The PI3K/Akt and ERK pathways elevate thyroid hormone receptor β1 and TRH receptor to decrease thyroid hormones after exposure to PCB153 and p,p′-DDE

PCBs and DDT cause the disturbance of thyroid hormone (TH) homeostasis in humans and animals. To test the hypothesis that the PI3K/Alct and MAPK pathways would play significant roles in TH imbalance caused by PCBs and DDT, Sprague-Dawley rats were dosed with PCB153 and p,p'-DDE intraperitoneally for 5 consecutive days, and human thyroid follicular epithelial (Nthy-ori 3-1 cell line) were treated with PCB153 and p,p'-DDE for different time. Results showed that serum total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were decreased, whereas serum free triiodothyronine (FT3) and thyrotropin releasing hormone (TRH) were not changed. The PI3K/Akt and ERK pathways were activated in vivo and in vitro after the treatment with PCB153 and p,p'-DDE. Moreover, TH receptor beta 1 (TR beta 1) was elevated after the activation of the PI3K/Akt pathway and was depressed after the inhibition of the PI3K/Akt pathway; TRH receptor (TRHr) was increased after the activation of the ERK pathway and was decreased after the inhibition of the ERR pathway. Though TM receptor alpha 1 (TR alpha 1) level was increased in the hypothalamus, TR alpha 1 and TSHr were not influenced by the status of signaling pathways in in vitro study. Taken together, after exposure to PCB153 and p,p'-DDE, activated PI3K/Akt and ERR pathways disrupt the hypothalamic-pituitary-thyroid (HPT) axis via TR beta 1 and TRHr and then decrease TM levels, and that would be a potential mechanism by which PCBs and DDT disturb TH homeostasis. (c) 2014 Elsevier Ltd. All rights reserved.