isoform specific T3 analogues including GC1. Without tachycardia, GC1 selectively targets the TRbeta1 in the liver and decreases cholesterol levels with more potent efficacy than that of atorvastatin, a potent HMG-CoA reductase. However, the reduction of serum TSH by GC1 should be overcome in future. Current reports also describe the existence of the complex cross-talks in the lipid metabolism between TR and other nuclear hormone receptors including peroxisome proliferator -activated receptors (PPARs), liver X receptor alpha (LXRalpha) and farnesoid X receptors (FXRs). Understanding for the function of TRs and other nuclear factors may provide the new approach to the control of hypercholesterolaemia.

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level.

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.

BACKGROUND: Thyroid hormones regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TR alpha and TR beta, and these two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities. RESULTS: We have designed and synthesized a thyroid hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TR beta over TR alpha. The compound, GC-1, was initially designed to solve synthetic problems that limit thyroid hormone analog preparation, and contains several structural changes with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T3). These changes include replacement of the three iodines with methyl and isopropyl groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain. CONCLUSIONS: The results of this study show that GC-1 is a member of a new class of thyromimetic compounds that are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. The TR beta selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiological roles of the different thyroid hormone receptor isoforms.