Novel insights into di‑(2‑ethylhexyl)phthalate activation: Implications for the hypothalamus‑pituitary‑thyroid axis

Abstract

Di (2-ethylhexyl) phthalate (DEHP), an environmental pollutant, is widely used as a plasticizer and causes serious pollution in the ecological environment. As previously reported, exposure to DEHP may cause thyroid dysfunction of the hypothalamic-pituitary-thyroid (HPT) axis. However, the underlying role of DEHP remains to be elucidated. The present study performed intragastrical administration of DEHP (150, 300 and 600 mg/kg) once a day for 90 consecutive days. DEHP-stimulated oxidative stress increased the thyroid follicular cavity diameter and caused thyrocyte oedema. Furthermore, DEHP exposure altered mRNA and protein levels. Thus, DEHP may perturb TH homeostasis by affecting biosynthesis, biotransformation, bio-transportation, receptor levels and metabolism through disruption of the HPT axis and activation of the thyroid-stimulating hormone (TSH)/TSH receptor signaling pathway. These results identified the formerly unappreciated endocrine-disrupting activities of phthalates and the molecular mechanisms of DEHP-induced thyrotoxicity.

Insights into the Endocrine Disrupting Activity of Emerging Non-Phthalate Alternate Plasticizers against Thyroid Hormone Receptor: A Structural Perspective

“…In another study in rats [ 53 ], along with lowering of T4 and increasing of T3, disruption of the redox status, accumulation of malondialdehyde, and depletion of reduced glutathione was found together with histological changes in thyroid follicles [ 53 ]. Similar effects have been reported in several other studies [ 40 , 54 ]. In addition, the DEHP interactions with other receptors such as ERα, ERβ, and PPARγ are reported in detail [ 55 , 56 , 57 ].…”

“…Phthalate plasticizers, especially DEHP, have been shown to affect the hypothalamic-pituitary-thyroid axis and perturb the thyroid hormone homeostasis in epidemiological studies in humans [ 42 , 45 ] and in experimental laboratory animal and in vitro studies [ 40 , 46 , 47 ]. Alternative plasticizers are increasingly replacing phthalates in commercial and household products, such as food packaging, medical devices, cosmetic products, sealants, carpet, plastic tubing, fabrics, children’s toys, vinyl flooring, and several other applications [ 19 ].…”

“…In addition, the percentage overlap of amino acid residues interacting in the ligand-binding pocket of TRα was higher for DINCH (96%) compared to that of DEHP (78%); the percentage for ATBC (78%) was similar to that of DEHP. As mentioned above, DEHP is a known disruptor of thyroid function [ 40 , 42 , 45 , 47 ]. Therefore, on a preliminary basis, based on the comparative binding energy values and the number of amino acid interactions with TRα, DINCH and ATBC may be considered as potential thyroid disruptors.…”

“…In addition, thyroid hormones are essential components of a cross talk among brain, gonads, sex steroid hormones, and reproductive function—a function which is conserved in almost all vertebrates [ 39 ]. Thyroid dysfunction can be due to many factors, such as iodine deficiency and autoimmune diseases, age, disease, etc., [ 40 ]. However, environmental factors, including chemical pollutants, are increasingly regarded as contributing factors of thyroid dysfunction because of their effects on the hypothalamic-pituitary-axis and thyroid hormone secretion, and transport and signaling leading to metabolic problems, developmental abnormalities, reproductive outcomes, etc., [ 40 , 41 ].…”

“…Thyroid dysfunction can be due to many factors, such as iodine deficiency and autoimmune diseases, age, disease, etc., [ 40 ]. However, environmental factors, including chemical pollutants, are increasingly regarded as contributing factors of thyroid dysfunction because of their effects on the hypothalamic-pituitary-axis and thyroid hormone secretion, and transport and signaling leading to metabolic problems, developmental abnormalities, reproductive outcomes, etc., [ 40 , 41 ]. In this regard, limited reports for alternate plasticizers have also demonstrated their effects on thyroid function.…”