Endocrine disruptors and the thyroid gland--a combined in vitro and in vivo analysis of potential new biomarkers.

Endocrine-disrupting chemicals (EDCs) became the focus of both public and scientific interest when defects in sexual behavior and reproductive ability of wild-living animals were ascribed to their steroid-like or anti-steroid androgenic properties (Colborn et al. 1993). In the aftermath, these observations were reproduced in many laboratory animal models. Whether human reproduction is also affected by the action of EDCs is currently a topic of controversial discussion (Safe 2004; Toppari 2002; Waring and Harris 2005). Furthermore, there is growing evidence that, in addition to the reproductive, other endocrine systems such as the hypothalamus–pituitary–thyroid (HPT) axis may be targets of endocrine disruption. In particular, poly-halogenated phenolic compounds such as polychlorinated biphenyls (PCBs) and poly-brominated diphenyl ethers (PBDEs), probably because of their structural resemblance to thyroid hormones (Cody et al. 1986), may cause disturbance of thyroid hormone homeostasis, hypothyroidism, thyroid hyperplasia, and neoplasia (Hagmar 2003; Siddiqi et al. 2003), and developmental defects of the central nervous system (CNS) in experimental animals and humans (Koopman-Esseboom et al. 1994; Meerts et al. 2004). It now has been shown that there may be multiple targets for interference by various EDCs with the complex regulatory network of thyroid hormone synthesis, metabolism, distribution, and action on the various levels of endocrine regulation and feedback control. These targets include thyrotropin receptor (Auf’mkolk et al. 1985a, 1985b; Santini et al. 2003); iodide uptake by the sodium iodide symporter (NIS; Schroder-van der Elst et al. 2004); type I 5′-deiodinase (5′DI) (Auf’mkolk et al. 1986; Ferreira et al. 2002; Schmutzler et al. 2004); transthyretin (TTR) (Kohrle et al. 1988; van den Berg 1990; Yamauchi et al. 2003); thyroid hormone receptor (TR) (Bogazzi et al. 2003; Moriyama et al. 2002); and thyroid hormone-dependent growth of pituitary cells (Ghisari and Bonefeld-Jorgensen 2005). In the brain, PCBs may disrupt normal differentiation regulated by thyroid hormones, although they do not act as thyroid hormone-like ligands (Zoeller 2005). Moreover, complex biological developmental programs controlled by thyroid hormones may be disturbed by EDC action such as metamorphosis in the amphibian Xenopus laevis (Kloas 2002). Yet, data on EDCs affecting the HPT axis are comparatively scarce. Within the CREDO (cluster of research into endocrine disruption in Europe) Cluster, which is part of the Sixth European Union framework program, the EURISKED (multi-organic risk assessment of selected endocrine disruptors) consortium worked on a group of projects assessing multiorganic effects of selected endocrine disruptors. These projects included a focus on the thyroid gland and its target organs. In this article we summarize the first results. Chosen for analysis was an environmentally and nutritionally relevant collection of substances suspected to have endocrine-disrupting activity because of their steroid-like or anti-steroid effects. These substances included genistein as well as glycitein and daidzein (isoflavones from soybean); resveratrol (phytoalexin from grapes); silymarin (flavonol–lignane mixture from the milk thistle); xanthohumol (XN; prenylated chalcone from hops, Humulus lupulus L.); 8-prenylnaringenin (8-PN; prenylated flavonone from hops); benzophenone-2, ben-zophenone-3, 4-methylbenzylidene camphor, and octyl-methoxycinnamate [BP2, BP3, OMC, 4-MBC, respectively; ultraviolet (UV) filters]; F21388 (synthetic, halogenated flavonoid); 4-nonylphenol (4-NP; e.g., emulgator); bisphenol A (BPA; building block for, e.g., polycarbonate plastics); dibutylphthalate (e.g., plasticizer); linuron and procymidon (pesticides); 5α-androstane-3β,17β-diol [adiol; proposed to be an endogenous ligand of estrogen receptor β (ER-β)] and 17β-estradiol benzoate (E2). We show that several of these substances also interfere with multiple targets at various levels of the HPT axis in a tissue-specific manner. These targets included weight and morphology of the thyroid gland, iodide uptake by the NIS, iodide organification by thyroid peroxidase (TPO), binding of the thyroid hormone thyroxine (T4) to TTR, the metabolism of thyroid hormones by deiodinases, and the action of the biologically active thyroid hormone triiodothyronine (T3) mediated by TRs functioning as ligand-dependent transcription factors.