Abstract
Simple SummaryFor proper fertility, the production of good-quality spermatozoa is essential. Nowadays, many environmental pollutants affect the spermatogenetic process, at different levels. For this reason, new approaches are needed to prevent/counteract these toxic effects. Here, we showed that the excitatory amino acid D-aspartic acid (D-Asp) prevents the deadly action of ethane dimethane sulfonate (EDS) on the testosterone-secreting Leydig cells in rat testis. We found that EDS, probably via the reduced testosterone level, alters the normal histology of the seminiferous epithelium, leading to germ cells death and to the decreased protein level of two Leydig cell “markers”: steroidogenic acute regulatory and prolyl endopeptidase. In addition, the same analysis performed on rats that were pre-treated with D-Asp revealed a protective role of this compound, since all the above parameters were quite normal. Moreover, we found that the protective mechanism of action involved in this scenario may be due to the ability of D-Asp to reduce the oxidative stress induced by EDS. Based on these findings, we could affirm that D-Asp may be an encouraging candidate to be used to alleviate the harmful action due to environmental pollutants exposure, in order to maintain appropriate fertility.Herein is reported the first evidence of the protective role of D-aspartic acid (D-Asp) in preventing the toxic effect exerted by the alkylating agent ethane dimethane sulfonate (EDS) in the rat testis. We confirmed that EDS treatment specifically destroyed Leydig cells (LC), resulting in the drastic decrease of the serum testosterone level and producing morphological changes in the germinal tubules, i.e., altered organization of the epithelium, loss of cell contacts and the consequent presence of empty spaces between them, and a reduce number of spermatozoa. Moreover, an increase of TUNEL-positive germ cells, other than alteration in the protein level and localization of two LC “markers”, StAR and PREP, were observed. Interestingly, results obtained from rats pre-treated with D-Asp for 15 days before EDS-injection showed that all the considered parameters were quite normal. To explore the probable mechanism(s) involved in the protection exerted by D-Asp, we considered the increased oxidative stress induced by EDS and the D-Asp antioxidant effects. Thiobarbiturc acid-reactive species (TBARS) levels increased following EDS-injection, while no change was observed in the D-Asp + EDS treated rats. Our results showed that D-Asp may be used as a strategy to mitigate the toxic effects exerted by environmental pollutants, as endocrine disrupters, in order to preserve the reproductive function.
Highlights
Male germ cells production is a finely regulated process which occurs in the extensive seminiferous epithelium, which is composed of two cell types: germ cells in different stages of differentiation, and Sertoli cells, which support and drive the germ cell during their differentiative progression [1]
D-aspartic acid (D-Asp) acts on the HPT axis, stimulating GnRH [15], luteinizing hormone (LH), and T [16] synthesis and release, as well as on the testicular cells [17,18,19,20], eliciting molecular pathways involved in Leydig cells (LC) steroidogenesis and in spermatogonia proliferation [21]
We recently demonstrated that D-Asp is involved in cytoskeletal remodeling, one of the main aspects of spermatogenesis [22,23], since it regulates the protein levels of prolyl endopeptidase (PREP) [24] and disheveled-associated activator of morphogenesis 1 (DAAM1) [25], that are associated to microtubules and actin, respectively
Summary
Male germ cells production is a finely regulated process which occurs in the extensive seminiferous epithelium, which is composed of two cell types: germ cells in different stages of differentiation, and Sertoli cells, which support and drive the germ cell during their differentiative progression [1]. D-aspartic acid (D-Asp) is one of the most studied factors in this regard. This D-amino acid is widely distributed in mammalian nervous and endocrine systems [13,14] controlling male gametogenesis thanks to its regulative role on two different levels. D-Asp acts on the HPT axis, stimulating GnRH [15], luteinizing hormone (LH), and T [16] synthesis and release, as well as on the testicular cells [17,18,19,20], eliciting molecular pathways involved in LC steroidogenesis and in spermatogonia proliferation [21]. We recently demonstrated that D-Asp is involved in cytoskeletal remodeling, one of the main aspects of spermatogenesis [22,23], since it regulates the protein levels of prolyl endopeptidase (PREP) [24] and disheveled-associated activator of morphogenesis 1
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