Thyroid hormone responsiveness in N-Tera-2 cells

Chan, Shiao-Yng; McCabe, Chris; Tj, Visser; Franklyn, Jayne A.; Kilby, Mark

doi:10.1677/joe.0.1780159

Cited by 11 publications

(10 citation statements)

References 56 publications

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“…Because T 4 was provided for only a short time, the interpretation was that the duration of T 4 treatment was not sufficient to produce a significant reduction in cellular levels of NSP-A mRNA. However, Chan et al (2003) have recently reported that NSP-A expression is not directly sensitive to TH in N-Tera-2 cells, indicating that NSP-A may not be directly regulated by TH. If maternal hypothyroidism increases NSP-A expression indirectly, and NSP-A is not directly regulated by TH, then our present results indicate that PCBs produce effects on the fetal brain by exerting direct TH-like effects as well as by inducing low maternal TH.…”

Section: Discussionmentioning

confidence: 99%

Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

Gauger

Kato

Haraguchi

et al. 2004

Environ Health Perspect

146

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Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants routinely found in human and animal tissues. Developmental exposure to PCBs is associated with neuropsychologic deficits, which may be related to effects on thyroid hormone (TH) signaling in the developing brain. However, PCBs may interfere with TH signaling solely by reducing circulating levels of TH, or they may exert direct effects on TH receptors (TRs). Therefore, we tested whether maternal exposure to a commercial PCB mixture, Aroclor 1254 (A1254), exerts effects in the fetal brain by one or both of these mechanisms. Dams were dosed daily with 0, 1, or 4 mg/kg A1254 from gestational day 6 (GD6) until they were sacrificed on GD16. A1254 significantly reduced circulating levels of triiodothyronine (T 3 ) and thyroxine (T 4 ) in pregnant rats but increased the expression of several THresponsive genes in the fetal cortex, including neuroendocrine-specific protein A (NSP-A), RC3/neurogranin, and Oct-1. These findings are consistent with a direct action of PCBs on TRs. However, we did not identify parent PCB congeners or metabolites that bound to rat TRs isolated from hepatic nuclei. These findings indicate that PCBs can interfere with TH signaling in the fetal brain by direct actions on the fetus rather than by producing maternal hypothyroidism. producing a variety of functional TR isoforms (TRβ1, TRβ2, TRβ3, TRα1) (Flamant and Samarut 2003). TRα1 and TRβ1 are the predominant isoforms that are expressed throughout brain development (Bradley et al. 1989(Bradley et al. , 1992(Bradley et al. , 1994 and in other tissues such as liver, intestine, and heart (Brent 2000). However, only one report has addressed this proposal directly (Cheek et al. 1999), finding that two hydroxylated PCB congeners (4´-OH-PCB-14 and 4´-OH-PCB-106) exhibit a relatively low affinity for human TRβ1 (K i = 32 µM).Considering these findings, the present studies were initiated for two reasons. First, we tested the hypothesis that maternal PCB exposure could affect the fetal cerebral cortex by reducing the availability of TH to the fetus. We previously showed that low maternal TH, produced experimentally by goitrogen treatment, can alter gene expression in the fetal cortex before the onset of fetal thyroid function (Dowling et al. , 2001. Therefore, if PCBs reduce circulating levels of maternal TH, then gene expression in the fetal cortex should respond in a manner consistent with hypothyroidism. Second, we tested the hypothesis that individual PCBs or their metabolites could bind to the TR. To test this, we used rat hepatic nuclei as a source of both TRα1 and TRβ1. Materials and MethodsChemicals. Aroclor 1254 (A1254; lot no. A8110048) and individual PCB congeners (PCBs 77, 105, 118, 126, 138, and 153) were purchased from AccuStandard, Inc. (New Haven, CT). Methylsulfonyl-PCBs (MeSO 2 -PCBs) were synthesized according to Haraguchi et al. (1987). The purity of these compounds was > 99% as determined by gas chromatography. The hydroxylated PCBs were synthesized using the ...

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Section: Discussionmentioning

confidence: 99%

Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

Gauger

Kato

Haraguchi

et al. 2004

Environ Health Perspect

146

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“…The mechanisms by which MND alters TR isoform expression are at present unclear but our results suggest that fetal hypothyroxinaemia may play a role. T 3 treatment of several CNS cell types in vitro results in an increase in TRβ1 mRNA expression (Lebel et al 1993; Chan et al 2003 b ), with little effect on mRNAs encoding the TRα isoforms. This is likely to be mediated via direct T 3 regulation at the two thyroid hormone response elements described in the promoter regions of the TRβ (c‐erbAβ) gene (Sakurai et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Maternal nutrient deprivation induces sex‐specific changes in thyroid hormone receptor and deiodinase expression in the fetal guinea pig brain

