Yunnan Key Lab of Fertility Regulation and Minority Birth Health, Yunnan Population and Family Planning Science and Technology Research Institute, Yunnan 650021, P.R. China.
School of Nursing, Chongqing Medical and Pharmaceutical College, Chongqing 400020, P.R. China.
Sci Rep. 2017 Jan 9;7:40153. doi: 10.1038/srep40153.
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.
邻苯二甲酸二（2-乙基己基）酯（DEHP）作为一种广泛存在的环境污染物和内分泌干扰物，可扰乱甲状腺激素（THs）的内稳态。为了阐明 MAPK 和 PI3K/Akt 通路以及肝酶在 DEHP 甲状腺干扰作用中的作用，将 Sprague-Dawley 大鼠连续灌胃 30 天给予 DEHP；用 NAC、k-Ras siRNA 或抑制剂（U0126 和wortmannin）处理 Nthy-ori 3-1 细胞。结果表明，DEHP 导致大鼠甲状腺和肝脏的组织病理学变化，如甲状腺滤泡腔直径减小、肝细胞水肿。三碘甲状腺原氨酸（T3）、甲状腺素（T4）和促甲状腺激素释放激素（TRH）减少。DEHP 导致 ROS 产生、氧化应激和 k-Ras 上调，从而在体内和体外激活 ERK 和 Akt 通路。此外，Akt 通路激活后，TRH 受体（TRHr）水平升高，Akt 通路抑制后 TRHr 水平降低。然而，ERK 通路不调节 TRHr。此外，肝酶，包括 Ugt1a1、CYP2b1、Sult1e1 和 Sult2b1，在 DEHP 暴露后显著诱导。总之，DEHP 可扰乱 TH 内稳态并降低 TH 水平。激活的 Ras/Akt/TRHr 通路和诱导的肝酶在 DEHP 的甲状腺干扰作用中起重要作用。
