Abstract
Di(2-ethylhexyl) phthalate (DEHP), as a widespread environmental pollutant and an endocrine disruptor, can disturb the homeostasis of thyroid hormones (THs). In order to elucidate roles of the MAPK and PI3K/Akt pathways and hepatic enzymes in thyroid-disrupting effects of DEHP, Sprague-Dawley rats were dosed with DEHP by gavage for 30 consecutive days; Nthy-ori 3-1 cells were treated with DEHP with NAC, k-Ras siRNA or inhibitors (U0126 and wortmannin). Results showed that DEHP led to histopathologic changes in rat thyroid and liver, such as the decrease in thyroid follicular cavity diameter, hepatocyte edema. Triiodothyronine (T3), thyroxine (T4) and thyrotropin releasing hormone (TRH) were reduced. DEHP caused ROS production, oxidative stress and k-Ras upregulation, thereby activating the ERK and Akt pathways in vivo and in vitro. Moreover, TRH receptor (TRHr) level was elevated after the activation of the Akt pathway and was downregulated after the inhibition of the Akt pathway. However, TRHr was not modulated by the ERK pathway. Additionally, hepatic enzymes, including Ugt1a1, CYP2b1, Sult1e1, and Sult2b1, were significantly induced after DEHP exposure. Taken together, DEHP can perturb TH homeostasis and reduce TH levels. The activated Ras/Akt/TRHr pathway and induced hepatic enzymes play vital roles in thyroid-disrupting effects of DEHP.
Highlights
Thyroid hormones (THs) that are synthesized and released by the thyroid play important roles in many physiological systems, such as development and differentiation of organs, metabolism of organisms, and energy homeostasis, and alterations in thyroid hormones (THs) levels would result in a series of adverse subclinical or clinical conditions
Circulating TH levels in serum were significantly reduced after exposure to Di2–ethylhexyl phthalate (DEHP), with maximum effects observed in the high-dose group
The present study explored roles of signaling pathways and hepatic enzymes in DEHP-mediated perturbation of TH homeostasis
Summary
Thyroid hormones (THs) that are synthesized and released by the thyroid play important roles in many physiological systems, such as development and differentiation of organs, metabolism of organisms, and energy homeostasis, and alterations in TH levels would result in a series of adverse subclinical or clinical conditions. As relatively more studies have been focusing on the disruptive effect of phthalates on thyroid function and TH homeostasis, some potential mechanisms have been suggested. A study in a rat FRTL-5 cells reported that DEHP treatment caused changes in iodide uptake of thyroid follicular cells[11]. Another mechanism proposed is associated with TH receptors. Our previous study found that DEHP suppressed gene and protein expression of TTR in rat liver, contributing to the decrease in circulating TH levels in serum[15]. There are very few studies that have examined roles of signaling pathways in thyroid-disrupting effects of phthalates
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