Endocrine disruption through membrane estrogen receptors and novel pathways leading to rapid toxicological and epigenetic effects

Abstract

Estrogen binding to estrogen receptors (ESR) triggers signaling cascades within cells. Historically, a major emphasis has been characterizing estrogen-induced genomic actions resulting from binding to nuclear estrogen receptor 1 (nESR1). However, recent evidence indicates the first receptors estrogens encounter as they enter a cell, membrane ESR1 (mESR1), also play crucial roles. Membrane and nuclear ESR are derived from the same transcripts but the former are directed to the membrane via palmitoylation. Binding and activation of mESR1 leads to rapid fluctuations in cAMP and Ca +2 and stimulation of protein kinase pathways. Endocrine disrupting chemicals (EDC) that mimic 17β-estradiol can signal through mESR1 and elicit non-genomic effects. Most current EDC studies have focused on genomic actions via nESR1. However, increasing number of studies have begun to examine potential EDC effects mediated through mESR1, and some EDC might have higher potency for signaling through mESR1 than nESR1. The notion that such chemicals might also affect mESR1 signaling via palmitoylation and depalmitoylation pathways has also begun to gain currency. Recent development of transgenic mice that lack either mESR1 or nESR1, while retaining functional ESR1 in the other compartment, will allow more precise in vivo approaches to determine EDC effects through nESR1 and/or mESR1. It is increasingly becoming apparent in this quickly evolving field that EDC directly affect mESR and estrogen signaling, but such chemicals can also affect proportion of ESR reaching the membrane.Future E D C studies should be designed to consider the full range of effects through mESR alone and in combination with nESR.

The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease

“…Xenoestrogens (XEs) mimic or block the synthesis, metabolism, and transport of normal endogenous hormones, disturbing normal endocrine function [ 45 ]. Xenoestrogens exert their effects through estrogen receptor signaling, resulting in epigenetic changes [ 46 ]. Multiple reviews on the environmental chemical(s) have suggested that the exposure to these chemicals depletes the ovarian reserve, leading to impaired functioning of the ovary and a shortening of the reproductive lifespan [ 47 , 48 ] and early menopause [ 49 ].…”

Mechanisms of endocrine disruption through nuclear receptors and related pathways

“…2). Indeed, it is now well accepted that a small amount of NRs (a few percent) are positioned at the membrane (mbNRs) as previously shown for ER and , and for many other NRs such as the progesterone, the androgen, the thyroid hormone or the vitamin D receptors [23][24][25][26]. As for ER, the receptor is directed to the plasma membrane/caveloae via palmytoylation of an internal cysteine residue (C447) that is located in the LBD.…”

Occurrence of selected endocrine disrupting compounds in the eastern cape province of South Africa

“…In antagonistic action, EDCs may modify the binding site of a normal hormone by binding to hormonal receptors but not activate it (Nguyen 2018). In this type, the normal hormone is prevented from binding to its site since an EDC has occupied it (Rosenfeld and Cooke 2019). EDCs may bind to hormone carrier or transport proteins in the blood thereby reducing the hormones in circulation (Rosenfeld and Cooke 2019).…”

“…In this type, the normal hormone is prevented from binding to its site since an EDC has occupied it (Rosenfeld and Cooke 2019). EDCs may bind to hormone carrier or transport proteins in the blood thereby reducing the hormones in circulation (Rosenfeld and Cooke 2019). Another way by which EDCs affect the body is to interfere with the metabolic processes by affecting the rate of synthesis or breakdown of natural hormones and disrupt the actions of enzymes involved in steroidogenesis (Yang et al 2015).…”