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

2017 ◽  
Author(s):  
Michael E. Baker ◽  
Richard Lathe
Keyword(s):  
Estrogen Receptor ◽  
Endocrine Disruptors ◽  
Estrogenic Activity ◽  
Structural Diversity ◽  
Estrogen Receptor Α ◽  
Industrial Chemicals ◽  
Reproductive Tissues ◽  
Synthetic Chemicals ◽  
Phenolic Group

ABSTRACTMany 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), Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of Δ5-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 Δ5-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. Some of these ER actions in non-reproductive tissues appeared early in vertebrate evolution, long before mammals evolved.

Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton

2018 ◽  
Vol 239 (3) ◽  
pp. 303-312 ◽  
Author(s):  
H H Farman ◽  
K L Gustafsson ◽  
P Henning ◽  
L Grahnemo ◽  
V Lionikaite ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Areal Bone Mineral Density ◽  
Male Mice ◽  
Mineral Density ◽  
Intact Male ◽  
Trabecular Thickness ◽  
Total Body

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

scholarly journals Association of Cryptorchidism with a Specific Haplotype of the Estrogen Receptor α Gene: Implication for the Susceptibility to Estrogenic Environmental Endocrine Disruptors

2005 ◽  
Vol 90 (8) ◽  
pp. 4716-4721 ◽  
Author(s):  
Rie Yoshida ◽  
Maki Fukami ◽  
Isoji Sasagawa ◽  
Tomonobu Hasegawa ◽  
Naoyuki Kamatani ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Endocrine Disruptors ◽  
Outcome Measure ◽  
Estrogen Receptor Α ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Main Outcome Measure ◽  
Environmental Endocrine Disruptors ◽  
Estrogenic Effects ◽  
Specific Haplotype

Context: The prevalence of cryptorchidism (CO) has increased during the past few decades in several countries, and this event has primarily been ascribed to the estrogenic effects of environmental endocrine disruptors (EEDs). Little is known, however, about the role of genetic susceptibility to EEDs in this phenomenon. Objective: The objective of this study was to determine whether CO is associated with a specific haplotype of the gene for estrogen receptor α (ESR1) that mediates the estrogenic effects of EEDs. Design: This was a case-control study. Setting: The study was performed at the National Research Institute and University Hospitals. Subjects: Sixty-three cryptorchid males, aged 1–13 yr, and 47 control males, aged 4–12 yr, were studied. Intervention: After genotyping 15 single nucleotide polymorphisms widely distributed in the greater than 300-kb genomic sequences of ESR1, haplotype analysis was performed. Main Outcome Measure: Identification of a specific ESR1 haplotype associated with CO was the main outcome measure. Results: A haplotype block was identified for an approximately 50-kb region encompassing single nucleotide polymorphisms 10–14 in the 3′ region of ESR1 in both groups. The frequency of the estimated AGATA haplotype within the block was higher in the patients than in the control males (34.0% vs. 21.3%; P = 0.037), and the association of this haplotype with CO phenotype was significant in a recessive mode (P = 0.0060). The homozygosity for this haplotype was identified only in the patients, and the frequency of the homozygotes was significantly different between the two groups (10 of 63 vs. zero of 47; P = 0.0042). Conclusions: The association of CO with homozygosity for the specific ESR1 haplotype suggests the relevance of genetic susceptibility to EEDs in the development of CO.

The Role of Biotransformation in the Activity of Endocrine Disruptors

2021 ◽  
Vol 22 ◽  
Author(s):  
Elif Ince Erguc ◽  
Alev Tascioglu-Aliyev ◽  
Bita Entezari ◽  
Hande Gurer-Orhan
Keyword(s):  
Parent Compound ◽  
Endocrine System ◽  
Decisive Role ◽  
Industrial Chemicals ◽  
Toxic Metabolites ◽  
Synthetic Chemicals ◽  
Polybrominated Biphenyls ◽  
Diverse Groups ◽  
Natural Hormones

: An “endocrine disruptor” has been broadly defined as an exogenous chemical that interferes with the production, release, transport, metabolism, binding, action, or elimination of endogenous hormones which are responsible for homeostasis, reproduction, development or behaviour. Diverse groups of chemicals such as pharmaceuticals, phytoestrogens, natural hormones, and synthetic chemicals such as pesticides, plasticizers, phthalates, parabens, polychlorinated/polybrominated biphenyls, bisphenols are shown to interfere with the endocrine system and defined as EDs in the last three decades. As for all chemicals, the biotransformation of EDs has a decisive role in their potential toxic effects. Humans are exposed to vast amounts of diverse chemicals throughout their life. Fortunately, most of the chemicals are converted, via biotransformation reactions catalysed by enzymes, into more hydrophilic metabolites, which are readily excreted in urine or bile. Biotransformation reactions resulting in less toxic metabolites are known as detoxification. However, some biotransformation reactions are called bioactivation in which more toxic metabolites are formed. In the case of EDs, metabolites formed via bioactivation usually have a higher affinity for a hormone receptor or induce/inhibit an enzyme involved in the synthesis or catabolism of an endogenous hormone more dramatically compared to their parent compound. In the present review, the role of bioactivation in endocrine modulating effects of chemicals from all groups of Eds is highlighted, namely endogenous estrogens, phytoestrogens, synthetic/industrial chemicals, and pharmaceuticals.

