PMID- 37189369
OWN - NLM
STAT- MEDLINE
DCOM- 20230517
LR  - 20230530
IS  - 2218-273X (Electronic)
IS  - 2218-273X (Linking)
VI  - 13
IP  - 4
DP  - 2023 Mar 30
TI  - D-Aspartate Depletion Perturbs Steroidogenesis and Spermatogenesis in Mice.
LID - 10.3390/biom13040621 [doi]
LID - 621
AB  - 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 alpha-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 17beta-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.
FAU - Santillo, Alessandra
AU  - Santillo A
AD  - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, 
      Universita degli Studi della Campania 'Luigi Vanvitelli', 81100 Caserta, Italy.
FAU - Falvo, Sara
AU  - Falvo S
AD  - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, 
      Universita degli Studi della Campania 'Luigi Vanvitelli', 81100 Caserta, Italy.
FAU - Venditti, Massimo
AU  - Venditti M
AUID- ORCID: 0000-0002-7357-5353
AD  - Dipartimento di Medicina Sperimentale, Sez. Fisiologia Umana e Funzioni 
      Biologiche Integrate, Universita degli Studi della Campania 'Luigi Vanvitelli', 
      80138 Napoli, Italy.
FAU - Di Maio, Anna
AU  - Di Maio A
AD  - Laboratorio di Neuroscienze Traslazionali, CEINGE Biotecnologie Avanzate, Franco 
      Salvatore, 80145 Napoli, Italy.
FAU - Chieffi Baccari, Gabriella
AU  - Chieffi Baccari G
AD  - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, 
      Universita degli Studi della Campania 'Luigi Vanvitelli', 81100 Caserta, Italy.
FAU - Errico, Francesco
AU  - Errico F
AUID- ORCID: 0000-0002-3636-7395
AD  - Laboratorio di Neuroscienze Traslazionali, CEINGE Biotecnologie Avanzate, Franco 
      Salvatore, 80145 Napoli, Italy.
AD  - Dipartimento di Agraria, Universita degli Studi di Napoli "Federico II", 80055 
      Portici, Italy.
FAU - Usiello, Alessandro
AU  - Usiello A
AD  - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, 
      Universita degli Studi della Campania 'Luigi Vanvitelli', 81100 Caserta, Italy.
AD  - Laboratorio di Neuroscienze Traslazionali, CEINGE Biotecnologie Avanzate, Franco 
      Salvatore, 80145 Napoli, Italy.
FAU - Minucci, Sergio
AU  - Minucci S
AUID- ORCID: 0000-0002-1007-7840
AD  - Dipartimento di Medicina Sperimentale, Sez. Fisiologia Umana e Funzioni 
      Biologiche Integrate, Universita degli Studi della Campania 'Luigi Vanvitelli', 
      80138 Napoli, Italy.
FAU - Di Fiore, Maria Maddalena
AU  - Di Fiore MM
AUID- ORCID: 0000-0003-4673-6729
AD  - Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, 
      Universita degli Studi della Campania 'Luigi Vanvitelli', 81100 Caserta, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230330
PL  - Switzerland
TA  - Biomolecules
JT  - Biomolecules
JID - 101596414
RN  - 30KYC7MIAI (Aspartic Acid)
RN  - 4SR0Q8YD1X (D-Aspartic Acid)
RN  - 3XMK78S47O (Testosterone)
RN  - EC 3.4.21.26 (Prolyl Oligopeptidases)
RN  - EC 3.6.1.- (Daam1 protein, mouse)
RN  - 0 (Microfilament Proteins)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Male
MH  - Mice
MH  - Animals
MH  - *Aspartic Acid/metabolism
MH  - *D-Aspartic Acid/metabolism
MH  - Spermatogenesis
MH  - Testis/metabolism
MH  - Testosterone
MH  - Prolyl Oligopeptidases/metabolism
MH  - Microfilament Proteins/metabolism
MH  - rho GTP-Binding Proteins/metabolism
PMC - PMC10136051
OTO - NOTNLM
OT  - D-aspartate
OT  - D-aspartate oxidase
OT  - DAAM1
OT  - PREP
OT  - knockin mice
OT  - spermatogenesis
OT  - steroidogenesis
COIS- The authors declare no conflict of interest.
EDAT- 2023/05/16 06:42
MHDA- 2023/05/17 06:42
PMCR- 2023/03/30
CRDT- 2023/05/16 01:09
PHST- 2023/02/21 00:00 [received]
PHST- 2023/03/23 00:00 [revised]
PHST- 2023/03/28 00:00 [accepted]
PHST- 2023/05/17 06:42 [medline]
PHST- 2023/05/16 06:42 [pubmed]
PHST- 2023/05/16 01:09 [entrez]
PHST- 2023/03/30 00:00 [pmc-release]
AID - biom13040621 [pii]
AID - biomolecules-13-00621 [pii]
AID - 10.3390/biom13040621 [doi]
PST - epublish
SO  - Biomolecules. 2023 Mar 30;13(4):621. doi: 10.3390/biom13040621.