Involvement of the PI3K/Nrf2 Pathway in Arsenic‐Induced Endocrine and Thyroid Toxicity in Rats

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.