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Endocrine Disruptors
Published in Brian D. Fath, Sven E. Jørgensen, Megan Cole, Managing Global Resources and Universal Processes, 2020
The first characterized mechanism of action of EDCs is to act directly as ligands to steroid hormone nuclear receptors (NRs), in particular, estrogen, androgen, and thyroid NRs. Nuclear receptors are a class of proteins found within cells. In response to the presence of hormones, these receptors work in concert with other proteins to regulate the expression of specific genes by a conformation change. Schematically, NRs may be classified into four classes according to their dimerization and DNA-binding proprieties.[10]
Reprotoxic and Endocrine Substances
Published in Małgorzata Pośniak, Emerging Chemical Risks in the Work Environment, 2020
Katarzyna Miranowicz-Dzierżawska
Nuclear receptors create a group of intracellular, structurally homologous proteins, which regulate the transcription of genes responsible for proper cell functioning. A number of these proteins require activation to bind small-molecule lipophilic ligands (e.g. steroid, retinoic acid, thyroxine), freely diffusing into the cell. Nuclear receptors after ligand binding move from the cytoplasm to the cell nucleus, where they act as transcription factors for a given receptor. Binding to a particular nucleotide sequence, they can activate or inhibit gene transcription processes. Active nuclear receptors can also indirectly inhibit gene transcription through interaction with other transcription factors [Kopij and Rapak 2008].
Stem Cell Engineering Using Bioactive Molecules for Bone-Regenerative Medicine
Published in Gilson Khang, Handbook of Intelligent Scaffolds for Tissue Engineering and Regenerative Medicine, 2017
A small molecule that could serve as an alternative to osteoinductive biological factors like BMPs is melatonin (N-acetyl-5-methoxytryptamine). Physiologically, melatonin is a hormone released from the pineal gland at the base of the brain, and its levels are regulated by environmental light.96 In recent years the role of melatonin in bone regeneration has been investigated.97–99 Roth et al. found that melatonin at concentrations as low as 50 nM could induce osteogenic differentiation of preosteoblasts, MC3T3-E1, and osteosarcoma 17/2.8 cell lines at 12 days. Roth et al. also reported abrogation of the osteogenic activity of melatonin by blocking the nuclear retinoid Z receptors (RZR-α 1 and RZR-β). Nuclear receptors are a class of proteins that are capable of binding to DNA through ligand-binding activation. Hence they act as transcription factors in a ligand-dependent manner. These receptors have melatonin binding sites and bind several osteogenic genes, including ALP and BSP.100 Postmenopausal osteoporosis is an age-related bone disorder in which decreased melatonin levels may be an important contributory factor. In studies of ovariectomized rats, lowered serum levels of melatonin at death correlated with increased biochemical markers of bone resorption.101 Additional study results indicated that melatonin could have positive effects on bone formation in ovariectomized mice with adequate estradiol levels, thus supporting the positive role of melatonin in bone formation and its potential as a therapeutic agent.101,102 Koyama et al. also reported that systemic administration of melatonin promoted bone health by reducing resorptive osteoclast activity through a dose-dependent benefit.103
Environmental chemicals and adverse pregnancy outcomes: Placenta as a target and possible driver of pre- and postnatal effects
Published in Critical Reviews in Environmental Science and Technology, 2023
Jing Li, Adrian Covaci, Da Chen
In vitro, in vivo, and epidemiological studies have suggested that selected environmental chemicals could affect the transcriptional activities of nuclear receptors in the placenta, thereby disrupting the placental development and functions. Nuclear receptors are a superfamily of ligand-regulated transcription factors that are important regulators for a wide variety of biological processes, such as metabolism, differentiation, apoptosis, as well as cell cycle progression (Sever & Glass, 2013). The interference of transcriptional activities of nuclear receptors by small, lipophilic molecules, such as environmental chemicals, and subsequent functional alternations have been related to various metabolic disorders, and inflammatory disease (Sever & Glass, 2013).
