Halogenated Phenolic Contaminants Inhibit the In Vitro Activity of the Thyroid-Regulating Deiodinases in Human Liver

Halogenated contaminants, particularly brominated flame retardants, disrupt circulating levels of thyroid hormones (THs) and potentially affecting growth and development. Disruption may be mediated by impacts on deiodinase (DI) activity, which regulate the levels of active hormones available to bind to nuclear receptors. The goal of this study was to develop a mass spectrometry-based method for measuring the activity of DI in human liver microsomes and to examine the effect of halogenated phenolic contaminants on DI activity. Thyroxine (T4) and reverse triiodothyronine (rT3) deiodination kinetics were measured by incubating pooled human liver microsomes with T4 or rT3 and monitoring the production of T3, rT3, 3,3′-diiodothyronine, and 3-monoiodothyronine by liquid chromatography tandem mass spectrometry. Using this method, the authors examined the effects of several halogenated contaminants, including 2,2′,4,4′,5-pentabromodiphenyl ether (BDE 99),several hydroxylated polybrominated di-Ph ethers (OH-BDEs), tribromophenol, tetrabromobisphenol A, and triclosan, on DI activity. The Michaelis constant (Km) of rT3 and T4 deiodination were determined to be 3.2 and 17.3 íM. The Vmax was 160 and 2.8 pmol/min mg protein, respectively. All studied contaminants inhibited DI activity in a dose response manner, with the exception of BDE 99 and two OH-BDEs.5′-Hydroxy 2,2′,4,4′,5-pentabromodiphenyl ether was found to be the most potent inhibitor of DI activity, and phenolic structures containing iodine were generally more potent inhibitors of DI activity relative to brominated, chlorinated, and fluorinated analogues. This study suggests that some halogenated phenolics, including current use compounds such as plastic monomers, flame retardants, and their metabolites, may disrupt TH homeostasis through the inhibition of DI activity in vivo.

Authors: Butt, Craig M.; Wang, Dongli; Stapleton, Heather M. ;Full Source: Toxicological Sciences [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][online computer file] 2011, 124(2), 339-347 (Eng) ;