Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo

Abstract

Previous results in experimental systems have suggested that hydroxylated PCBs may decrease thyroid hormone levels through associative interaction with transthyretin. In the present paper it was investigated whether this property was also shared by various industrial chemicals, mainly pesticides. In total, 65 compounds from 12 chemical groups were analyzed for direct interference with the T4 binding site of transthyretin using a competitive binding assay. Sixty per cent of the compounds were competitive at a concentration level of 100 microM. Relatively strong interactions were observed by several chlorophenols, chlorophenoxy acids and nitrophenols, as well as by individual compounds such as hexachlorobenzene, dicofol, bromoxynil and tetrachlorohydroquinone. Examples from these chemical groups, e.g. pentachlorophenol, 2,4-dichlorophenoxybutyric acid, dinoseb and bromoxynil, also reduced plasma TT4 levels in rats. In addition, bromoxynil decreased plasma TT3 levels. The results suggest the existence of a number of halogenated industrial chemicals with a potential for lowering plasma thyroid hormone levels through interference with hormone transport carriers.

A model of the development of the brain as a construct of the thyroid system.

“…In young adult rats, RA is displaced from its serum transport protein, retinol binding protein, and the transthyretin-retinol binding protein complex by PCB 77 (112). Similar effects by PCB 77 on binding to transport proteins and serum levels of T 4 have been reported (99,105). Subchronic exposure to 2 , 2´, 3 , 3´, 4 , 4´-h e x a c h l o r o b i p h e n y l decreased kidney and liver levels of vitamin A and significantly lowered frontal cortex dopamine levels in rats dosed for 4 weeks after weaning (113).…”

“…Chemical exposure can also lead to a decrease in serum protein-bound iodide levels, perhaps largely due to inhibition of the thyroid peroxidase enzyme, which disrupts the normal production of thyroid hormone (96)(97)(98). The displacement of T 4 /T 3 from the transport proteins (TBG, transthyretin, and albumin) may result in decreased ability of thyroid hormone to reach its target tissue and may facilitate the transport of the chemicals into the fetus (92,99). Chemical disruption of the T 4 /T 3 metabolism can influence deiodinase, glucuronidase, and sulfatase activity, and may ultimately result in increased biliary elimination of T 4 /T 3 .…”

Environmental Thyroid Disruptors and Human Endocrine Health

“…thyroid binding globulin, transthyretin and albumin) may result in decreased ability of THs to reach its target tissue and then, may facilitate the transport of the chemicals into the fetus (Brouwer et al, 1998;Van den Berg et al, 1991). Boas M et al European Journal of Endocrinology 2006;154:599-611).…”

“…Inhibition of deiodinase enzymes can result as decrease in T3 available to elicit thyroid action at tissue level (Maiti & Kar, 1997). Conversely, deiodinase activity may increase in response to TD exposure, either as direct effect or in response to increased clearance of T4/T3 by the chemical stimulation of glucuronidase or sulfatase enzymes (Spear et al, 1990;van Raaij et al, 1993). Brucker-Davis (Brucker-Davis, 1998) suggested that such increases in the metabolism and in the clearance of T3 could result in goiter as the thyroid gland increases production to maintain proper TH levels.…”

Influence of pesticides on male fertility

“…Pesticides like chlorophenols, chlorophenoxy acids, organochlorines, and quinones have been shown to alter thyroid gland function and to reduce circulating thyroid hormone levels (60,61). A reduction of thyroid hormone levels can compromise the catalytic activity of hepatic cytochrome P450 monooxygenases and result in an altered hepatic androgen metabolism (62).…”