Computational prediction models for assessing endocrine disrupting potential of chemicals
Published in Journal of Environmental Science and Health, Part C, 2018
Sugunadevi Sakkiah, Wenjing Guo, Bohu Pan, Rebecca Kusko, Weida Tong, Huixiao Hong
EDCs, mimic the natural hormones, are exogenous substances interacting with various proteins in the endocrine system and alter endocrine functions including metabolism, development, secretion, reproductive, and transport.1 Hormones bind with the proteins to produce signals which are essential to activate or depress the physiological functions of the protein. EDCs disrupt the endocrine system through various mechanisms by binding with other normally functioning proteins causing2–4: (i) elevation or depression of signal strength; (ii) inhibition of signal; or (iii) alteration of hormone synthesis and metabolism. Most EDCs interact with nuclear receptors. Nuclear receptors are ligand-dependent transcriptional factors that play a major role in reproduction, homeostatic, metabolism, transport, and more. The nuclear receptor superfamily is divided into three classes5,6: (i) steroid receptor family including glucocorticoid receptor, androgen receptor (AR), estrogen receptor (ER), and progesterone receptor; (ii) thyroid/retinoid family including vitamin D receptor, peroxisome proliferation-activated receptor, thyroid receptor and retinoic acid receptor; and (iii) nuclear receptors. A nuclear receptor is a single polypeptide chain that contains three major domains: (i) amino terminal domain, (ii) highly conserved DNA binding domain, and (iii) C-terminal or ligand binding domain.7 The DNA binding domain is a highly conserved domain and contains a DNA binding-specific motif that helps the formation of homo- or hetero-dimerization.8 The linker region, present between the DNA binding domain and Ligand binding domain, is a flexible region and contains a nuclear localization signal. The LBD contains a transcriptional activation function 2 and facilitates interaction with the chromatin remodeling and transcriptional activation functions.
Xenobiotic metabolism and transport in Caenorhabditis elegans
Published in Journal of Toxicology and Environmental Health, Part B, 2021
Jessica H. Hartman, Samuel J. Widmayer, Christina M. Bergemann, Dillon E. King, Katherine S. Morton, Riccardo F. Romersi, Laura E. Jameson, Maxwell C. K. Leung, Erik C. Andersen, Stefan Taubert, Joel N. Meyer
Although vertebrate endocrine-related receptors are not generally thought of as major regulators of xenobiotic transport and metabolism, a digression on the potential for C. elegans to be used as a model organism for endocrine disruption is warranted. Endocrine disruptors are molecules that interfere with an organism’s intrinsic endocrine systems, which often act by targeting NHRs that regulate endogenous endocrine signals such as estrogen and mammalian NHR estrogen receptor. As such, endocrine disruptors have the potential to disturb the normal physiology and development of an organism. Endocrine disruption is a major concern in environmental toxicology with great relevance for human and wildlife health (Hotchkiss et al. 2008; National Academies of Sciences, Engineering, and Medicine 2017). There are some investigations reporting results of using C. elegans to study endocrine disruption, and clearly chemicals that are agonists of vertebrate endocrine receptors exert effects in C. elegans (Cao et al. 2020; Chen et al. 2019; Custodia et al. 2001; Fischer et al. 2012; Jeong, Kim, and Choi 2019; Mimoto et al. 2007). However, it needs to be emphasized that conclusions regarding the mechanism by which these effects are mediated be interpreted with great caution. It is far from clear that responses result from presumed receptor agonist or antagonist binding to a worm homolog of the vertebrate receptor. As noted above, sequence comparisons suggest that the NR1I group of classical detoxification NHRs is apparently absent in C. elegans. In addition, the families encoding the classical mammalian steroid/thyroid receptors: NR1A thyroid hormone receptors (TRs), NR3A estrogen receptors (ERs), and NR3C 3-ketosteroid receptors including glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR) are also absent (Nuclear Receptors Nomenclature, Committee 1999; Taubert, Ward, and Yamamoto 2011; Weikum, Liu, and Ortlund 2018). Accordingly, to our knowledge, no broad evidence base supports the concept that any C. elegans NHR is (in)activated by (ant)agonists of any of these vertebrate NHR, which would render it and the nematode susceptible to endocrine disruption by the presumed pathway, such as by a xenoestrogens acting on a worm “estrogen receptor.” Therefore, although it is not impossible that functional homologs of vertebrate endocrine receptors exist, one can argue that the burden of proof is on demonstrating such functional homology, which needs to be tested rigorously. On the other hand, it is entirely possible that C. elegans may serve as a useful model for the influence of NHR-activating xenobiotics in invertebrates (Hoss and Weltje 2007). Although evidence for such events is currently also lacking, one cannot rule out that endocrine disruption of DAF-12 driven developmental pathways may occur.