Thyroid hormone economy in mice overexpressing iodothyronine deiodinases

Yamauchi, Ichiro; Sakane, Yoriko; Yamashita, Takafumi; Hakata, Takuro; Sugawa, Taku; Fujita, Haruyuki; Okamoto, Kentaro; Taura, Daisuke; Hirota, Keisho; Ueda, Yohei; Fujii, Toshihito; Yasoda, Akihiro; Inagaki, Nobuya

doi:10.1096/fj.202101288rr

Cited by 6 publications

(8 citation statements)

References 49 publications

(105 reference statements)

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“…The present study has several limitations. First, the TSH overexpressed in our system might not have post-translational modifications because it was predominantly produced in the liver (26), not the pituitary gland, which is different from physiological TSH secretion. Likewise, TSHR-stimulating antibodies in Graves’ disease might affect TSHR signaling differently.…”

Section: Discussionmentioning

confidence: 99%

“…Reverse transcription (RT)-PCR was performed using the Emerald Amp MAX PCR master mix (Takara Bio, Shiga, Japan). Quantitative RT-PCR was performed using THUNDERBIRD SYBR qPCR MIX (TOYOBO Life Science) with the StepOnePlus Real-time PCR System (Thermo Fisher Scientific), as in our previous studies (26, 27, 66, 67). Results were normalized using Ppia and Hprt as reference genes; relative mRNA expression of target genes was evaluated using the comparative threshold cycle method.…”

Section: Methodsmentioning

confidence: 99%

“…TSH forms a heterodimer consisting of a specific β subunit encoded by TSHB (23) and an α subunit coded by CGA that is common to luteinizing hormone, follicle-stimulating hormone, and chorionic gonadotropin (24). Therefore, we cloned human TSHB and CGA genes into pLIVE vectors and hydrodynamically injected 25 μg of these vectors into C57BL/6J mice according to our previous studies (25)(26)(27). At 1 week after hydrodynamic gene delivery, human TSH was not detected in the serum when each vector was separately injected, but TSH was strongly detected when both vectors were co-injected (Supplementary Figure 1A).…”

Section: Generation Of Hyperthyroid Micementioning

confidence: 99%

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Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Yamauchi,

Sugawa,

Hakata

et al. 2023

Preprint

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Hyperthyroidism is a condition with excessive thyroid hormone secretion. Activation of thyroid stimulating hormone receptor (TSHR) fundamentally leads to hyperthyroidism. The details of TSHR signaling remain to be elucidated. We conducted transcriptome analyses for hyperthyroid mice that we generated by overexpressing TSH. TSH overexpression via hydrodynamic gene delivery with pLIVE-TSHBand pLIVE-CGAvectors consistently caused hyperthyroidism and goiters for at least 4 weeks in C57BL/6J mice. RNA sequencing analysis of their thyroid glands revealed that thiamazole slightly changed the thyroid transcriptome, which reinforces a conventional theory that thiamazole decreases thyroid hormone secretion via inhibition of thyroid peroxidase activity. Meanwhile, TSH overexpression drastically changed the thyroid transcriptome. In particular, enrichment analyses identified the cell cycle, phosphatidylinositol-3 kinase/Akt pathway, and Ras-related protein 1 pathway as possibly associated with goiter development. Regarding the role of TSHR signaling in hyperthyroidism, it is noteworthy thatSlc26a4was exclusively upregulated among genes crucial to thyroid hormone secretion at both 1 and 4 weeks after hydrodynamic gene delivery. To verify the relationship between this upregulation and hyperthyroidism, we overexpressed TSH inSlc26a4knockout mice. TSH overexpression caused hyperthyroidism inSlc26a4knockout mice, equivalent to that in control mice. To summarize, we analyzed hyperthyroid mice generated by TSH overexpression. We did not observe significant changes in known genes and pathways involved in thyroid hormone secretion. Thus, our datasets might include candidate genes that have not yet been identified as regulators of thyroid function. Our transcriptome datasets regarding hyperthyroidism can contribute to future research on TSHR signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Generation Of Hyperthyroid Micementioning

