The promiscuous estrogen receptor: evolution of physiological estrogens and response to phytochemicals and endocrine disruptors

Abstract

Many actions of estradiol (E2), the principal physiological estrogen in vertebrates, are mediated by estrogen receptor-α (ERα) and ERβ. An important physiological feature of vertebrate ERs is their promiscuous response to several physiological steroids, including estradiol (E2), Δ 5 -androstenediol, 5α-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of Δ 5 -androstenediol, 5α-androstanediol, and 27-hydroxycholesterol is the presence of a C19 methyl group, which precludes the presence of an aromatic A ring with a C3 phenolic group that is a defining property of E2. The structural diversity of these estrogens can explain the response of the ER to synthetic chemicals such as bisphenol A and DDT, which disrupt estrogen physiology in vertebrates, and the estrogenic activity of a variety of plant-derived chemicals such as genistein, coumestrol, and resveratrol. Diversity in the A ring of physiological estrogens also expands potential structures of industrial chemicals that can act as endocrine disruptors. Compared to E2, synthesis of 27-hydroxycholesterol and Δ 5 -androstenediol is simpler, leading us, based on parsimony, to propose that one or both of these steroids or a related metabolite was a physiological estrogen early in the evolution of the ER, with E2 assuming this role later as the canonical estrogen.In addition to the well-studied role of the ER in reproductive physiology, the ER also is an important transcription factor in non-reproductive tissues such as the cardiovascular system, kidney, bone, and brain.

Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1

“…Anthropogenic persistent organic pollutants such as DDT, and its more persistent metabolite DDE, are highly stable, highly lipophilic with a log Kow of 7, and recognized to rapidly and readily bioconcentrate in the environment and bioaccumulate in living organisms (Coffin et al, 2017;Mansouri et al, 2017;Nicolopoulou-Stamati et al, 2016). DDT and DDE are well-recognized EDC, exhibiting estrogenic and/or anti-androgenic properties (Baker and Lathe, 2018;Kelce et al, 1995;Kojima et al, 2004). We previously published a finding that confirmed o,p 0 -DDE activates ESRs, and also presented the novel data indicating that it can bind to skeletal muscle RyR1 (Morisseau et al, 2009).…”

“…Toxicity studies demonstrate that high concentrations of DDT are required to mediate neurotoxicity in mammals (Silver et al, 2017), thus its endocrine disrupting properties have been more widely investigated. The original technical mixture of DDT consisted of a combination of both p,p 0 -DDT (77%) and o,p 0 -DDT (23%) with the latter recognized as the more estrogenic isoform (Baker and Lathe, 2018;Gellert et al, 1972;Kojima et al, 2004). One of its major and persistent metabolites, p,p 0 -DDE has also been identified as an endocrine disrupting compound (EDC), possessing anti-androgenic properties (Bornman et al, 2018;Kelce et al, 1995;Kojima et al, 2004;Patrick et al, 2016).…”

Steroid Receptors and Vertebrate Evolution

“…Testosterone, progesterone, cortisol and aldosterone contain an A ring with an unsaturated bond between C4 and C5 and a C3-ketone, and a C19 methyl group. Estradiol is important in female and male physiology [25,26]. Aldosterone is the main physiological mineralocorticoid in vertebrates [27][28][29].…”

“…Δ5-androstenediol and 27-hydroxycholesterol contain a B ring with an unsaturated bond between C5 and C6. Δ5-androstenediol, 5α-androstanediol and 27hydroxycholesterol are physiological estrogens [25,26,56,65,66]. Paraestrol A, which has an aromatic A ring, is synthesized by corals binds to the ancestral SR [68,69].…”

“…Estradiol is synthesized in three steps (3β/Δ 5-4 -hydroxysteroid dehydrogenase (3β/Δ 5-4 -HSD), cytochromeP450 19 (CYP19), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1)) from dehydroepiandrosterone (DHEA) [17,58,70]. In contrast, Δ5-androstenediol is synthesized from dehydroepiandrosterone (DHEA) in one step (17β-hydroxysteroid dehydrogenase type14 (17β-HSD14)) [26,70]. 27-hydroxycholesterol is synthesized in one step from cholesterol [26,58].…”