Mechanism of the serum thyroid hormone lowering effect of perfluoro‐n‐decanoic acid (PFDA) in rats

Abstract

The mechanism and consequences of the serum thyroid hormone lowering effect of perfluorodecanoic acid (PFDA) were examined. Thyroid and pituitary gland functions in PFDA-treated rats were assessed by measuring radioiodine uptake from the circulation and the ability of the thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3) in response to thyrotropin-releasing hormone (TRH) stimulation. Serum levels of reverse triiodothyronine (rT3) were measured to test for possible conversion of T4 to a biologically inactive product and the displacement of radiolabeled T4 from rat albumin in vitro by PFDA was examined. Finally, changes in activity of the thyroid hormone-sensitive liver enzymes glycerophosphate dehydrogenase (GPD) and malic enzyme (ME) in response to PFDA were analyzed. Functional activities of the thyroid and/or pituitary glands appear to be somewhat depressed by PFDA treatment. There was no increased conversion of T4 to rT3. PFDA displaced radiolabeled T4 from rat albumin with an affinity similar to thyroxine. The activities of both GPD and ME were significantly increased in livers from PFDA-treated rats. These results suggest that decreased serum levels of thyroid hormones may be due to (1) reduced responsiveness of the thyroid and/or pituitary glands to hormonal stimulation and (2) a displacement of circulating hormones from plasma protein binding sites by PFDA. Increased activity of the liver enzymes GPD and ME does not reflect the reduction in circulating thyroid hormones and indicates that PFDA-treated rats are apparently not functionally hypothyroid at the tissue level.

Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

“…There are several different TH physiological steps PFCs may interfere with, such as TH biosynthesis, transport, metabolism, or action on receptor pathways in target cells (Boas et al 2006). Earlier mechanistic studies suggest that PFCs might reduce serum THs levels by reducing the responsiveness of the hypothalamuspituitary-thyroid axis or by displacing circulating THs from the transport proteins such as transthyretin and albumin (Gutshall et al 1989;Chen and Guo 2009;Weiss et al 2009). Several other studies have indicated that increased conjugation of T4 in the liver by the hepatic enzyme uridine diphospho glucuronosyltransferase and increased conversion of T4 to T3 by type 1 deiodinase might be partly responsible for the effects involved in PFOS-induced hypothyroxinemia in rats (Yu et al 2009a, b).…”

Environmental Thyroid Disruptors and Human Endocrine Health

“…Depression of serum T4 and T3 in PFOS-exposed rats has been reported (Lau et al, 2003;Luebker et al, 2005;Seacat et al, 2003), without the concomitant increase in TSH that would be expected through feedback stimulation. Earlier mechanistic studies of structurally related perfluorodecanoic acid showed that it could reduce serum TH levels apparently by reducing the responsiveness of the hypothalamus-pituitary-thyroid axis and by displacing circulating THs from their plasma protein-binding sites (Gutshall et al, 1989). Although circulating hormone levels were depressed, the activities of TH-sensitive liver enzymes were elevated, suggesting that functional hypothyroidism was not occurring.…”

Perfluorooctane Sulfonate and Perfluorooctanoic Acid in Surgical Thyroid Specimens of Patients with Thyroid Diseases

“…The potential effects of PFAS as thyroid function disruptors were mainly investigated in the rat (12,(21)(22)(23)(24)(25)(26). Several studies (12,(21)(22)(23)(24)(25)(26) demonstrated a decrease in the serum levels of total thyroxine (T4) and triiodothyronine (T3) in PFOS-exposed rats, with no corresponding elevation of thyroid-stimulating hormone (TSH) through feedback stimulation of the hypothalamic-pituitary thyroid axis. Indeed, serum free T4 (FT4) levels in PFOS-treated rats were found to be comparable to those of controls (22).…”