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.

A single ip injection of perfluoro-n-decanoic acid (PFDA) to male Wistar rats resulted in an initially rapid, then gradual decrease in food consumption and a parallel loss of body weight. Body temperatures and resting heart rates were significantly depressed by PFDA treatment. As early as 12 h following a single dose of PFDA, serum thyroxine (T4) levels were significantly reduced and remained depressed throughout the 8 day study. Serum triiodothyronine (T3) was reduced by 35% 12 h following PFDA treatment and remained at that level throughout the study. These preliminary data suggest that an action on the thyroid axis may be an early primary response to PFDA and that some of the observed subsequent effects may in part be secondary to the change in thyroid hormone levels.

The toxic responses of rats to a single dose of perfluorodecanoic acid (PFDA) include reduced food consumption, severe body weight loss ("wasting syndrome"), and hypothermia. Recent studies have suggested that some of these effects may be due to alterations of basic metabolic processes in animals treated with PFDA. In order to test this hypothesis the effects of PFDA on respiratory activity of isolated rat liver mitochondria were examined. PFDA concentrations up to 87.5 micrograms/ml produced a linear increase in oxygen consumption during state 4 (nonphosphorylating) respiration. This suggested uncoupling of electron transport and oxidative phosphorylation was supported by the observation that PFDA released mitochondrial state 3 respiration from inhibition by oligomycin and stimulated latent ATPase activity. Concentrations of PFDA greater than 87.5 micrograms/ml produced progressively less increase in state 4 oxygen consumption, and a single high concentrations (150 micrograms/ml) completely inhibited state 3 respiration and prevented the uncoupling effect of 2,4-dinitrophenol. These observations suggest that in addition to uncoupling electron transport and oxidative phosphorylation PFDA may affect other energy-transducing functions of liver mitochondria such as inhibiting electron transport. These effects on mitochondrial respiration may help to explain the "wasting syndrome" characteristic of PFDA toxicity.

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