confidence: 99%

See 1 more Smart Citation

Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Yamauchi,

Sugawa,

Hakata

et al. 2023

Preprint

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“…SecTRAPs can also be created in mammalian cells by inhibition of endogenous TrxR1 with compounds that target the Sec residue, which also leads to apoptosis [ 186 ]. Transient transfection of plasmids containing DIO1, DIO2, or DIO3, with their corresponding SECIS sequences in the 3′-UTR, allowed successful production of full-length DIO1 and DIO3, but not DIO2 in HEK 293T cells [ 187 ]. Interestingly, relatively low levels of Sec-containing DIO1 and DIO3 were produced compared to HEK 293T cells transfected with plasmids containing Sec-to-Cys mutants, and high levels of DIO1 and DIO3 truncated at the UGA codon were observed [ 187 ].…”

Section: Overexpression and Delivery Of Selenoproteins In Mammalian C...mentioning

confidence: 99%

Biosynthesis, Engineering, and Delivery of Selenoproteins

Wright,

O’Donoghue

2023

IJMS

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Selenocysteine (Sec) was discovered as the 21st genetically encoded amino acid. In nature, site-directed incorporation of Sec into proteins requires specialized biosynthesis and recoding machinery that evolved distinctly in bacteria compared to archaea and eukaryotes. Many organisms, including higher plants and most fungi, lack the Sec-decoding trait. We review the discovery of Sec and its role in redox enzymes that are essential to human health and important targets in disease. We highlight recent genetic code expansion efforts to engineer site-directed incorporation of Sec in bacteria and yeast. We also review methods to produce selenoproteins with 21 or more amino acids and approaches to delivering recombinant selenoproteins to mammalian cells as new applications for selenoproteins in synthetic biology.

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“…The aim of the study presented here was to elucidate the impact of exogenous TRIAC on TH action. We administered TRIAC to mice and analyzed the animals using our methods to evaluate various elements that regulate TH action (19)(20)(21). To determine TRIAC's effects, we administered 3,3′,5-triiodo-L-thyronine (LT3) to other mice for comparison.…”

Section: Introductionmentioning

confidence: 99%

TRIAC disrupts cerebral thyroid hormone action via a negative feedback loop and heterogenous distribution among organs

Yamauchi

Hakata

Ueda

et al. 2022

Preprint

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3,3',5-triiodothyroacetic acid (TRIAC) is a metabolite of endogenous thyroid hormones (THs) that can bind to and activate TH receptors. As TRIAC was previously detected in sewage effluent, we aimed to investigate exogenous TRIAC's potential for endocrine disruption. We administered either TRIAC or 3,3',5-triiodo-L-thyronine (LT3) to both euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC alleviated growth retardation, suppressed the hypothalamus-pituitary-thyroid (HPT) axis, and upregulated TH-responsive genes in the pituitary gland, liver, and heart. We observed that, unlike LT3, TRIAC does not upregulate the expression of TH-responsive genes in the cerebrum. Measurement of organ-specific TRIAC levels suggested that TRIAC was not efficiently trafficked into the cerebrum. Furthermore, by analyzing euthyroid mice, we found that cerebral TRIAC levels did not increase despite TRIAC administration at higher concentrations, whereas serum and cerebral TH levels were substantially decreased. Hence, TH-responsive genes in the cerebrum appear to be downregulated by TRIAC. In summary, TRIAC administration decreases circulating TH levels by suppressing the HPT axis, while the consequent attenuation of TH actions was compensated by TRIAC in peripheral tissues but not in the cerebrum due to the relative impermeability of the blood-brain barrier towards TRIAC. We verified that exogenous TRIAC disrupts TH actions in the cerebrum. This disruption is apparently due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogenous distribution of TRIAC among different organs. Our findings indicate that environmental TRIAC poses a potential neurodevelopmental risk.

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Thyroid hormone economy in mice overexpressing iodothyronine deiodinases

Cited by 6 publications

References 49 publications

Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Transcriptomic Landscape of Hyperthyroidism in Mice Overexpressing Thyroid Stimulating Hormone

Biosynthesis, Engineering, and Delivery of Selenoproteins

TRIAC disrupts cerebral thyroid hormone action via a negative feedback loop and heterogenous distribution among organs

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