Chan

Andrews

Lingas

et al. 2005

The Journal of Physiology

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Thyroid hormone deprivation during fetal life has been implicated in neurodevelopmental morbidity. In humans, poor growth in utero is also associated with fetal hypothyroxinaemia. In guinea pigs, a short period (48 h) of maternal nutrient deprivation at gestational day (gd) 50 results in fetuses with hypothyroxinaemia and increased brain/body weight ratios. Thyroid hormone action is mediated by nuclear thyroid hormone receptors (TRs) and is dependent upon the prereceptor regulation of supply of triiodothyronine (T 3 ) by deiodinase enzymes. Examination of fetal guinea pig brains using in situ hybridization demonstrated widespread expression of mRNAs encoding TRα1, α2 and β1, with regional colocalization of deiodinase type 2 (D2) mRNA in the developing forebrain, limbic structures, brainstem and cerebellum at gd52. With maternal nutrient deprivation, TRα1 and β1 mRNA expression was significantly increased in the male, but decreased in the female fetal hippocampus and cerebellum and other areas showing high TR expression under euthyroid conditions. Maternal nutrient deprivation resulted in elevated D2 mRNA expression in males and females. Deiodinase type 3 (D3) mRNA expression was confined to the shell of the nucleus accumbens, the posterior amygdalohippocampal area, brainstem and cerebellum, and did not change with maternal nutrient deprivation. In conclusion, maternal nutrient deprivation resulted in sex-specific changes in TR mRNA expression and a generalized increase in D2 mRNAs within the fetal brain. These changes may represent a protective mechanism to maintain appropriate thyroid hormone action in the face of fetal hypothyroxinaemia in order to optimize brain development.

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“…Cells were passaged and split 1:4 twice weekly, and cultured at 37°C and 5% CO 2 . Differentiation of NT2 precursor cells to terminally differentiated neurons with retinoic acid (RA) treatment was conducted based on methods previously described (Pleasure et al 1992; Chan et al 2003). Charcoal‐stripped FBS (First Link Ltd, Birmingham, UK), which is virtually devoid of THs, was used to create a T3‐depleted environment.…”

Section: Methodsmentioning

confidence: 99%

“…Since NT2 cells were unable to tolerate 5 weeks in culture with media supplemented with charcoal‐stripped FBS alone, differentiation experiments were performed in media containing 2% of normal FBS with 8% of charcoal‐stripped FBS (combination media) with the addition of 10 n m T3 (T3‐replete) and without T3 (T3‐depleted) along with 10 μ m RA (Sigma‐Aldrich). We had previously shown that the dose of 10 n m T3 was optimal in the induction of T3‐responsive gene expression in NT2 cells (Chan et al 2003).…”

Section: Methodsmentioning

confidence: 99%

The expression of thyroid hormone transporters in the human fetal cerebral cortex during early development and in N‐Tera‐2 neurodifferentiation

Chan

Martin‐Santos

Loubière

et al. 2011

The Journal of Physiology

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Non-technical summary Thyroid hormones are important in brain development and they enter cells through thyroid hormone transporters at the cell membrane. Thyroid hormone transporters are thought to play an important role since gene defects in one of these transporters, MCT8, have been associated with severe mental retardation. This paper describes the expression of a range of thyroid hormone transporters in the human fetal brain during early pregnancy, and suggests that these transporters could regulate the supply of thyroid hormones into brain cells from very early in development. Surprisingly, the reduction of thyroid hormones and MCT8 expression do not affect the differentiation of an unspecialised cell to a specialised human nerve cell in the brain. Thyroid hormones and MCT8 are thus likely to affect other processes during human brain development. To find out how thyroid hormones influence human fetal brain development requires further research.Abstract Associations of neurological impairment with mutations in the thyroid hormone (TH) transporter, MCT8, and with maternal hypothyroxinaemia, suggest that THs are crucial for human fetal brain development. It has been postulated that TH transporters regulate the cellular supply of THs within the fetal brain during development. This study describes the expression of TH transporters in the human fetal cerebral cortex (7-20 weeks gestation) and during retinoic acid induced neurodifferentiation of the human N-Tera-2 (NT2) cell line, in triiodothyronine (T3) replete and T3-depleted media. Compared with adult cortex, mRNAs encoding OATP1A2, OATP1C1, OATP3A1 variant 2, OATP4A1, LAT2 and CD98 were reduced in fetal cortex at different gestational ages, whilst mRNAs encoding MCT8, MCT10, OATP3A1 variant 1 and LAT1 were similar. From the early first trimester, immunohistochemistry localised MCT8 and MCT10 to the microvasculature and to undifferentiated CNS cells. With neurodifferentiation, NT2 cells demonstrated declining T3 uptake, accompanied by reduced expressions of MCT8, LAT1, CD98 and OATP4A1. T3 depletion significantly reduced MCT10 and LAT2 mRNA expression at specific time points during neurodifferentiation but there were no effects upon T3 uptake, neurodifferentiation marker expression or neurite lengths and branching. MCT8 repression also did not affect NT2 neurodifferentiation. In conclusion, many TH transporters are expressed in the human fetal cerebral cortex from the first trimester, which could regulate cellular TH supply during early development. However, human NT2 neurodifferentiation is not dependent upon T3 or MCT8 and there were no compensatory changes to promote T3 uptake in a T3-depleted environment.

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Thyroid hormone responsiveness in N-Tera-2 cells

Cited by 11 publications

References 56 publications

Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors.

Maternal nutrient deprivation induces sex‐specific changes in thyroid hormone receptor and deiodinase expression in the fetal guinea pig brain

The expression of thyroid hormone transporters in the human fetal cerebral cortex during early development and in N‐Tera‐2 neurodifferentiation

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