Endocrinology and Metabolism

Original Articles

Endocrine Research
DEHP Down-Regulates Tshr Gene Expression in Rat Thyroid Tissues and FRTL-5 Rat Thyrocytes: A Potential Mechanism of Thyroid Disruption: Min Joo Kim, Hwan Hee Kim, Young Shin Song, Ok-Hee Kim, Kyungho Choi, Sujin Kim, Byung-Chul Oh, Young Joo Park; Endocrinol Metab. 2021;36(2):447-454. Published online March 31, 2021; DOI: https://doi.org/10.3803/EnM.2020.920

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Background
Di-2-ethylhexyl phthalate (DEHP) is known to disrupt thyroid hormonal status. However, the underlying molecular mechanism of this disruption is unclear. Therefore, we investigated the direct effects of DEHP on the thyroid gland.
Methods
DEHP (vehicle, 50 mg/kg, and 500 mg/kg) was administered to Sprague-Dawley rats for 2 weeks. The expression of the thyroid hormone synthesis pathway in rat thyroid tissues was analyzed through RNA sequencing analysis, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemical (IHC) staining. DEHP was treated to FRTL-5 rat thyroid cells, and an RT-PCR analysis was performed. A reporter gene assay containing the promoter of thyroid stimulating hormone receptor (TSHR) in Nthy-ori 3-1 human thyroid cells was constructed, and luciferase activity was determined.
Results
After DEHP treatment, the free thyroxine (T4) and total T4 levels in rats significantly decreased. RNA sequencing analysis of rat thyroid tissues showed little difference between vehicle and DEHP groups. In the RT-PCR analysis, Tshr expression was significantly lower in both DEHP groups (50 and 500 mg/kg) compared to that in the vehicle group, and IHC staining showed that TSHR expression in the 50 mg/kg DEHP group significantly decreased. DEHP treatment to FRTL-5 cells significantly down-regulated Tshr expression. DEHP treatment also reduced luciferase activity in a reporter gene assay for TSHR.
Conclusion
Although overall genetic changes in the thyroid hormone synthesis pathway are not clear, DEHP exposure could significantly down-regulate Tshr expression in thyroid glands. Down-regulation of Tshr gene appears to be one of potential mechanisms of thyroid disruption by DEHP exposure.

