In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert thyroid effects through a variety of mechanisms of action, and some animal experiments and in vitro studies have focused on elucidating the mode of action of specific chemical compounds. Long-term human studies on effects of environmental chemicals on thyroid related outcomes such as growth and development are still lacking. The human exposure scenario with life long exposure to a vast mixture of chemicals in low doses and the large physiological variation in thyroid hormone levels between individuals render human studies very difficult. However, there is now reasonably firm evidence that PCBs have thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties. 相似文献
Objective: Tamoxifen, a nonesteroidal antiesterogen, is widely used in the treatment of breast cancer. Recently, the effect of tamoxifen on thyroid function has caused considerable concern, yet the results of different studies are controversial and the precise mechanism of such influence is obscure. In view of the fact that some drugs such as furosemide, diclofenac and mefenamic acid, based on the structural similarities to thyroxine could compete for binding to thyroxine binding globulin (TBG) and appears that there are some structural similarities between tamoxifen and thyroxine, one can hypothesize that tamoxifen is also able to compete for TBG binding and thereby affecting thyroid function tests.
Design and methods: In this study, we designed an in vitro binding assay as well as computational methods using MOPAC 7 package for evaluation of competitive potency of tamoxifen for TBG binding in comparison with well-known TBG competitors (including furosemide, mefenamic acid and diclofenac).
Results: The result of competition assay and Scatchard analysis revealed that tamoxifen does not bind to TBG at the T4 binding site, thus it is not a thyroxine competitor. Computational results also indicated that structural characteristics of tamoxifen are significantly different from those of T4 and its well-known competitors.
Conclusion: In conclusion, the probability of competition between tamoxifen and T4 is ruled out by these results. 相似文献
The niacin receptor GPR109A is a Gi-protein-coupled receptor which mediates the effects of niacin on inhibiting intracellular triglyceride lipolysis in adipocytes. However, the role of GPR109A in mediating the effects of niacin on high density lipoprotein (HDL) metabolism is unclear. We found niacin has no effect on HDL-C in GPR109A knockout mice. Furthermore, niacin lowered intracellular cAMP in primary hepatocytes mediated by GPR109A. We used an adeno-associated viral (AAV) serotype 8 vector encoding GPR109A under the control of the hepatic-specific thyroxine-binding globulin promoter to specifically overexpress GPR109A in mouse liver. Plasma HDL-C, hepatic ABCA1 and the HDL cholesterol production rate were significantly reduced in mice overexpressing GPR109A. Overexpression of GPR109A reduced primary hepatocyte free cholesterol efflux to apoA-I; conversely, GPR109A deficient hepatocytes had increased ABCA1-mediated cholesterol efflux. These data support the concept that the HDL-C lowering effect of niacin in wild-type mice is mediated through stimulation of GPR109A in hepatocytes; such an effect then leads to reduced hepatocyte ABCA1 expression and activity, decreased cholesterol efflux to nascent apoA-I, and reduced HDL-C levels. These results indicate that niacin-mediated activation of GP109A in liver lowers ABCA1 expression leading to reduced hepatic cholesterol efflux to HDL. 相似文献
Resistance to thyroid hormones syndrome is defined as increased thyroxine (T4) and triiodothyronine (T3) concentrations associated with normal or sometimes increased thyrotropin (TSH) concentration. This is usually due to a pathogenic variant with loss of function of the gene coding for thyroid hormone receptor β (THRB). This discrepancy in thyroid hormones (TH) and TSH concentrations is also frequently observed in the presence of analytical interference, notably alteration of TH transport proteins in serum. During 2017, 58 samples were sent to our laboratory in the Angers University Hospital Rare Thyroid and Hormone Receptor Disease Reference Center in order to identify an etiology for discrepant TSH and TH results. We sequenced the genes involved in TH regulation, action and transport (THRB,THRA, SECISBP2, SLC16A, ALB, TTR, SERPINA7). Free T4 and free T3 assay were performed with a second immunoassay (Siemens ADVIA Centaur). A genetic cause of discrepancy in TH and TSH concentrations, with mutation in THRB, was found in 26% of cases (15/58). Biological interference due to TH serum transport protein variant was found in 24% (14/58) of cases. No pathogenic variants were found in the other genes studied. Biological interference was also suspected in 26% of cases without genetic variant, in which the biological discrepancy was not confirmed by a second analytical technique (15/58). Finally, no etiology for the biological discrepancy could be found in 24% of cases (14/58). Clinically, patients in whom biological discrepancy was due to analytic interference were more often asymptomatic, and patients with no identified etiology tended to be older. To limit diagnostic errors associated with the finding of discrepant TSH and TH, we recommend initially conducting a second thyroid function test (TSH, free T4 and free T3) with a different assay, and then screening for a genetic variant in gene coding for thyroid hormone receptor β (THRB) and the TH serum transport proteins (ALB, TTR, SERPINA7). 相似文献
Serum total thyroxine (T4) level was markedly decreased, without significant increases in the levels of hepatic T4-UDP-glucuronosyltransferase (T4-UGT) and serum thyroid-stimulating hormone, 3 days after treatment with 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB153) (100 mg/kg, ip) in both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 and TCDD-resistant DBA/2 mice. Likewise, in either strain of mice, no CB153-mediated changes in the binding levels of [125I]T4 to serum proteins, such as transthyretin, albumin, and thyroxine binding globulin, were observed, while in CB153-pretreated C57BL/6 mice, but not in CB153-pretreated DBA/2 mice, the levels of biliary [125I]T4 and [125I]T4-glucuronide at 90-120 min after injection of [125I]T4 slightly increased, as compared with those in the corresponding control mice. Concerning tissue distribution of [125I]T4, liver-selective increases in the [125I]T4 accumulation by CB153-pretreatment were observed in both C57BL/6 and DBA/2 mice, and the hepatic levels of [125I]T4 in the C57BL/6 and DBA/2 mice became more than 44% and 34% of the [125I]T4 dosed, respectively. The present findings indicated that the CB153-mediated decreases in the level of serum total T4 in C57BL/6 and DBA/2 mice occur mainly through an increase in the accumulation of T4 in the liver. 相似文献
Zusammenfassung Eine hormonale Kontrazeption bewirkt Veränderungen des T3-und T4-Tests, die auf eine erhöhte Bindungskapazität des thyroxin-bindenden Globulins (TBG) schließen lassen. Mit Hilfe der Laurell-Elektrophorese und einem von den Behringwerken entwickelten Anti-TBG-Serum ist jetzt die quantitative Bestimmung des TBG, des wichtigsten Trägerproteins der Schilddrüsenhormone, ohne größeren Aufwand möglich. Untersucht wurden insgesamt 137 Seren gesunder Frauen, die verschiedenartige hormonale Kontrazeptiva über mindestens 3 Monate einnahmen. Die hormonale Kontrazeption führt generell zu einem signifikanten Anstieg der TBG-Konzentration im Serum. Dabei erzielen die Präparate zum Teil sehr unterschiedliche Konzentrationserhöhungen. Präparate mit einer betont östrogenen Wirksamkeit bewirken im Mittel einen weit höheren Anstieg der TBG-Serum-Konzentration als die mehr gestagen-betonten Präparate. Der unterschiedliche Anstieg ist statistisch hoch signifikant. Die Vermehrung des TBG-Gehaltes im Serum unter hormonaler Kontrazeption ist demnach östrogenbedingt, dagegen ist das Ausmaß der TBG-Vermehrung von der Art des beteiligten Progestagens abhängig. 相似文献