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A) Classic thyroid hormone (TH) feedback loop. TH exerts a negative feedback at the level of the hypothalamus and anterior pituitary. (B) Model for thyroid hormone (TH) transport and metabolism in the human hypothalamus. The model indicates distinct roles for the different TH transporters in hypothalamic TH action by affecting intracellular TH concentrations through import and efflux. T2 = 3,3′-T2 (Adapted from Alkemade et al., 2011).
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Thyroid hormone (TH) plays an essential role in normal brain development and function. Both TH excess and insufficiency during development lead to structural brain abnormalities. Proper TH signaling is dependent on active transport of the prohormone thyroxine (T4) across the blood-brain-barrier and into brain cells. In the brain T4 undergoes local...
Contexts in source publication
Context 1
... the present review I will focus mainly on TH signaling in the developing human hypothalamus. pituitary and hypothalamus ( Figure 1A). Hypothalamic TH signaling is also involved in circadian rhythmicity, feeding and adaptation to environmental challenges (Costa-e-Sousa and Hollenberg, 2012). ...
Context 2
... is released predominantly as thyroxine (T4), a prohormone, and to a lesser extent as the active 3,3 ,5-triiodothyronine (T3). T4 is converted locally into T3 providing a negative feedback at the level of the pituitary as well as the hypothalamus ( Figure 1A). T3 mainly acts by regulation of gene expression via binding of nuclear TRs, although nongenomic effects of T3 have been described as well (Cheng et al., 2010;Davis et al., 2013). ...
Context 3
... the human and rat hypothalamus TRs are expressed in a number of nuclei, including the PVN where the hypophysiotropic TRH neurons are located ( Lechan et al., 1994;Alkemade et al., 2005b). We, and others have proposed models for TH signaling in the hypothalamus, which involves both glial cells and neurons (Guadaño-Ferraz et al., 1997; Tu et al., 1997;Diano et al., 2003;Lechan and Fekete, 2004;Alkemade et al., 2005a; Figure 1B). ...
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Citations
... The PVN can receive hypocretin input signals 33 , which is also the central point of the regulation of the HPT axis 34 . Hypophysiotropic neurons of the PVN of the hypothalamus expressing TRH project to the portal system, via which it reaches the thyrotropin-producing cells of the anterior pituitary 35 . Thyroid hormone secretion is suppressed during starvation, while preprohypocretin mRNA is upregulated in the LHA 36 . ...
The loss of hypocretin is thought to be the main pathophysiological mechanism of narcolepsy. There is strong evidence that hypocretin is related to the regulation of endocrine functions and depression. To explore thyroid hormone levels in narcolepsy patients was our aim. In addition, further is to analyze the relationship between thyroid hormone levels and sleep quality, anxiety, and depression in narcolepsy patients. There are 40 patients with narcolepsy and 40 healthy controls (HCs) were conducted. Blood samples were explored for thyroid function. Correlation analysis between thyroid hormones and clinical characteristics of narcolepsy was performed using Pearson or Spearman. Narcolepsy patients had significantly lower free thyroxine (FT 4 ) levels in comparison to controls (p < 0.001). No subject was diagnosed with primary hypothyroidism. There were 4 (10%) subjects with subclinical hypothyroidism. The serum FT4 levels were positively correlated with HAMA 14 score (r = − 0.343, p = 0.030) by Pearson correlation analysis. The serum TSH levels and HAMD 24 score (r = − 0.807 p ˂0.001), and ESS score (r = − 0.317, p = 0.046) both showed a negative correction. Hypocretin deficiency may be associated with the regulation of thyroid hormones in narcolepsy patients. The serum thyroid hormones may affect the severity and neuropsychological functions of narcolepsy patients.
... The PVN can receive hypocretin input signals 33 , which is also the central point of the regulation of the HPT axis 34 . Hypophysiotropic neurons of the PVN of the hypothalamus expressing TRH project to the portal system, via which it reaches the thyrotropin-producing cells of the anterior pituitary 35 . Thyroid hormone secretion is suppressed during starvation, while preprohypocretin mRNA is upregulated in the LHA 36 . ...
