Molecular Mechanisms of Endocrine Disruption in Estrogen Dependent Processes
Rajesh K. Naz in Endocrine Disruptors, 2004
For the most part, knowledge of the mechanisms of action of xenoestrogens follows progress in our understanding of how natural estrogens exert their effects at the cellular and molecular levels. Since the discovery of the estrogen receptor (ER) in the late 1950s, there has been an appreciation of how this ligand-activated transcription factor functions. Research in this area has led to an understanding of mechanisms not only at the molecular level but, indeed, down to the intramolecular level. Also, mechanisms for cross-talk between growth factor stimulated pathways and nuclear estrogen receptor have been discovered, and extra-nuclear actions of estrogens and estrogen receptors have been elucidated. It appears that these newly discovered mechanisms account for hitherto unexplained rapid, non-genomic actions of estrogen. In addition to these direct cellular pathways, xenobiotics can disrupt normal estrogen physiology by altering metabolism, leading to decreased levels of the endogenous hormone. Metabolism also plays a role in transforming weak xenoestrogens into ones that are more potent. Furthermore, metabolic products of natural hormones and xenoestrogens can be mutagenic. Thus, this review covers three areas of research on xenoestrogens: genomic action through ligand activation of ER; nongenomic mechanisms of action that is either ER-dependent or ER-independent; and the role of metabolism. Throughout, we attempt to link molecular mechanisms with toxicities associated with environmental endocrine disruptor chemicals.
Roles of membrane and nuclear estrogen receptors in spermatogenesis
C. Yan Cheng in Spermatogenesis, 2018
Transgenic mice have allowed normal E2 functions in males to be identified. This work has also shown that disrupted E2 signaling secondarily affects spermatogenesis, as described above. There is also extensive literature documenting effects of early DES exposure on male reproductive tract development in animal models and humans.27–29 Over the past two decades, extensive work has documented estrogenic effects of many man-made and natural chemicals in the environment. Given known effects of xenoestrogens such as DES on male reproduction and the critical role of estrogen signaling in male reproductive tracts, one important question is whether exposure of men and males of other species to estrogenic environmental chemicals significantly impacts male reproduction.
Regulation of Reproduction by Dopamine
Nira Ben-Jonathan in Dopamine, 2020
Xenoestrogens represent a subclass of EDCs that specifically mimic or interfere with the actions of estrogens. They encompass a wide array of compounds, some of which are naturally made by plants (phytoestrogens) or fungi (mycoestrogens), while others are synthetic chemicals (Table 10.2). The latter group includes pharmaceuticals, cosmetics, plastic additives, industrial solvents, pesticides, herbicides, and by-products of combustion and industrial manufacturing processes. The times at which exposure to xenoestrogens occurs (i.e., during fetal, neonatal, pubertal, or adult life) are of critical importance in the manifestation of their effects on expression of sexual traits.
Environmental toxin exposure in polycystic ovary syndrome women and possible ovarian neoplastic repercussion
Published in Current Medical Research and Opinion, 2020
Ilaria Soave, Tommaso Occhiali, Chiara Assorgi, Roberto Marci, Donatella Caserta
EDCs can cause epigenetic modifications, especially during pre- and peri-natal exposition158. These subtle epigenetic alterations accompany the individual throughout their life and can lead to carcinogenesis. The data available on epigenetic changes and ovarian cancer mainly show that ERs are involved, particularly downregulating suppressor receptors (ERβ), through gene promoter hypermethylation, resulting in silencing gene activity109. In the context of PCOS and EDC exposure, the shift toward ERα-only expression may be included in a pro-estrogenic milieu granted by abundant adipose tissue (PCOS), xenoestrogens (EDCs) and a spontaneous receptor selection already undertaken by the ovarian neoplasm striving to grow. Many xenoestrogens can only exert a modest estrogenic effect, but they have greater bioavailability (almost complete) when compared to endogenous estrogens. Moreover, xenoestrogens of different kinds can work synergically with one another and with endogenous estrogens159–162.
The role of xenobiotic-metabolizing enzymes in the placenta: a growing research field
Published in Expert Review of Clinical Pharmacology, 2020
Ricardo Blanco-Castañeda, Carlos Galaviz-Hernández, Paula C. S. Souto, Victor Vitorino Lima, Fernanda R. Giachini, Carlos Escudero, Alicia E Damiano, L. Jazel Barragán-Zúñiga, Gerardo Martínez-Aguilar, Martha Sosa-Macías
The exposition to xenobiotics during pregnancy is not only related to drug consumption/prescription, there are a lot of substances taken from either diet or environment that may have repercussion on the fetal development and wellbeing. One of these is bisphenol A (BPA), a xenoestrogen used as a monomer in the manufacture of plastic products [199]. BPA has been detected in measurable levels in umbilical cord serum both in mid-gestation and close to delivery [147,148]. In these studies, BPA and sulfated BPA levels in cord serum were higher than glucuronided BPA ones [147,148]. This could reflect the metabolic activity of conjugation in placenta, since several studies have reported higher sulfotransferase activity and lower UGT activity in the human placenta compared with liver [200–202]. Further, Liu et al. (2017) detected higher concentrations of conjugated BPA metabolites in cord serum than in paired maternal one, which could be the result of the placental and fetal metabolism at least at the end of pregnancy [148]. It has been found a limited placental permeability of BPA-glucuronide in a human placenta perfusion study [203], and a slower clearance of conjugated BPA in feto-placental compartment in animal studies [204,205]. The BPA exposure in-utero may provoke fewer parenchymal tissue development in endocrine pancreas, kidney, and uterus; triggering diabetogenic and atherogenic effects [199]. Besides, BPA exposure increases the risk of developing either attention-deficit/hyperactivity and/or autism spectrum disorders [206] and may be associated with adverse reproductive outcomes [207,208].
Bisphenol A modified DNA: A possible immunogenic stimulus for anti-DNA autoantibodies in systemic lupus erythematosus
Published in Autoimmunity, 2019
Homaidan T. Alhomaidan, Naila Rasheed, Salem Almatrafi, Fahad H. Al-Rashdi, Zafar Rasheed
Xenoestrogens have now been considered as environmental pollutants which are involved either directly or indirectly to change the hormonal mode of action and may cause damage to the nucleic acid [5]. Importantly, bisphenol A (BPA) is one of them, which is basically a synthetic compound widely used in manufacturing of polycarbonate plastic and also in various other daily use products such as epoxide resin [6,7]. Upon mixing in the diet, BPA caused several health hazards including DNA damaged and the damaged caused on the cell signalling molecules, which are directly or indirectly associated with the pathogenesis of several human disorders [6,8]. Not only have these, BPA is also known for its oestrogenic activity and excessive amount of BPA has also been reported in various human tissues [6–9]. Despite of these detorious implications of BPA and its associated causative effects in the pathogenesis of several human disorders, its status or contribution in SLE has never been investigated. In this study, we hypothesise that nucleic acids in SLE patients are continuously exposed to BPA, which may alter their structures and lead to the generation of unique epitopes that might be one of the factors responsible for the induction of autoimmunity against nucleic acid antigens in SLE. To test this hypothesis, we modified human DNA by commercially available BPA in-vitro and the specificity of SLE immunoglobin Gs (IgGs) towards BPA damaged DNA was evaluated.