title: Dehydroepiandrosterone and 7-oxo-dehydroepiandrosterone in male reproductive health: Implications of differential regulation of human Sertoli cells metabolic profile.
abstract: Dehydroepiandrosterone (DHEA) is a precursor of androgen synthesis whose action is partially exerted through its metabolites. 7-Oxo-dehydroepiandrosterone (7-oxo-DHEA) is a common DHEA metabolite, non-convertible to androgens, which constitutes a promising therapeutic strategy for multiple conditions. Sertoli cells (SCs) are responsible for the support of spermatogenesis, having unique metabolic characteristics strongly modulated by androgens. Consequently, disruptions in androgen synthesis compromise SCs function and hence male fertility. We aimed to evaluate the effects of DHEA and 7-oxo-DHEA in human SCs (hSCs) metabolism and oxidative profile. To do so, hSCs were exposed to increasing concentrations of DHEA and 7-oxo-DHEA (0.025, 1 and 50 μM) that revealed to be non-cytotoxic in these experimental conditions. We measured hSCs metabolites consumption/production by (1)H NMR, the protein expression levels of key players of the glycolytic pathway by Western blot as well as the levels of carbonyl groups, nitration and lipid peroxidation by Slot blot. The obtained data demonstrated that 7-oxo-DHEA is a more potent metabolic modulator than DHEA since it increased hSCs glycolytic flux. DHEA seem to redirect hSCs metabolism to the Krebs cycle, while 7-oxo-DHEA has some inhibitory effect in this path. The highest 7-oxo-DHEA concentrations (1 and 50 μM) also increased lactate production, which is of extreme relevance for the successful progression of spermatogenesis in vivo. None of these steroids altered the intracellular oxidative profile of hSCs, illustrating that, at the concentrations used they do not have pro- nor antioxidant actions in hSCs. Our study represents a further step in the establishment of safe doses of DHEA and 7-oxo-DHEA to hSCs, supporting its possible use in hormonal and non-hormonal therapies against male reproductive problems.
authors.affiliation: CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: Tânia R
authors.initials: TR
authors.lastname: Dias
authors.affiliation: CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: Marco G
authors.initials: MG
authors.lastname: Alves
authors.affiliation: Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal.
authors.forename: Susana P
authors.initials: SP
authors.lastname: Almeida
authors.affiliation: Centre for Reproductive Genetics Prof. Alberto Barros, 4100-009 Porto, Portugal.
authors.forename: Joaquina
authors.initials: J
authors.lastname: Silva
authors.affiliation: Centre for Reproductive Genetics Prof. Alberto Barros, 4100-009 Porto, Portugal; Department of Genetics, Faculty of Medicine, University of Porto, 4100-009 Porto, Portugal; Institute of Health Research and Innovation, University of Porto, 4100-009 Porto, Portugal.
authors.forename: Alberto
authors.initials: A
authors.lastname: Barros
authors.affiliation: Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal; Centre for Reproductive Genetics Prof. Alberto Barros, 4100-009 Porto, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Sousa
authors.affiliation: CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal.
authors.forename: Branca M
authors.initials: BM
authors.lastname: Silva
authors.affiliation: CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal; CNC-Center for Neurosciences and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Silvestre
authors.affiliation: CICS-UBI-Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal; Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, 4050-313 Porto, Portugal. Electronic address: pfobox@gmail.com.
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Oliveira
mesh_terms: D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D018384:Oxidative Stress; D011773:Pyruvates / Q000378:metabolism; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D011773:Pyruvates; C002914:7-oxodehydroepiandrosterone; D003687:Dehydroepiandrosterone; D005947:Glucose
keywords: 7-Oxo-dehydroepiandrosterone; Dehydroepiandrosterone; Glycolytic pathway; Human Sertoli cells; Oxidative profile; Spermatogenesis