Citations

Citations to this article as recorded by

ARTS is essential for di-2-ethylhexyl phthalate (DEHP)-induced apoptosis of mouse Leydig cells
Yue Li, Linlin Xu, Chaoju Hao, Si Yang, Jinglei Wang, Jiaxiang Chen
Ecotoxicology and Environmental Safety.2024; 270: 115882. CrossRef
Thyroid dysfunction caused by exposure to environmental endocrine disruptors and the underlying mechanism: A review
Jie He, Jie Xu, Mucong Zheng, Kai Pan, Lilin Yang, Lina Ma, Chuyang Wang, Jie Yu
Chemico-Biological Interactions.2024; 391: 110909. CrossRef
Intrauterine exposure to di(2-ethylhexyl) phthalate (DEHP) disrupts the function of the hypothalamus-pituitary-thyroid axis of the F1 rats during adult life
Érica Kássia Sousa-Vidal, Guilherme Henrique, Renata Elen Costa da Silva, Caroline Serrano-Nascimento
Frontiers in Endocrinology.2023;[Epub] CrossRef
Drinking water disinfection byproduct iodoacetic acid affects thyroid hormone synthesis in Nthy-ori 3–1 cells
Jingyi Xiao, Yujie Sha, Yuwen Huang, Kunling Long, Huan Wu, Yan Mo, Qiyuan Yang, Shengkun Dong, Qiang Zeng, Xiao Wei
Ecotoxicology and Environmental Safety.2023; 257: 114926. CrossRef
Assessment of five typical environmental endocrine disruptors and thyroid cancer risk: a meta-analysis
Yuyao Yang, Xiaoyue Bai, Juan Lu, Ronghao Zou, Rui Ding, Xiaohui Hua
Frontiers in Endocrinology.2023;[Epub] CrossRef
Investigation of the effects of phthalates on in vitro thyroid models with RNA-Seq and ATAC-Seq
Marta Nazzari, Mírian Romitti, Duncan Hauser, Daniel J. Carvalho, Stefan Giselbrecht, Lorenzo Moroni, Sabine Costagliola, Florian Caiment
Frontiers in Endocrinology.2023;[Epub] CrossRef
Di(2-ethylhexyl) phthalate (DEHP) and thyroid: biological mechanisms of interference and possible clinical implications
Xueting Zhang, Wen Qi, Qi Xu, Xu Li, Liting Zhou, Lin Ye
Environmental Science and Pollution Research.2022; 29(2): 1634. CrossRef
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Naima Abd El-Halim Sherif, Asmaa El-Banna, Rehab Ahmed Abdel-Moneim, Zahraa Khalifa Sobh, Manal Ibrahim Fathy Balah
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Environmental disruption of reproductive rhythms
Marie-Azélie Moralia, Clarisse Quignon, Marine Simonneaux, Valérie Simonneaux
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Endocrine-disruptor endpoints in the ovary and thyroid of adult female rats exposed to realistic doses of di-(2-ethylhexyl) phthalate
Amel Jebara, Asma Beltifa, Guissepa Di Bella, Lotfi Mabrouk, Hedi Ben Mansour
Journal of Water and Health.2022; 20(8): 1256. CrossRef
The influence of sunitinib and sorafenib, two tyrosine kinase inhibitors, on development and thyroid system in zebrafish larvae
Gang Wei, Cao-xu Zhang, Yu Jing, Xia Chen, Huai-dong Song, Liu Yang
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Endocrine Research
Thyroid Hormone Regulates the mRNA Expression of Small Heterodimer Partner through Liver Receptor Homolog-1: Hwa Young Ahn, Hwan Hee Kim, Ye An Kim, Min Kim, Jung Hun Ohn, Sung Soo Chung, Yoon-Kwang Lee, Do Joon Park, Kyong Soo Park, David D. Moore, Young Joo Park; Endocrinol Metab. 2015;30(4):584-592. Published online December 31, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.4.584

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Background

Expression of hepatic cholesterol 7α-hydroxylase (CYP7A1) is negatively regulated by orphan nuclear receptor small heterodimer partner (SHP). In this study, we aimed to find whether thyroid hormone regulates SHP expression by modulating the transcriptional activities of liver receptor homolog-1 (LRH-1).

Methods

We injected thyroid hormone (triiodothyronine, T3) to C57BL/6J wild type. RNA was isolated from mouse liver and used for microarray analysis and quantitative real-time polymerase chain reaction (PCR). Human hepatoma cell and primary hepatocytes from mouse liver were used to confirm the effect of T3 in vitro. Promoter assay and electrophoretic mobility-shift assay (EMSA) were also performed using human hepatoma cell line

Results

Initial microarray results indicated that SHP expression is markedly decreased in livers of T3 treated mice. We confirmed that T3 repressed SHP expression in the liver of mice as well as in mouse primary hepatocytes and human hepatoma cells by real-time PCR analysis. LRH-1 increased the promoter activity of SHP; however, this increased activity was markedly decreased after thyroid hormone receptor β/retinoid X receptor α/T3 administration. EMSA revealed that T3 inhibits specific LRH-1 DNA binding.

Conclusion

We found that thyroid hormone regulates the expression of SHP mRNA through interference with the transcription factor, LRH-1.

Citations

Citations to this article as recorded by

Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease
Ting-ying Jiao, Yuan-di Ma, Xiao-zhen Guo, Yun-fei Ye, Cen Xie
Acta Pharmacologica Sinica.2022; 43(5): 1103. CrossRef
Loperamide induces excessive accumulation of bile acids in the liver of mice with different diets
Zili Lei, Hedong Rong, Yanhong Yang, Siping Yu, Tianle Zhang, Lei Chen, Ya Nie, Qi Song, Qing Hu, Jiao Guo
Toxicology.2022; 477: 153278. CrossRef
Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms
Giuseppe Ferrandino, Rachel R. Kaspari, Olga Spadaro, Andrea Reyna-Neyra, Rachel J. Perry, Rebecca Cardone, Richard G. Kibbey, Gerald I. Shulman, Vishwa Deep Dixit, Nancy Carrasco
Proceedings of the National Academy of Sciences.2017;[Epub] CrossRef

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