Mechanisms of endocrine disruption through nuclear receptors and related pathways

Abstract

Endocrine-disrupting chemicals (EDCs) are a broad class of molecules present in our environment that are suspected to cause adverse effects in the endocrine system by interfering with the synthesis, transport, degradation or action of endogenous hormones. Humans are generally exposed to low doses of pollutants, and current researches aim at deciphering the mechanisms accounting for the health impact of EDCs at environmental concentrations. Here, we review different mechanisms through which EDCs might alter hormonal functions by interfering with the nuclear receptors and related pathways, including extranuclear signalling by membrane-bound receptors mediating rapid nongenomic responses, and the aryl hydrocarbon receptor (AhR).

Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors

“…AHR is a ligand-activated transcription factor that can bind over 400 different endogenous and exogenous compounds, including several endocrine disrupting chemicals and environmental contaminants (17)(18)(19). AHR activation leads to the transactivation of genes encoding phase I and II xenobiotics metabolizing enzymes, thus representing a key factor of the intracellular detoxification systems (20).…”

Predicting Potential Endocrine Disrupting Chemicals Binding to Estrogen Receptor α (ERα) Using a Pipeline Combining Structure-Based and Ligand-Based in Silico Methods

“…For the docking procedure, the structures were directly downloaded from the NR-DBIND database [ 64 ] since they are already enumerated, annotated, and cleaned. Format conversion from PDB to the appropriate docking format was done accordingly to the requirements of the software, i.e., PDB were converted into mol2 format using the software chimera [ 70 ], into pdbqt with the prepare_receptor4.py python script available with the MGLTool [ 18 ]. In order to generate the structure-based pharmacophores, structures were directly downloaded from the RCSB website [ 71 ] via the LigandScout graphical interface.…”

“…In the indirect mechanism, EDCs affect other transcription factors or hormone metabolism through interaction with components of the hormone signaling pathway, stimulation or inhibition of endogenous hormones biosynthesis, binding to circulating hormone-binding protein, stimulation or inhibition of hormone-binding protein synthesis or degradation, stimulation or inhibition of hormone receptor expression [ 16 , 17 ]. Other potential targets of EDCs include the membrane-associated NRs and the G protein-coupled receptor GPR30/G protein-coupled estrogen receptor [ 18 ]. Experimental campaigns are conducted to identify potential EDCs and better understand their mechanism of action.…”

Nuclear Receptors and Development of Marine Invertebrates

“…Unfortunately, their ligand-dependent activity also makes them susceptible to a class of environmental pollutants defined as endocrine disrupting chemicals (EDCs), exogenous substances that alter the function of the endocrine system [ 41 , 42 ]. EDCs mimic the structure of endogenous NR ligands and can act as either agonists or antagonists of NR signaling pathways [ 42 , 43 ]. EDC exposure thus adversely affects the adult endocrine system and impacts developmental processes, leading to pathophysiological and pathological conditions, such as neurodevelopmental disorders and developmental dysfunction/arrest in all vertebrate taxa [ 42 , 43 ].…”

“…EDCs mimic the structure of endogenous NR ligands and can act as either agonists or antagonists of NR signaling pathways [ 42 , 43 ]. EDC exposure thus adversely affects the adult endocrine system and impacts developmental processes, leading to pathophysiological and pathological conditions, such as neurodevelopmental disorders and developmental dysfunction/arrest in all vertebrate taxa [ 42 , 43 ]. It was initially thought that invertebrates are not affected by EDCs as they were said to lack an endocrine system similar to that of vertebrates [ 44 , 45 ].…”