Background: The loss of hypocretin is thought to be the main pathophysiological mechanism of narcolepsy. There is strong evidence that hypocretin is related to the regulation of endocrine functions and depression. To explore thyroid hormone levels in narcolepsy patients was our aim. In addition, further is to analyze the relationship between thyroid hormone levels and sleep quality, anxiety, and depression in narcolepsy patients.
Methods: There are 40 patients with narcolepsy and 40 healthy controls (HCs) were conducted. Blood samples were explored for thyroid function. Correlation analysis between thyroid hormones and clinical characteristics of narcolepsy was performed using Pearson or Spearman.
Results: Narcolepsy patients had significantly lower free thyroxine (FT4) levels in comparison to controls (p ＜ 0.001). No subject was diagnosed with primary hypothyroidism. There were 4 (10 %) subjects with subclinical hypothyroidism. The serum FT4 levels were positively correlated with HAMA14 score (r = -0.343, p = 0.030) by Pearson correlation analysis. The serum TSH levels and HAMD24 score (r = -0.807 p ˂0.001), and ESS score (r = -0.317, p = 0.046) both showed a negative correction.
Conclusion: Hypocretin deficiency may be associated with the regulation of thyroid hormones in narcolepsy patients. The serum thyroid hormones may affect the severity and neuropsychological functions of narcolepsy patients.
... As an alternative of BDE-209, DBDPE shares similar chemical structure and has also been proved to interfere with the thyroid system of mouse (Sun et al., 2018), zebrafish (Wang et al., 2019a), rats (Wang et al., 2019b) and even humans . Considering that thyroid hormones are very essential to the development of brain (Alkemade, 2015), DBDPE may also have the potential to induce neurotoxicity. Additionally, DBDPE was detected to accumulate in chicken (Gallus gallus domesticus) brain with concentrations ranging from 0 to 1130 ng/g lw, which may have the possibility to cause potential adverse effects on nervous system (Zheng et al., 2015). ...
Decabromodiphenyl ethane (DBDPE), a widely used novel brominated flame retardant, is gaining concerns due to rapidly increased contents in various environmental and biota samples. In the present study, zebrafish (Danio rerio) embryos were exposed to 2.91, 9.71, 29.14 and 97.12 μg/L of DBDPE until 120 h post-fertilization (hpf) to investigate the potential developmental neurotoxicity and underlying mechanisms. Chemical analysis revealed concentration-dependently increased body burdens of DBDPE in zebrafish larvae, with bioaccumulation factors (BCFs) ranging from 414 to 726. Embryonic exposure to DBDPE caused hyperactivity without affecting the development of secondary motoneuron axons and muscle fibers. However, further results implicated that DBDPE may affect the locomotor regulatory network via different mechanisms at lower and higher concentrations. On the one hand, embryonic exposure to 2.91 μg/L DBDPE transiently promoted spontaneous coiling contractions, but showed no effects on touch-response and swimming activity in zebrafish larvae. The whole-body contents of neurotransmitters were significantly decreased. Significant decreased protein abundances of α1-TUBULIN and SYN2a and molecular docking results pointed out possible interactions of DBDPE with these two proteins. However, these changes may be unconcerned with the transient hyperactivity, and the exact molecular mechanisms need further investigation. On the other hand, 29.14 and 97.12 μg/L DBDPE exposure caused longer-lasting effects in promoting spontaneous coiling contractions, and also touch-response and swimming activity. At the same time, increased ACh contents (without changes of other neurotransmitters) and ChAT activity and inhibited transcription of nAChRs were observed at higher concentrations. Molecular docking indicated direct interaction of DBDPE with ChAT. The results suggested that DBDPE induced hyperactivity at higher concentrations was probably involved with disrupted cholinergic system, with ChAT as a potential target. Given that the body burden of DBDPE in lower concentration group was comparable with those detected in wild fish, the current results may provide useful information for ecological risk assessment.
