DEHP reduces thyroid hormones via interacting with hormone synthesis-related proteins, deiodinases, transthyretin, receptors, and hepatic enzymes in rats

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is used extensively in many personal care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. Limited studies suggest that exposure to DEHP may be associated with altered thyroid function, but detailed mechanisms are unclear. In order to elucidate potential mechanisms by which DEHP disturbs thyroid hormone homeostasis, Sprague-Dawley (SD) rats were dosed with DEHP by gavage at 0, 250, 500, and 750 mg/kg/day for 30 days and sacrificed within 24 h after the last dose. Gene expressions of thyroid hormone receptors, deiodinases, transthyretin, and hepatic enzymes were measured by RT-PCR; protein levels of transthyretin were also analyzed by Western blot. Results showed that DEHP caused histological changes in the thyroid and follicular epithelial cell hypertrophy and hyperplasia were observed. DEHP significantly reduced thyroid hormones (T3, T4) and thyrotropin releasing hormone (TRH) levels, whereas thyroid stimulating hormone (TSH) was not affected. After exposure to DEHP, biosynthesis of thyroid hormones was suppressed, and sodium iodide symporter (NIS) and thyroid peroxidase (TPO) levels were significantly reduced. Additionally, levels of deiodinases and transthyretin were also affected. TSH receptor (TSHr) level was downregulated, while TRH receptor (TRHr) level was upregulated. Metabolism of thyroid hormones was accelerated due to elevated gene expression of hepatic enzymes (UDPGTs and CYP2B1) by DEHP. Taken together, observed findings indicate that DEHP could reduce thyroid hormones through influencing biosynthesis, biotransformation, biotransport, receptor levels, and metabolism of thyroid hormones.

Correction and Republication: Effect of Di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-thyroid axis in adolescent rat

“…In the hypothalamus, the lowered circulating levels of T4 and T3 in the DEHP-treated rats may primarily be the consequence of thyroid toxicity, resulting in the increased TRH expression. These results, DEHP down-regulated the levels of THs and increased TRH expression in rats, are consistent with a previous study [20]. Another report that involved animal studies described that decreased the levels of serum T4 with prolonged DEHP exposure [21].…”

“…Some studies have observed an inverse association between MEHP urinary concentrations and free T4 and T3 serum levels in men and similar negative correlations have been found in pregnant women [18,19]. In animal studies, rats and fishes fed with diets contaminated with DEHP were found to have thyroid alterations and lower plasma T4 concentrations [20,21]. But the detailed mechanisms that are involved in this process are unclear.…”

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

“…However, no significant changes in D1 and D2 protein levels in the liver and hypothalamus were observed after triclosan exposure. Similar results were also found in other studies [22]. However, the study reported that D2 expression was downregulated in gargarizans embryos that were exposed to 60 and 150 µg/L triclosan [23].…”

Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy

“…Additionally, limited in vitro studies have shown that phthalates may have thyroid hormone receptor antagonist activity (Shen et al 2009; Sugiyama et al 2005). Several studies have also demonstrated potential phthalate actions on thyroid hormone biosynthesis and biotransport (Breous et al 2005; Ishihara et al 2003; Liu et al 2015; Wenzel et al 2005; Zhai et al 2014). …”

“…Animal and in vitro studies suggest that phthalates may be capable of disrupting circulating thyroid hormone levels, although the exact biological mechanism(s) of action remain unclear (Boas et al 2012; Liu et al 2015; Zhai et al 2014). Additionally, a limited number of epidemiological studies have shown that phthalates may alter thyroid hormone levels in adult men and nonpregnant women as well as children (Boas et al 2010; Meeker et al 2007; Meeker and Ferguson 2011).…”