Abstract
Di-(2-ethylhexyl)phthalate (DEHP) was a widely used chemical with human toxicity. Recent in vivo and in vitro studies suggested that DEHP-exposure may be associated with altered serum thyroid hormones (THs) levels, but the underlying molecular mechanisms were largely unknown. To explore the possible molecular mechanisms, 128 Wistar rats were dosed with DEHP by gavage at 0, 150, 300, and 600 mg/kg/day for 3 months (M) and 6 M, respectively. After exposure, expression of genes and proteins in the thyroid, pituitary, and hypothalamus tissues of rats were analyzed by Q-PCR and western blot, while the sera and urine samples were assayed by radioimmunoassay and ELISA. Results showed that serum THs levels were suppressed by DEHP on the whole. DEHP treatment influenced the levels of rats’ thyrotropin releasing hormone receptor (TRHr), Deiodinases 1 (D1), thyroid stimulating hormone beta (TSHβ), sodium iodide symporter (NIS), thyroid stimulating hormone receptor (TSHr), thyroperoxidase (TPO), thyroid transcription factor 1 (TTF-1), and thyroglobulin (TG) mRNA/protein expression in the hypothalamus-pituitary-thyroid (HPT) axis and decreased urine iodine. Taken together, observed findings indicate that DEHP could reduce thyroid hormones via disturbing the HPT axis, and the activated TSH/TSHR pathway is required to regulate thyroid function via altering TRHr, TSHβ, NIS, TSHr, TPO, TTF-1 and TG mRNA/protein expression of the HPT axis.
Highlights
Thyroid diseases are endocrine disorders of the body [1]
DEHP-treated higher during entire treatment period, starting from the first week, and gradually stabilized after weeks. This suggest that starting from the first week, and gradually stabilized after 12 weeks (Figure 1). This suggest the that the body weights of the rats should be sensitive to the toxicity induced by long-term exposure to DEHP
Our results demonstrated that DEHP intervention could prompt the upregulation of TTf-1 and thyroid stimulating hormone receptor (TSHr) and cause an increase in thyroid stimulating hormone (TSH)/TSHR signaling, which can increase the expression of thyroid tissue NIS and the secretion of thyroid hormones
Summary
Thyroid diseases are endocrine disorders of the body [1]. In addition to genetic factors, increasing evidence indicates that environmental factors, such as endocrine-disrupting chemical pollutants affect thyroid hormone levels, causing changes of thyroid morphology, autoimmune thyroid disease, and thyroid tumor, etc. [2,3,4,5] Among these chemicals, the ubiquitous plasticizer di(2-ethylhexyl)phthalate (DEHP) has been reported to induce pathologic alterations in the thyroid in rats [6]. DEHP is considered as antiandrogenic endocrine disruptors because of its possible effect on animal gonads and reproduction [8,9]. Very few studies focused on the thyroid-disrupting effects of DEHP [10,11]. A recent in vitro study reported that DEHP
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