17-α-ethinyl estradiol in vitro treatment of rat primary hippocampal neurons shapes glutamatergic developmental program: molecular and morphological dynamics at the postsynapse.
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| Title: | 17-α-ethinyl estradiol in vitro treatment of rat primary hippocampal neurons shapes glutamatergic developmental program: molecular and morphological dynamics at the postsynapse. |
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| Authors: | Serafini MM; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy. Electronic address: melania.serafini@unimi.it., Midali M; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy., Aram F; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy., Barzasi M; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy., Grumelli G; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy., Marinovich M; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy; Center of Research on New Approach Methodologies (NAMs) in Chemical Risk Assessment (SAFE-MI), Università degli Studi di Milano, Milan, Italy., Corsini E; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy; Center of Research on New Approach Methodologies (NAMs) in Chemical Risk Assessment (SAFE-MI), Università degli Studi di Milano, Milan, Italy., Viviani B; Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy; Center of Research on New Approach Methodologies (NAMs) in Chemical Risk Assessment (SAFE-MI), Università degli Studi di Milano, Milan, Italy. |
| Source: | European journal of pharmacology [Eur J Pharmacol] 2025 Dec 05; Vol. 1008, pp. 178364. Date of Electronic Publication: 2025 Nov 13. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2005- : Amsterdam : Elsevier Science Original Publication: Amsterdam, North Holland Pub. Co. |
| MeSH Terms: | Hippocampus*/cytology , Hippocampus*/drug effects , Hippocampus*/metabolism , Neurons*/drug effects , Neurons*/metabolism , Neurons*/cytology , Synapses*/drug effects , Synapses*/metabolism , Ethinyl Estradiol*/pharmacology , Glutamic Acid*/metabolism, Animals ; Rats ; Receptors, N-Methyl-D-Aspartate/metabolism ; Receptors, AMPA/metabolism ; Rats, Wistar ; Cells, Cultured |
| Abstract: | Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 17-α-ethinyl-estradiol (EE2) is the estrogen-like semi-synthetic hormone contained in most combined contraceptives and drugs for hormone replacement therapy. Due to its interference with estrogen pathways, EE2 is classified as an endocrine-disrupting chemical (EDC). Considering its widespread use, EE2 is an environmental contaminant in soil and water. EE2 can cross both the placental and blood-brain barriers (BBB), reaching the developing hippocampus, a glutamatergic area that expresses hormone receptors. Hormones (e.g., estrogens, thyroid hormones) influence synaptogenesis and synapse development. This process is timely regulated by the N-methyl-D-aspartate (NMDA) receptor subtype 2B (GluN2B) to NMDA receptor subtype 2A (GluN2A) switch in glutamatergic synapses. This study investigates the EE2 effect on the expression and distribution of glutamatergic receptor subunits in rat primary hippocampal neurons exposed during their development, and the consequences on spine maturation and postsynaptic calcium transients. Neurons treated with EE2 following different exposure schemes are analyzed for NMDA receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in the homogenate and at the postsynaptic site. Results obtained suggest that EE2 alters the developmental program of the glutamatergic system when administered at 7 days in vitro (DIV). Depending on the exposure time window, altered expression (7 DIV 24h) or translocation to the postsynaptic sites (7-18 DIV) of selected NMDA and AMPA receptor subunits occurred. Moreover, morphological analyses by confocal microscopy in transfected neurons revealed a decrease in mature mushroom-shaped and an increase in thin-shaped spines, while bicuculline, a GABA (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Contributed Indexing: | Keywords: 17-α-ethinyl estradiol; Bicuculline-induced calcium transients; Glutamatergic receptors subunits; Rat primary hippocampal neurons; Spine morphology |
| Substance Nomenclature: | 0 (Receptors, N-Methyl-D-Aspartate) 0 (Receptors, AMPA) 423D2T571U (Ethinyl Estradiol) 3KX376GY7L (Glutamic Acid) 0 (NR2B NMDA receptor) |
| Entry Date(s): | Date Created: 20251115 Date Completed: 20251128 Latest Revision: 20251128 |
| Update Code: | 20251129 |
| DOI: | 10.1016/j.ejphar.2025.178364 |
| PMID: | 41241330 |
| Database: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br />17-α-ethinyl-estradiol (EE2) is the estrogen-like semi-synthetic hormone contained in most combined contraceptives and drugs for hormone replacement therapy. Due to its interference with estrogen pathways, EE2 is classified as an endocrine-disrupting chemical (EDC). Considering its widespread use, EE2 is an environmental contaminant in soil and water. EE2 can cross both the placental and blood-brain barriers (BBB), reaching the developing hippocampus, a glutamatergic area that expresses hormone receptors. Hormones (e.g., estrogens, thyroid hormones) influence synaptogenesis and synapse development. This process is timely regulated by the N-methyl-D-aspartate (NMDA) receptor subtype 2B (GluN2B) to NMDA receptor subtype 2A (GluN2A) switch in glutamatergic synapses. This study investigates the EE2 effect on the expression and distribution of glutamatergic receptor subunits in rat primary hippocampal neurons exposed during their development, and the consequences on spine maturation and postsynaptic calcium transients. Neurons treated with EE2 following different exposure schemes are analyzed for NMDA receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in the homogenate and at the postsynaptic site. Results obtained suggest that EE2 alters the developmental program of the glutamatergic system when administered at 7 days in vitro (DIV). Depending on the exposure time window, altered expression (7 DIV 24h) or translocation to the postsynaptic sites (7-18 DIV) of selected NMDA and AMPA receptor subunits occurred. Moreover, morphological analyses by confocal microscopy in transfected neurons revealed a decrease in mature mushroom-shaped and an increase in thin-shaped spines, while bicuculline, a GABA <subscript>A</subscript> blocker, induced an enhancement of postsynaptic calcium transients in control but not in EE2-treated neurons (7-18 DIV).<br /> (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.) |
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| ISSN: | 1879-0712 |
| DOI: | 10.1016/j.ejphar.2025.178364 |