scholarly journals Expression of Estrogen Receptor Alpha and Evaluation of Histological Degeneration Scores in Fibroblasts of Hypertrophied Ligamentum Flavum: A Qualitative Study

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1752
Author(s):  
Christina C. Westhoff ◽  
Christian-Dominik Peterlein ◽  
Hanna Daniel ◽  
Juergen R. Paletta ◽  
Roland Moll ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Ligamentum Flavum ◽  
Estrogen Receptor Α ◽  
Group Differences ◽  
Elastic Fibers ◽  
Disk Herniation ◽  
Spinal Decompression ◽  
Lumbar Spinal

The most common spinal disorder in elderly is lumbar spinal stenosis (LSS), resulting partly from ligamentum flavum (LF) hypertrophy. Its pathophysiology is not completely understood. The present study wants to elucidate the role of estrogen receptor α (ER α) in fibroblasts of hypertrophied LF. LF samples of 38 patients with LSS were obtained during spinal decompression. Twelve LF samples from patients with disk herniation served as controls. Hematoxylin & Eosin (H&E) and Elastica stains and immunohistochemistry for ER α were performed. The proportions of fibrosis, loss and/or degeneration of elastic fibers and proliferation of collagen fibers were assessed according to the scores of Sairyo and Okuda. Group differences in the ER α and Sairyo and Okuda scores between patients and controls, male and female sex and absence and presence of additional orthopedic diagnoses were assessed with the Mann–Whitney U test. There was a tendency towards higher expression of ER α in LF fibroblasts in the hypertrophy group (p = 0.065). The Sairyo and Okuda scores were more severe for the hypertrophy group but, in general, not statistically relevant. There was no statistically relevant correlation between the expression of ER α and sex (p = 0.326). ER α expression was higher in patients with osteochondrosis but not statistically significant (p = 0.113). In patients with scoliosis, ER α expression was significantly lower (p = 0.044). LF hypertrophy may be accompanied by a higher expression of ER α in fibroblasts. No difference in ER α expression was observed regarding sex. Further studies are needed to clarify the biological and clinical significance of these findings.

The Effect of Structural Diversity on Ligand Specificity and Resulting Signaling Differences of Estrogen Receptor α

2019 ◽  
Vol 32 (6) ◽  
pp. 1002-1013 ◽  
Author(s):  
Qiao Xue ◽  
Xian Liu ◽  
Xiu-Chang Liu ◽  
Wen-Xiao Pan ◽  
Jian-Jie Fu ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Structural Diversity ◽  
Estrogen Receptor Α ◽  
Ligand Specificity

scholarly journals Probiotic antigenotoxic activity as a DNA bioprotective tool: a minireview with focus on endocrine disruptors

2020 ◽  
Vol 367 (3) ◽  
Author(s):  
Natalia Garcia-Gonzalez ◽  
Roberta Prete ◽  
Monia Perugini ◽  
Carmine Merola ◽  
Natalia Battista ◽  
...  
Keyword(s):  
Dna Damage ◽  
Endocrine Disruptors ◽  
Food Packaging ◽  
Estrogenic Activity ◽  
Endocrine System ◽  
Protective Role ◽  
Hormonal Function ◽  
Genotoxic Compounds ◽  
Exogenous Substances

ABSTRACT Nowadays, the interest in the role of dietary components able to influence the composition and the activity of the intestinal microbiota and, consequently, to modulate the risk of genotoxicity and colon cancer is increasing in the scientific community. Within this topic, the microbial ability to have a protective role at gastrointestinal level by counteracting the biological activity of genotoxic compounds, and thus preventing the DNA damage, is deemed important in reducing gut pathologies and is considered a new tool for probiotics and functional foods. A variety of genotoxic compounds can be found in the gut and, besides food-related mutagens and other DNA-reacting compounds, there is a group of pollutants commonly used in food packaging and/or in thousands of everyday products called endocrine disruptors (EDs). EDs are exogenous substances that alter the functions of the endocrine system through estrogenic and anti-estrogenic activity, which interfere with normal hormonal function in human and wildlife. Thus, this paper summarizes the main applications of probiotics, mainly lactobacilli, as a bio-protective tool to counteract genotoxic and mutagenic agents, by biologically inhibiting the related DNA damage in the gut and highlights the emerging perspectives to enlarge and further investigate the microbial bio-protective role at intestinal level.

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