... Early life disruptions in the synthesis and secretion of thyroid hormones caused by EDCs have been hypothesized to play a role in ASD etiology given their critical role in neurodevelopmental processes (Andersen et al., 2014;Chevrier et al., 2013;Gillberg et al., 1992;Johns et al., 2015;Khan et al., 2014;Morreale de Escobar, 2001;Morreale De Escobar et al., 2004;Román, 2007;Stamou et al., 2013). TH abnormalities are known causes of mental retardation (Büyükgebiz, 2006;Pemberton et al., 2005), and evidence suggests abnormal maternal and neonatal TH levels can impact other neurodevelopmental outcomes and structural brain development (Alkemade, 2015;Blackburn, 2009;Freire et al., 2010;Haddow et al., 1999;Morreale de Escobar, 2001;Morreale De Escobar et al., 2004;Rovet, 2014;Williams, 2008). A recent study indicates that while maternal thyroid conditions are associated with increased ASD risk in children, the link may not be due to the direct effects of thyroid hormones (Rotem et al., 2020). ...
Lay abstract:
Autism spectrum disorders comprise a complex group with many subtypes of behaviorally defined neurodevelopmental abnormalities in two core areas: deficits in social communication and fixated, restricted, repetitive, or stereotyped behaviors and interests each with potential unique risk factors and characteristics. The underlying mechanisms and the possible causes of autism spectrum disorder remain elusive and while increased prevalence is undoubtable, it is unclear if it is a reflection of diagnostic improvement or emerging risk factors such as endocrine disrupting chemicals. Epidemiological studies, which are used to study the relation between endocrine disrupting chemicals and autism spectrum disorder, can have inherent methodological challenges that limit the quality and strength of their findings. The objective of this work is to systematically review the treatment of these challenges and assess the quality and strength of the findings in the currently available literature. The overall quality and strength were "moderate" and "limited," respectively. Risk of bias due to the exclusion of potential confounding factors and the lack of accuracy of exposure assessment methods were the most prevalent. The omnipresence of endocrine disrupting chemicals and the biological plausibility of the association between prenatal exposure and later development of autism spectrum disorder highlight the need to carry out well-designed epidemiological studies that overcome the methodological challenges observed in the currently available literature in order to be able to inform public policy to prevent exposure to these potentially harmful chemicals and aid in the establishment of predictor variables to facilitate early diagnosis of autism spectrum disorder and improve long-term outcomes.
... Как при избытке, так и при дефиците гормонов ЩЖ отмечаются расстройства центральной и периферической нервной системы. В частности, гипофункция щитовидной железы у детей является самой распространенной причиной умственной отсталости и неврологических расстройств, а пациенты психиатрического профиля, страдающие униполярной и биполярной депрессией, часто имеют нарушения гипоталамо-гипофизарно-тиреоидной системы [1,3]. Однако морфофункциональные механизмы данных нарушений изучены недостаточно. ...
... This decrease in thyroid hormone levels will be followed not only by increased in TSH levels, but also by an increase in TRH levels through the hypothalamic-pituitary-thyroid axis. (Alkemade, 2015;Guissouma et al., 2002). ...
... It can be assumed with a high degree of certainty that both the regulation of metabolic changes and the cognitive function of the brain depend on the functional activity of the hypothalamic-pituitary-thyroid system [8,22]. The insufficiency of functional activity of this system can significantly affect the developing organism and lead to a violation of embryogenesis which in its turn further leads to mnestic and behavioral disorders [2]. A number of diseases lead to a pathology of the thyroid gland [21,32]. ...
... AND ANTITHYROID AGENT TREATMENT 1 Proshin S., 2 Bagaturiya G., 3 Karpova I., 2 Kurbanov R., 2 hyperthyroid group was 0.257±0.135 μIU/ml. ...
... AND ANTITHYROID AGENT TREATMENT 1 Proshin S., 2 Bagaturiya G., 3 Karpova I., 2 Kurbanov R., 2 The state of physiological functions of the whole organism, its vital activity and adaptation to various changes in the surrounding and internal environment is controlled by neurohumoral mechanisms. The main place in the implementation of those mechanisms belongs to hormones. ...
