Xiaowei Ma, Yujian Zheng, Hongyun Li, Mei Yang, Jun Wu
{"title":"Involvement of the PI3K/Nrf2 Pathway in Arsenic-Induced Endocrine and Thyroid Toxicity in Rats.","authors":"Xiaowei Ma, Yujian Zheng, Hongyun Li, Mei Yang, Jun Wu","doi":"10.1002/jat.4905","DOIUrl":null,"url":null,"abstract":"<p><p>Humans' exposure to arsenic (As) has been associated with the development of various diseases. Some health effects may be mediated by arsenic-induced toxicity to the thyroid and endocrine systems, but its underlying mechanisms remain unclear. The overall aim of our study was focused on using sodium arsenite (NaAsO<sub>2</sub>)-exposed rats to investigate the involvement of the phosphatidylinositol 3-kinase (PI3K) and transcription factor NF-E2-related factor 2 (Nrf2) pathways in toxicity to the thyroid and endocrine systems. In our in vitro study, exposure of thyroid cells (a thyroid follicular epithelial cell line) to 0, 0.4, 0.8, and 3.2 μM. NaAsO<sub>2</sub> caused reduced triiodothyronine (T3) and thyroxine (T4) levels, significantly increased estrogen receptor alpha (ERα) and thyroid hormone receptor alpha (TRα) mRNA levels, reduced Kelch-like epichlorohydrin-associated protein-1 (Keap1) and AKT serine (AKT) mRNA expression, and increased Nrf2 and PI3K mRNA expression (p < 0.05). In the in vivo study, Wistar rats were treated with 0, 0.8, 4.0, and 20.0 mg/kg/d of NaAsO<sub>2</sub> for 20 weeks. The exposure caused dose-dependent histopathological changes in the thyroid, a significant increase in serum estradiol (E2), accompanied by alterations in thyroid hormone metabolism, as evidenced by decreased triiodothyronine (TG), T3, and T4 (p < 0.05). Additionally, mRNA expression levels of ERα and TRα were significantly altered in the thyroid tissues. Keap1, Nrf2, PI3K, and AKT mRNA expression levels were increased (p < 0.05). Specifically, exposure to NaAsO<sub>2</sub> disrupted normal thyroid functions by regulating the PI3K/Nrf2 pathway. Our findings indicate that NaAsO<sub>2</sub> exposure induced cytotoxicity and disrupted estrogen production both in vivo and in vitro investigations, leading to thyroid dysfunction through altered expression of the PI3K/Nrf2 pathway. These findings highlight the complex mechanisms through which arsenic disrupted thyroid function and endocrine homeostasis.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Applied Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/jat.4905","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Humans' exposure to arsenic (As) has been associated with the development of various diseases. Some health effects may be mediated by arsenic-induced toxicity to the thyroid and endocrine systems, but its underlying mechanisms remain unclear. The overall aim of our study was focused on using sodium arsenite (NaAsO2)-exposed rats to investigate the involvement of the phosphatidylinositol 3-kinase (PI3K) and transcription factor NF-E2-related factor 2 (Nrf2) pathways in toxicity to the thyroid and endocrine systems. In our in vitro study, exposure of thyroid cells (a thyroid follicular epithelial cell line) to 0, 0.4, 0.8, and 3.2 μM. NaAsO2 caused reduced triiodothyronine (T3) and thyroxine (T4) levels, significantly increased estrogen receptor alpha (ERα) and thyroid hormone receptor alpha (TRα) mRNA levels, reduced Kelch-like epichlorohydrin-associated protein-1 (Keap1) and AKT serine (AKT) mRNA expression, and increased Nrf2 and PI3K mRNA expression (p < 0.05). In the in vivo study, Wistar rats were treated with 0, 0.8, 4.0, and 20.0 mg/kg/d of NaAsO2 for 20 weeks. The exposure caused dose-dependent histopathological changes in the thyroid, a significant increase in serum estradiol (E2), accompanied by alterations in thyroid hormone metabolism, as evidenced by decreased triiodothyronine (TG), T3, and T4 (p < 0.05). Additionally, mRNA expression levels of ERα and TRα were significantly altered in the thyroid tissues. Keap1, Nrf2, PI3K, and AKT mRNA expression levels were increased (p < 0.05). Specifically, exposure to NaAsO2 disrupted normal thyroid functions by regulating the PI3K/Nrf2 pathway. Our findings indicate that NaAsO2 exposure induced cytotoxicity and disrupted estrogen production both in vivo and in vitro investigations, leading to thyroid dysfunction through altered expression of the PI3K/Nrf2 pathway. These findings highlight the complex mechanisms through which arsenic disrupted thyroid function and endocrine homeostasis.
期刊介绍：
Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.
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