GLIS3 mediated by the Rap1/PI3K/AKT signal pathway facilitates real-ambient PM2.5 exposure disturbed thyroid hormone homeostasis regulation

Siying Tang; Daochuan Li; Hao Ding; Menghui Jiang; Yanjie Zhao; Dianke Yu; Rong Zhang; Wen Chen; Rui Chen; Yuxin Zheng; Jinmei Piao

doi:10.1016/j.ecoenv.2022.113248

GLIS3 mediated by the Rap1/PI3K/AKT signal pathway facilitates real-ambient PM_2.5 exposure disturbed thyroid hormone homeostasis regulation

Ecotoxicol Environ Saf. 2022 Mar 1:232:113248. doi: 10.1016/j.ecoenv.2022.113248. Epub 2022 Jan 29.

Authors

Siying Tang¹, Daochuan Li², Hao Ding³, Menghui Jiang¹, Yanjie Zhao¹, Dianke Yu¹, Rong Zhang⁴, Wen Chen², Rui Chen⁵, Yuxin Zheng¹, Jinmei Piao⁶

Affiliations

¹ School of Public Health, Qingdao University, Qingdao 266021, Shandong Province, China.
² Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China.
³ School of Public Health, Qingdao University, Qingdao 266021, Shandong Province, China; The Second People's Hospital of Qidong, Nantong 226200, Jiangsu Province, China.
⁴ Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China.
⁵ School of Public Health, Capital Medical University, Beijing 100000, China.
⁶ School of Public Health, Qingdao University, Qingdao 266021, Shandong Province, China. Electronic address: jinmeipark@163.com.

PMID: 35093813
DOI: 10.1016/j.ecoenv.2022.113248

Abstract

Exposure to fine particulate matter (PM_2.5) could damage multiple organs and systems. Recent epidemiological studies have shown that PM_2.5 can disrupt dynamic balance of thyroid hormone (TH). However, the underlying mechanism by which PM_2.5 interferes with TH remains unclear. This study evaluated the role of Gli-similar3 (GLIS3) in the effect of PM_2.5 on TH synthesis in mice using a real-ambient exposure system, in Shijiazhuang City, Hebei Province. The PM_2.5exposure group (PM) and filtered air group (FA) were placed in the exposure device for four and eight weeks. The results showed that the PM_2.5 exposure altered the structure of the thyroid gland. Moreover, after PM_2.5 exposure for eight weeks, the exposure level of free thyroxine (FT4) increased and the expression level of thyroid stimulating hormone (TSH) decreased in serum of mice. In addition, PM_2.5 exposure significantly increased the expression of proteins related to thyroid hormone synthesis, such as sodium iodide transporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG). Next, we found that GLIS3 and thyroid transcription factor Paired box 8 (PAX8) also increased after PM_2.5 exposure. In order to further explore the potential molecular mechanism, we carried out transcriptome sequencing. KEGG analysis of the top 10 pathways revealed that the Ras-associated protein 1 (Rap1) signaling pathway could activate transcription factors and is related to thyroid cell survival. Additionally, PM_2.5 exposure significantly increased the protein levels of Rap1 and its active form (Rap1 +GTP). We speculate that the active state of Rap1 is believed to be involved in activating the expression of transcription factor GLIS3. In conclusion, PM_2.5 exposure induces histological changes in the thyroid gland and thyroid dysfunction in mice. The exposure activates GLIS3 through the Rap1/PI3K/AKT pathway to promote the expression of proteins related to thyroid hormone synthesis, leading to increased dysregulating TH homeostasis.

Keywords: GLIS3; PM(2.5); Real-ambient PM exposure system; Thyroid gland.

MeSH terms

Animals
DNA-Binding Proteins / metabolism
Homeostasis
Mice
Particulate Matter / metabolism
Phosphatidylinositol 3-Kinases* / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Repressor Proteins / metabolism
Signal Transduction
Thyroid Gland*
Thyroid Hormones / metabolism
Trans-Activators / metabolism

Substances

DNA-Binding Proteins
Glis3 protein, mouse
Particulate Matter
Repressor Proteins
Thyroid Hormones
Trans-Activators
Proto-Oncogene Proteins c-akt