The state of physiological functions of the whole organism, its vital activity and adaptation to various changes in the surrounding and internal environment is controlled by neurohumoral mechanisms. The main place in the implementation of those mechanisms belongs to hormones. A clinically relevant problem is currently the relationship between activity of thyroid gland and prolactin. Aim of study. - To elucidate further the relationship of thyroid-stimulating hormone, thyroxine and prolactin. The study was performed on virgin 30 mature male mice and 33 mature female mice of the inbred line C3H-A. On male and female mice was reproduced a model of experimental hyperthyroid and hypothyroid status by the administration to L-thyroxin and propylthyouracil, accordingly. The blood samples from animals were assayed for TSH, T4 (total) and prolactin. In the hyperthyroid male mice the level of T4 (total) was significantly higher as compared to the hypothyroid and control groups. No deference for the level of TSH and prolactin was found between the hyperthyroid and the hypothyroid groups. In the hypothyroid female mice the level of TSH and T4 (total) was significantly lower and the level of prolactin was significantly higher as compared to the hyperthyroid and the control groups. The male and female mice responded in different ways upon the administration to L-thyroxin and propylthyouracil on the level of TSH, T4 (total) and prolactin.
... BPA also competitively inhibits the binding of protein disulfide isomerase to thyroid hormone 3,3′,5-triodo-L-thyronine ( Hiroi et al., 2006). Throughout pregnancy, the embryo is largely dependent on the maternal thyroid hormone supply, and proper hypothalamus development requires thyroid hormone signaling ( Alkemade, 2015). Thyroid hormone regulates the morphology and density of microglia in the cortex during the prenatal and postnatal periods in mice ( Lima et al., 2001). ...
Bisphenol A (BPA) is a widely used compound in the food packaging industry. Prenatal exposure to BPA induces histological abnormalities in the neocortex and hypothalamus in association with abnormal behaviors. Yet, the molecular and cellular neurodevelopmental toxicological mechanisms of BPA are incompletely characterized on neuroinflammatory-related endopoints. To evaluate the neurodevelopmental effects of BPA exposure in mouse embryos, we examined microglial numbers as well as the expression of microglial-related factors in the E15.5 embryonic brain. BPA-exposed embryos exhibited significant increases in Iba1-immunoreactive microglial numbers in the dorsal telencephalon and the hypothalamus compared to control embryos. Further, the expression levels of microglial markers (Iba1, CD16, iNOS, and CD206), inflammatory factors (TNFα and IL4), signal transducing molecules (Cx3Cr1 and Cx3Cl1), and neurotrophic factor (IGF1) were altered in BPA-exposed embryos. These findings suggest that BPA exposure increases microglial numbers in the brain and alters the neuroinflammatory status at a transcriptional level. Together, these changes may represent a novel target for neurodevelopmental toxicity assessment after BPA exposure.
... Similarly, RTHb affects tissue with relatively high expression of Thrb2 mRNA, such as the brain, pituitary gland, retina, and inner ear (1,28,29). However, the relative distribution of THRA and THRB protein isoforms in these tissues remains unknown (30)(31)(32). Alternatively, functional differences between the isoforms could also explain these syndromes. ...
Thyroid hormone (TH) action is mediated by the products of two genes, thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) that encode several closely related receptor isoforms with differing tissue distributions. The vast majority of THR isoform-specific effects are thought to be due to tissue-specific differences in THR isoform expression levels. We investigated the alternative hypothesis that intrinsic functional differences among THR isoforms mediate these tissue-specific effects. To achieve the same level of expression of each isoform, we created HA-tagged THR isoforms and tested their DNA and functional properties in vitro. We found significant homodimerization and functional differences among the THR isoforms. THRA1 was unable to form homodimers on DR4 DNA elements and was also defective in TH-dependent repression of Tshb and Rxrg in a thyrotroph cell line, TαT1.1. In contrast, THRB2 was both homodimer sufficient and fully functional on these negatively regulated genes. Using domain exchanges and individual amino acid switches between THRA1 and THRB2, we identified three amino acids in helix 10 of THRB2 ligand binding domain that are required for negative regulation and are absent in THRA1.
... However, as for the other regions mentioned above, their exact impact on prenatal development is only partly understood. This could be very important, as it is believed that embryonic TH signalling fine-tunes the adult set point of the HPT axis by affecting hypothalamic neuroanatomical development (Alkemade, 2015;Friesema et al., 2012). ...
