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.

P38/TRHr-Dependent Regulation of TPO in Thyroid Cells Contributes to the Hypothyroidism of Triclosan-Treated Rats

“…The results indicate that TRHr is modulated by the p38 pathway in the present study. It is shown that abnormal expressions of hormone receptors would interfere with the normal hormone signal transduction in the HPT axis and subsequently disturb TH homeostasis [4]. In our current study, T4 and T3 levels in plasma were reduced and the magnitude of observed hypothyroidism is consistent with previous studies in rats [5, 7], whereas TSH and TRH were not increased as expected to compensate decrements in THs, suggesting impairments of the negative feedback system of the HPT axis.…”

“…Even small changes or an imbalance in thyroid homeostasis may adversely affect human health. Especially for children, the disturbance of thyroid homeostasis during nervous system development would lead to irreversible mental retardation [4]. Therefore, disturbing factors of thyroid homeostasis are of great concern.…”

Longitudinal assessment of prenatal phthalate exposure on serum and cord thyroid hormones homeostasis during pregnancy - Tainan birth cohort study (TBCS)

“…Furthermore, phthalates can affect thyroid hormones not only through biosynthesis and biotransport but also through biotransformation and metabolism (Liu et al 2015). Recent animal experiments have suggested that DEHP can influence thyroid hormones by disturbing the hypothalamus-pituitary-thyroid axis (Dong et al 2017) and activating the Ras-Aktthyrotropin-releasing hormone receptor pathway and inducing hepatic enzymes (Ye et al 2017).…”

Toxic Effects of Di-2-ethylhexyl Phthalate: An Overview

“…Studies on elderly people suggest that insulin resistance is increased after DEHP exposure due to an imbalance between oxidative stress production and antioxidant defenses, as DEHP is known to induce oxidative stress, which might also lead to insulin resistance in elderly people [ 28 ]. DEHP can disturb thyroid hormone homeostasis and reduce TH levels [triiodothyronine (T3), thyroxine (T4), and thyrotropin-releasing hormone (TRH) can be reduced] by activating the Ras/Akt/TRHr pathway and affect hepatic enzymes that play vital roles in thyroid-disrupting effects [ 29 ].…”