Gestational Exposure to Di(2-ethylhexyl)phthalate Modifies the Expression Pattern of Genes Controlling Thyroid Hormone Biosynthesis in Puberal Rat Progeny

Abstract

Di(2-ethylhexyl) phthalate (DEHP), a plasticizer, is known to disrupt thyroid functions but the underlying molecular mechanism remains obscure. The present study was conducted testing the hypothesis that gestational exposure to DEHP would modify the expression of specific genes controlling biosynthesis and action of thyroid hormones in the male progeny at puberal age. Pregnant rats were administered with DEHP [1, 10 and 100 mg (in olive oil)/Kg b.wt./day] from embryonic day 9 to 21 through oral route. The pups were sacrificed on post-natal day 60. Enzyme Immuno-Assay (EIA) revealed a dose-dependent decrease in serum 3,5,3’ triiodothyronine (T 3 ) and L-thyroxine (T 4 ) titres in DEHP-treated rats. Real-time RT-PCR and western blot analyses of thyroidal genes revealed decreased expression level of sodium/iodide symporter (Nis) and thyroid hormone receptor α (Trα) , whereas the expression of thyroid stimulating hormone receptor (Tshr) , thyroid hormone receptor β (Trβ) and pendrin (Pds) increased. While western blot detection showed decreased expression level of thyroperoxidase (Tpo) , RTPCR data pointed out augmented expression. Western blot detection of transcriptional factors showed decreased expression levels of fork-headbox e1 (Foxe1) and hematopoietically expressed homeobox (Hhex), whereas thyroid transcription factor-1 (Ttf-1) and paired-box domain 8 (Pax8) increased. Our study demonstrates, for the first time, that gestational exposure to DEHP affects the expression of genes controlling thyroid hormone synthesis in puberal rat progeny, and the hypothyroid state in these rats may be linked to decreased expression of Nis, Tpo , Foxe1 and Hhex.