{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:56:14Z","timestamp":1768456574333,"version":"3.49.0"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Campania \u201cLuigi Vanvitelli\u201d","award":["B68D19001880005"],"award-info":[{"award-number":["B68D19001880005"]}]},{"name":"University of Campania \u201cLuigi Vanvitelli\u201d","award":["PRIN 2017"],"award-info":[{"award-number":["PRIN 2017"]}]},{"name":"University of Campania \u201cLuigi Vanvitelli\u201d","award":["M42834"],"award-info":[{"award-number":["M42834"]}]},{"name":"University of Campania \u201cLuigi Vanvitelli\u201d","award":["PRIN 2020"],"award-info":[{"award-number":["PRIN 2020"]}]},{"name":"University of Campania \u201cLuigi Vanvitelli\u201d","award":["2020K53E57"],"award-info":[{"award-number":["2020K53E57"]}]},{"name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","award":["B68D19001880005"],"award-info":[{"award-number":["B68D19001880005"]}]},{"name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","award":["PRIN 2017"],"award-info":[{"award-number":["PRIN 2017"]}]},{"name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","award":["M42834"],"award-info":[{"award-number":["M42834"]}]},{"name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","award":["PRIN 2020"],"award-info":[{"award-number":["PRIN 2020"]}]},{"name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","award":["2020K53E57"],"award-info":[{"award-number":["2020K53E57"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>High levels of free D-aspartate (D-Asp) are present in vertebrate testis during post-natal development, coinciding with the onset of testosterone production, which suggests that this atypical amino acid might participate in the regulation of hormone biosynthesis. To elucidate the unknown role of D-Asp on testicular function, we investigated steroidogenesis and spermatogenesis in a one-month-old knockin mouse model with the constitutive depletion of D-Asp levels due to the targeted overexpression of D-aspartate oxidase (DDO), which catalyzes the deaminative oxidation of D-Asp to generate the corresponding \u03b1-keto acid, oxaloacetate, hydrogen peroxide, and ammonium ions. In the Ddo knockin mice, we found a dramatic reduction in testicular D-Asp levels, accompanied by a significant decrease in the serum testosterone levels and testicular 17\u03b2-HSD, the enzyme involved in testosterone biosynthesis. Additionally, in the testes of these Ddo knockin mice, the expression of PCNA and SYCP3 proteins decreased, suggesting alterations in spermatogenesis-related processes, as well as an increase in the cytosolic cytochrome c protein levels and TUNEL-positive cell number, which indicate an increase in apoptosis. To further investigate the histological and morphometric testicular alterations in Ddo knockin mice, we analyzed the expression and localization of prolyl endopeptidase (PREP) and disheveled-associated activator of morphogenesis 1 (DAAM1), two proteins involved in cytoskeletal organization. Our results showed that the testicular levels of DAAM1 and PREP in Ddo knockin mice were different from those in wild-type animals, suggesting that the deficiency of D-Asp is associated with overall cytoskeletal disorganization. Our findings confirmed that physiological D-Asp influences testosterone biosynthesis and plays a crucial role in germ cell proliferation and differentiation, which are required for successful reproduction.<\/jats:p>","DOI":"10.3390\/biom13040621","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T04:45:35Z","timestamp":1680151535000},"page":"621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["D-Aspartate Depletion Perturbs Steroidogenesis and Spermatogenesis in Mice"],"prefix":"10.3390","volume":"13","author":[{"given":"Alessandra","family":"Santillo","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universit\u00e0 degli Studi della Campania \u2018Luigi Vanvitelli\u2019, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Falvo","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universit\u00e0 degli Studi della Campania \u2018Luigi Vanvitelli\u2019, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7357-5353","authenticated-orcid":false,"given":"Massimo","family":"Venditti","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Sez. Fisiologia Umana e Funzioni Biologiche Integrate, Universit\u00e0 degli Studi della Campania \u2018Luigi Vanvitelli\u2019, 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Di Maio","sequence":"additional","affiliation":[{"name":"Laboratorio di Neuroscienze Traslazionali, CEINGE Biotecnologie Avanzate, Franco Salvatore, 80145 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Chieffi Baccari","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universit\u00e0 degli Studi della Campania \u2018Luigi Vanvitelli\u2019, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3636-7395","authenticated-orcid":false,"given":"Francesco","family":"Errico","sequence":"additional","affiliation":[{"name":"Laboratorio di Neuroscienze Traslazionali, CEINGE Biotecnologie Avanzate, Franco Salvatore, 80145 Napoli, Italy"},{"name":"Dipartimento di Agraria, Universit\u00e0 degli Studi di Napoli \u201cFederico II\u201d, 80055 Portici, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Usiello","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universit\u00e0 degli Studi della Campania \u2018Luigi Vanvitelli\u2019, 81100 Caserta, Italy"},{"name":"Laboratorio di Neuroscienze Traslazionali, CEINGE Biotecnologie Avanzate, Franco Salvatore, 80145 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1007-7840","authenticated-orcid":false,"given":"Sergio","family":"Minucci","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale, Sez. Fisiologia Umana e Funzioni Biologiche Integrate, Universit\u00e0 degli Studi della Campania \u2018Luigi Vanvitelli\u2019, 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-6729","authenticated-orcid":false,"given":"Maria Maddalena","family":"Di Fiore","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universit\u00e0 degli Studi della Campania \u2018Luigi Vanvitelli\u2019, 81100 Caserta, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1007\/s00726-014-1759-2","article-title":"Current knowledge of D-aspartate in glandular tissues","volume":"46","author":"Santillo","year":"2014","journal-title":"Amino Acids"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Di Fiore, M.M., Santillo, A., Falvo, S., Longobardi, S., and Chieffi, G. 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