Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders

  1. Ingemar Pongratz
  1. Department for Biosciences and Nutrition, Karolinska Institute at Novum, S-141 57 Huddinge, Sweden
    1Functional Foods Forum and Department of Biochemistry and Food Chemistry, University of Turku, FI-20014 Turku, Finland
  1. (Correspondence should be addressed to J Rüegg; Email: joerue{at}ki.se)
  1. Figure 1

    Signaling pathways of AhR and NRs. (A) In the absence of ligand, AhR is located in the cytoplasm in a complex with chaperones and co-chaperones. Upon ligand binding, AhR translocates to the nucleus where it forms a complex with ARNT and co-activators, binds to xenobiotic response elements (XREs) on the DNA, and induces transcription of target genes. (B) In the absence of ligand, NRs reside either in the cytoplasm (I, e.g. glucocorticoid receptor) or in the nucleus (II, e.g. estrogen receptors), bound to chaperones and/or co-repressors. Ligand binding induces nuclear translocation and/or exchange of co-repressors to co-activators, binding to NR response elements (NREs), and gene transcription. (C) Some NRs like the thyroid receptors are bound to the DNA even in the absence of ligand, thereby repressing target gene expression. Ligand binding results in co-activator recruitment and subsequent activation of these genes.

  2. Figure 2

    Mechanisms of endocrine disruption. (A) Many endocrine disruptive chemicals (EDCs) have similar structures to NR ligands and can directly bind to NRs. They can either act as agonists and induce gene expression (I) or function as antagonists and inhibit the activity of the receptor (II). (B) EDCs can affect receptor function by I: inducing receptor degradation, II: inducing e.g., the AhR signaling pathway, which in turn sequesters common co-activators and ARNT away from the NRs, and III: by associating with the AhR that can bind to inhibitory XREs close to NREs. (C) Enzymes induced by activated AhR are not only involved in metabolism of xenobiotics but also in the catabolism of e.g., steroid hormones. Thus, induction of these enzymes can lead to reduced availability of endogenous hormones.

  3. Figure 3

    Summary of effects of EDCs on the metabolic system. Schematic showing simplified complex interactions between released adipokines, receptors, and EDCs in adipose tissue and pancreas as discussed in this article (for references, see text). ERs, estrogen receptors, GPR30, G protein-coupled estrogen receptor 1, PBDE, polybrominated diphenyl ether, TBT, tributyltin, RXR, retinoid X receptor, PPAR, peroxisome proliferator-activated receptor, POPs, persistent organic pollutants, BFRs, brominated flame retardants and MetS, metabolic syndrome.

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