title: Di2-ethylhexyl phthalate disrupts thyroid hormone homeostasis through activating the Ras/Akt/TRHr pathway and inducing hepatic enzymes.
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.
authors.affiliation: 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.
authors.forename: Hanfeng
authors.initials: H
authors.lastname: Ye
authors.affiliation: School of Nursing, Chongqing Medical and Pharmaceutical College, Chongqing 400020, P.R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Ha
authors.affiliation: Key Lab of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Key Lab of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.affiliation: 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.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Key Lab of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, P.R. China.
authors.forename: Changjiang
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D011905:Genes, ras; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D018384:Oxidative Stress; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000378:metabolism; D015398:Signal Transduction; D000072637:Thyroid Epithelial Cells / Q000187:drug effects; D013961:Thyroid Gland / Q000473:pathology / Q000648:ultrastructure; D013963:Thyroid Hormones / Q000378:metabolism*
chemical_list: D052244:Endocrine Disruptors; D017382:Reactive Oxygen Species; D018025:Receptors, Thyrotropin-Releasing Hormone; D013963:Thyroid Hormones; D004051:Diethylhexyl Phthalate; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt