Publications by authors named "Silvia Fasano"

62 Publications

LINCking the Nuclear Envelope to Sperm Architecture.

Genes (Basel) 2021 Apr 27;12(5). Epub 2021 Apr 27.

Dipartimento di Medicina Sperimentale, Università degli Studi della Campania L. Vanvitelli, Via Costantinopoli 16, 80138 Napoli, Italy.

Nuclear architecture undergoes an extensive remodeling during spermatogenesis, especially at levels of spermatocytes (SPC) and spermatids (SPT). Interestingly, typical events of spermiogenesis, such as nuclear elongation, acrosome biogenesis, and flagellum formation, need a functional cooperation between proteins of the nuclear envelope and acroplaxome/manchette structures. In addition, nuclear envelope plays a key role in chromosome distribution. In this scenario, special attention has been focused on the LINC (linker of nucleoskeleton and cytoskeleton) complex, a nuclear envelope-bridge structure involved in the connection of the nucleoskeleton to the cytoskeleton, governing mechanotransduction. It includes two integral proteins: KASH- and SUN-domain proteins, on the outer (ONM) and inner (INM) nuclear membrane, respectively. The LINC complex is involved in several functions fundamental to the correct development of sperm cells such as head formation and head to tail connection, and, therefore, it seems to be important in determining male fertility. This review provides a global overview of the main LINC complex components, with a special attention to their subcellular localization in sperm cells, their roles in the regulation of sperm morphological maturation, and, lastly, LINC complex alterations associated to male infertility.
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http://dx.doi.org/10.3390/genes12050658DOI Listing
April 2021

Characterization of Estrogenic Activity and Site-Specific Accumulation of Bisphenol-A in Epididymal Fat Pad: Interfering Effects on the Endocannabinoid System and Temporal Progression of Germ Cells.

Int J Mol Sci 2021 Mar 3;22(5). Epub 2021 Mar 3.

Department of Experimental Medicine, Sez. Bottazzi, Università degli Studi della Campania "L. Vanvitelli", Via Costantinopoli 16, 80138 Napoli, Italy.

The objective of this work has been to characterize the estrogenic activity of bisphenol-A (BPA) and the adverse effects on the endocannabinoid system (ECS) in modulating germ cell progression. Male offspring exposed to BPA during the foetal-perinatal period at doses below the no-observed-adverse-effect-level were used to investigate the exposure effects in adulthood. Results showed that BPA accumulates specifically in epididymal fat rather than in abdominal fat and targets testicular expression of 3β-hydroxysteroid dehydrogenase and cytochrome P450 aromatase, thus promoting sustained increase of estrogens and a decrease of testosterone. The exposure to BPA affects the expression levels of some ECS components, namely type-1 (CB1) and type-2 cannabinoid (CB2) receptor and monoacylglycerol-lipase (MAGL). Furthermore, it affects the temporal progression of germ cells reported to be responsive to ECS and promotes epithelial germ cell exfoliation. In particular, it increases the germ cell content (i.e., spermatogonia while reducing spermatocytes and spermatids), accelerates progression of spermatocytes and spermatids, promotes epithelial detachment of round and condensed spermatids and interferes with expression of cell-cell junction genes (i.e., zonula occcludens protein-1, vimentin and β-catenin). Altogether, our study provides evidence that early exposure to BPA produces in adulthood sustained and site-specific BPA accumulation in epididymal fat, becoming a risk factor for the reproductive endocrine pathways associated to ECS.
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http://dx.doi.org/10.3390/ijms22052540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961766PMC
March 2021

Kisspeptins, new local modulators of male reproduction: A comparative overview.

Gen Comp Endocrinol 2020 12 18;299:113618. Epub 2020 Sep 18.

Dipartimento di Medicina Sperimentale, Università degli Studi della Campania "L. Vanvitelli", Napoli, Italy.

Spermatogenesis is a complex process that leads to the production of male gametes within the testis through the coordination of mitotic, meiotic and differentiation events, under a deep control of endocrine, paracrine and autocrine modulators along the Hypothalamus-pituitary-gonad (HPG) axis. The kisspeptin system plays a fundamental role along the HPG axis as it is the main positive modulator upstream of the hypothalamic neurons that secrete the Gonadotropin Releasing Hormone (GnRH), the decapeptide that supports pituitary gonadotropins and the production of gonadal sex steroid. Currently, kisspeptins and their receptor, KISS1R, have a recognized activity in the central control of puberty onset, sex maturation, reproduction and sex-steroid feedback mechanisms in both animal models and human. However, kisspeptin signaling has been widely reported in peripheral tissues, particularly in the testis of mammalian and non-mammalian vertebrates, with functions related to Leydig cells physiology and steroid biosynthesis, spermatogenesis progression and spermatozoa functions, but its mandatory role within the testis is still a matter of discussion. This review provides a summary of the main intratesticular effects of kisspeptin in vertebrates, via a comparative approach. Particular emphasis was devoted to data from the anuran amphibian Pelophylax esculentus, the first animal model in which the direct intratesticular activity of kisspeptin was reported.
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http://dx.doi.org/10.1016/j.ygcen.2020.113618DOI Listing
December 2020

CircRNA Role and circRNA-Dependent Network (ceRNET) in Asthenozoospermia.

Front Endocrinol (Lausanne) 2020 10;11:395. Epub 2020 Jul 10.

Dipartimento di Medicina Sperimentale, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

The role of circRNA in reproduction is under investigation. CircRNAs are expressed in human testis, spermatozoa (SPZ), and seminal plasma. Their involvement in embryo development has also been suggested. Asthenozoospermia, a common cause of male infertility, is characterized by reduced or absent sperm motility in fresh ejaculate. While abnormal mitochondrial function, altered sperm tail, and genomic causes have been deeply investigated, the epigenetic signature of asthenozoospermic derived SPZ still remains unexplored. CircRNAs may take part in the repertoire of differentially expressed molecules in infertile men. Considering this background, we carried out a circRNA microarray, identifying a total of 9,138 transcripts, 22% of them novel based and 83.5% with an exonic structure. Using KEGG analysis, we evaluated the circRNA contribution in pathways related to mitochondrial function and sperm motility. In order to discriminate circRNAs with a differential expression in SPZ with differential morphological parameters, we separated sperm cells by Percoll gradient and analyzed their differential circRNA payload. A bioinformatic approach was then utilized to build a circRNA/miRNA/mRNA network. With the aim to demonstrate a dynamic contribution of circRNAs to the sperm epigenetic signature, we verified their modulation as a consequence of an oral amino acid supplementation, efficacious in improving SPZ motility.
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http://dx.doi.org/10.3389/fendo.2020.00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366322PMC
May 2021

The Cannabinoid Receptor CB1 Stabilizes Sperm Chromatin Condensation Status During Epididymal Transit by Promoting Disulphide Bond Formation.

Int J Mol Sci 2020 Apr 28;21(9). Epub 2020 Apr 28.

Department of Experimental Medicine, Sez. Bottazzi, Università degli Studi della Campania "L. Vanvitelli", Via Costantinopoli 16, 80138 Napoli, Italy.

The cannabinoid receptor CB1 regulates differentiation of spermatids. We recently characterized spermatozoa from epididymis of -knock-out mice and identified a considerable number of sperm cells with chromatin abnormality such as elevated histone content and poorly condensed chromatin. In this paper, we extended our findings and studied the role of CB1 in the epididymal phase of chromatin condensation of spermatozoa by analysis of spermatozoa from and epididymis of wild-type and -knock-out mouse in both a homozygous or heterozygous condition. Furthermore, we studied the impact of -gene deletion on histone displacement mechanism by taking into account the hyperacetylation of histone H4 and players of displacement such as Chromodomain Y Like protein (CDYL) and Bromodomain testis-specific protein (BRDT). Our results show that CB1, via local and/or endocrine cell-to-cell signaling, modulates chromatin remodeling mechanisms that orchestrate a nuclear condensation extent of mature spermatozoa. We show that -gene deletion affects the epididymal phase of chromatin condensation by interfering with inter-/intra-protamine disulphide bridges formation, and deranges the efficiency of histone removal by reducing the hyper-acetylation of histone H4. This effect is independent by gene expression of and mRNA. Our results reveal a novel and important role for CB1 in sperm chromatin condensation mechanisms.
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http://dx.doi.org/10.3390/ijms21093117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247701PMC
April 2020

Fetal-Perinatal Exposure to Bisphenol-A Affects Quality of Spermatozoa in Adulthood Mouse.

Int J Endocrinol 2020 20;2020:2750501. Epub 2020 Mar 20.

Department of Experimental Medicine, Sez. Bottazzi, Università degli Studi della Campania "L. Vanvitelli", Via Costantinopoli 16, 80138 Napoli, Italy.

Bisphenol-A (BPA) is considered an endocrine disruptor with estrogenic activity. It is described as an environment-polluting industrial chemical whose adverse effects on the male reproductive system depend on the period of exposure (i.e., fetal, prepubertal, or adult life). We exposed male mice to BPA during the fetal-perinatal period (from 10 days post to 31 days post ) and investigated the impact of this early-life exposure on gamete health in adulthood animals at 78 days of age. Both in control and BPA-exposed mice, viability and motility of spermatozoa, as well as sperm motility acquisition and chromatin condensation of spermatozoa, have been evaluated. Results reveal harmful effect of BPA on viability and motility of sperm cells as well as on chromatin condensation status during epididymal maturation of spermatozoa. In particular, BPA exposure interferes with biochemical mechanism useful to stabilize sperm chromatin condensation, as it interferes with oxidation of thiol groups associated to chromatin.
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http://dx.doi.org/10.1155/2020/2750501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109585PMC
March 2020

Histone Post-Translational Modifications and CircRNAs in Mouse and Human Spermatozoa: Potential Epigenetic Marks to Assess Human Sperm Quality.

J Clin Med 2020 Feb 27;9(3). Epub 2020 Feb 27.

Department of Experimental Medicine, University of Campania "L. Vanvitelli", Via Costantinopoli 16, 80138 Napoli, Italy.

Spermatozoa (SPZ) are motile cells, characterized by a cargo of epigenetic information including histone post-translational modifications (histone PTMs) and non-coding RNAs. Specific histone PTMs are present in developing germ cells, with a key role in spermatogenic events such as self-renewal and commitment of spermatogonia (SPG), meiotic recombination, nuclear condensation in spermatids (SPT). Nuclear condensation is related to chromatin remodeling events and requires a massive histone-to-protamine exchange. After this event a small percentage of chromatin is condensed by histones and SPZ contain nucleoprotamines and a small fraction of nucleohistone chromatin carrying a landascape of histone PTMs. Circular RNAs (circRNAs), a new class of non-coding RNAs, characterized by a nonlinear back-spliced junction, able to play as microRNA (miRNA) sponges, protein scaffolds and translation templates, have been recently characterized in both human and mouse SPZ. Since their abundance in eukaryote tissues, it is challenging to deepen their biological function, especially in the field of reproduction. Here we review the critical role of histone PTMs in male germ cells and the profile of circRNAs in mouse and human SPZ. Furthermore, we discuss their suggested role as novel epigenetic biomarkers to assess sperm quality and improve artificial insemination procedure.
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http://dx.doi.org/10.3390/jcm9030640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141194PMC
February 2020

The Epigenetics of the Endocannabinoid System.

Int J Mol Sci 2020 Feb 7;21(3). Epub 2020 Feb 7.

Dipartimento di Medicina Sperimentale, Università della Campania L. Vanvitelli, via Costantinopoli 16, 80138 Cord Napoli, Italy.

The endocannabinoid system (ES) is a cell-signalling system widely distributed in biological tissues that includes endogenous ligands, receptors, and biosynthetic and hydrolysing machineries. The impairment of the ES has been associated to several pathological conditions like behavioural, neurological, or metabolic disorders and infertility, suggesting that the modulation of this system may be critical for the maintenance of health status and disease treatment. Lifestyle and environmental factors can exert long-term effects on gene expression without any change in the nucleotide sequence of DNA, affecting health maintenance and influencing both disease load and resistance. This potentially reversible "epigenetic" modulation of gene expression occurs through the chemical modification of DNA and histone protein tails or the specific production of regulatory non-coding RNA (ncRNA). Recent findings demonstrate the epigenetic modulation of the ES in biological tissues; in the same way, endocannabinoids, phytocannabinoids, and cannabinoid receptor agonists and antagonists induce widespread or gene-specific epigenetic changes with the possibility of trans-generational epigenetic inheritance in the offspring explained by the transmission of deregulated epigenetic marks in the gametes. Therefore, this review provides an update on the epigenetics of the ES, with particular attention on the emerging role in reproduction and fertility.
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http://dx.doi.org/10.3390/ijms21031113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037698PMC
February 2020

Neuro-toxic and Reproductive Effects of BPA.

Curr Neuropharmacol 2019 ;17(12):1109-1132

Department of Movement Sciences and Wellbeing, Parthenope University of Naples, Naples, Italy.

Background: Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide. It has recognized activity as an endocrine-disrupting chemical and has suspected roles as a neurological and reproductive toxicant. It interferes in steroid signaling, induces oxidative stress, and affects gene expression epigenetically. Gestational, perinatal and neonatal exposures to BPA affect developmental processes, including brain development and gametogenesis, with consequences on brain functions, behavior, and fertility.

Methods: This review critically analyzes recent findings on the neuro-toxic and reproductive effects of BPA (and its analogues), with focus on neuronal differentiation, synaptic plasticity, glia and microglia activity, cognitive functions, and the central and local control of reproduction.

Results: BPA has potential human health hazard associated with gestational, peri- and neonatal exposure. Beginning with BPA's disposition, this review summarizes recent findings on the neurotoxicity of BPA and its analogues, on neuronal differentiation, synaptic plasticity, neuroinflammation, neuro-degeneration, and impairment of cognitive abilities. Furthermore, it reports the recent findings on the activity of BPA along the HPG axis, effects on the hypothalamic Gonadotropin Releasing Hormone (GnRH), and the associated effects on reproduction in both sexes and successful pregnancy.

Conclusion: BPA and its analogues impair neuronal activity, HPG axis function, reproduction, and fertility. Contrasting results have emerged in animal models and human. Thus, further studies are needed to better define their safety levels. This review offers new insights on these issues with the aim to find the "fil rouge", if any, that characterize BPA's mechanism of action with outcomes on neuronal function and reproduction.
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http://dx.doi.org/10.2174/1570159X17666190726112101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057208PMC
April 2020

Expression Patterns of Circular RNAs in High Quality and Poor Quality Human Spermatozoa.

Front Endocrinol (Lausanne) 2019 3;10:435. Epub 2019 Jul 3.

Dipartimento di Medicina Sperimentale, Università degli Studi della Campania L. Vanvitelli, Naples, Italy.

Circular RNAs (circRNAs) are expressed in human testis and seminal plasma. Until today, there is missing information about a possible payload of circRNAs in human spermatozoa (SPZ). With this in mind, we carried out a circRNA microarray identifying a total of 10.726 transcripts, 28% novel based and 84.6% with exonic structure; their potential contribution in molecular pathways was evaluated by KEGG analysis. Whether circRNAs may be related to SPZ quality was speculated evaluating two different populations of SPZ (A SPZ = good quality, B SPZ = low quality), separated on the basis of morphology and motility parameters, by Percoll gradient. Thus, 148 differentially expressed (DE)-circRNAs were identified and the expression of selected specific SPZ-derived circRNAs was evaluated in SPZ head/tail-enriched preparations, to check the preservation of these molecules during SPZ maturation and their transfer into oocyte during fertilization. Lastly, circRNA/miRNA/mRNA network was built by bioinformatics approach.
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http://dx.doi.org/10.3389/fendo.2019.00435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626923PMC
July 2019

CircNAPEPLD is expressed in human and murine spermatozoa and physically interacts with oocyte miRNAs.

RNA Biol 2019 09 14;16(9):1237-1248. Epub 2019 Jun 14.

c Dipartimento di Medicina Sperimentale, sez "F. Bottazzi", Università della Campania "Luigi Vanvitelli" , Napoli , Italy.

Circular RNAs (circRNAs) have a critical role in the control of gene expression. Their function in spermatozoa (SPZ) is unknown to date. Twenty-eight genes, involved in SPZ/testicular and epididymal physiology, were given in circBase database to find which of them may generate circular transcripts. We focused on circNAPEPLDiso1, one of the circular RNA isoforms of NAPEPLD transcript, because expressed in human and murine SPZ. In order to functionally characterize circNAPEPLDiso1 as potential microRNA (miRNA) sponge, we performed circNAPEPLDiso1-miR-CATCH and then profiled the expression of 754 miRNAs, by using TaqMan® Low Density Arrays. Among them, miRNAs 146a-5p, 203a-3p, 302c-3p, 766-3p and 1260a (some of them previously shown to be expressed in the oocyte), resulted enriched in circNAPEPLDiso1-miR-CATCHed cell lysate: the network of interactions generated from their validated targets was centred on a core of genes involved in the control of cell cycle. Moreover, computational analysis of circNAPEPLDiso1 sequence also showed its potential translation in a short form of NAPEPLD protein. Interestingly, the expression analysis in murine-unfertilized oocytes revealed low and high levels of circNAPEPLDiso1 and circNAPEPLDiso2, respectively. After fertilization, circNAPEPLDiso1 expression significantly increased, instead circNAPEPLDiso2 expression appeared constant. Based on these data, we suggest that SPZ-derived circNAPEPLDiso1 physically interacts with miRNAs primarily involved in the control of cell cycle; we hypothesize that it may represent a paternal cytoplasmic contribution to the zygote and function as a miRNA decoy inside the fertilized oocytes to regulate the first stages of embryo development. This role is proposed here for the first time.
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http://dx.doi.org/10.1080/15476286.2019.1624469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693540PMC
September 2019

Editorial: The Multiple Facets of Kisspeptin Activity in Biological Systems.

Front Endocrinol (Lausanne) 2018 3;9:727. Epub 2018 Dec 3.

Department of Movement Sciences and Wellbeing, Parthenope University of Naples, Naples, Italy.

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http://dx.doi.org/10.3389/fendo.2018.00727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286967PMC
December 2018

Analysis of Endocannabinoid System in Rat Testis During the First Spermatogenetic Wave.

Front Endocrinol (Lausanne) 2018 29;9:269. Epub 2018 May 29.

Department of Experimental Medicine, Sez. Bottazzi, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy.

Endocannabinoids are lipid mediators, enzymatically synthesized and hydrolyzed, that bind cannabinoid receptors. Together with their receptors and metabolic enzymes, they form the "endocannabinoid system" (ECS). Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the main endocannabinoids studied in testis. In this study, using the first wave of spermatogenesis as an model to verify the progressive appearance of germ cells in seminiferous tubules [i.e., spermatogonia, spermatocytes, and spermatids], we analyzed the expression of the main enzymes and receptors of ECS in rat testis. In particular, the expression profile of the main enzymes metabolizing AEA and 2-AG as well as the expression of cannabinoid receptors, such as CB1 and CB2, and specific markers of mitotic, meiotic, and post-meiotic germ cell appearance or activities have been analyzed by RT-PCR and appropriately correlated. Our aim was to envisage a relationship between expression of ECS components and temporal profile of germ cell appearance or activity as well as among ECS components. Results show that expression of ECS components is related to germ cell progression. In particular, CB2 and 2-AG appear to be related to mitotic/meiotic stages, while CB1 and AEA appear to be related to spermatogonia stem cells activity and spermatids appearance, respectively. Our data also suggest that a functional interaction among ECS components occurs in the testis. Indeed, -incubated testis show that AEA-CB2 activity affects negatively monoacylglycerol-lipase levels upregulation of CB1 suggesting a CB1/CB2-mediated relationship between AEA and 2-AG. Finally, we provide the first evidence that CB1 is present in fetal gonocytes, during mitotic arrest.
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http://dx.doi.org/10.3389/fendo.2018.00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986923PMC
May 2018

Chronic exposure to low dose of bisphenol A impacts on the first round of spermatogenesis via SIRT1 modulation.

Sci Rep 2018 02 13;8(1):2961. Epub 2018 Feb 13.

Department of Movement Sciences and Wellbeing, University of Naples "Parthenope", Via Medina 40, 80133, Naples, Italy.

Spermatogenesis depends on endocrine, autocrine and paracrine communications along the hypothalamus-pituitary-gonad axis. Bisphenol A (BPA), an estrogen-mimic endocrine disrupting chemical, is an environmental contaminant used to manufacture polycarbonate plastics and epoxy resins with toxic effects for male reproduction. Here we investigated whether the chronic exposure to low BPA doses affects spermatogenesis through the modulation of SIRT1, a NAD-dependent deacetylase involved in the progression of spermatogenesis, with outcomes on apoptosis, oxidative stress, metabolism and energy homeostasis. BPA exposure via placenta first, and lactation and drinking water later, affected the body weight gain in male offspring at 45 postnatal days and the first round of spermatogenesis, with impairment of blood testis barrier, reactive oxygen species production, DNA damage and decreased expression of SIRT1. The analysis of SIRT1 downstream molecular pathways revealed the increase of acetyl-p53, γH2AX foci, the decrease of oxidative stress defenses and the higher apoptotic rate in the testis of treated animals, with partial rescue at sex maturation. In conclusion, SIRT1 pathways disruption after BPA exposure can have serious consequences on the first round of spermatogenesis.
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http://dx.doi.org/10.1038/s41598-018-21076-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811609PMC
February 2018

Impact of Dietary Fats on Brain Functions.

Curr Neuropharmacol 2018 ;16(7):1059-1085

Department of Movement and Wellness Sciences, Parthenope University of Naples, Naples, Italy.

Background: Adequate dietary intake and nutritional status have important effects on brain functions and on brain health. Energy intake and specific nutrients excess or deficiency from diet differently affect cognitive processes, emotions, behaviour, neuroendocrine functions and synaptic plasticity with possible protective or detrimental effects on neuronal physiology. Lipids, in particular, play structural and functional roles in neurons. Here the importance of dietary fats and the need to understand the brain mechanisms activated by peripheral and central metabolic sensors. Thus, the manipulation of lifestyle factors such as dietary interventions may represent a successful therapeutic approach to maintain and preserve brain health along lifespan.

Methods: This review aims at summarizing the impact of dietary fats on brain functions.

Results: Starting from fat consumption, nutrient sensing and food-related reward, the impact of gut-brain communications will be discussed in brain health and disease. A specific focus will be on the impact of fats on the molecular pathways within the hypothalamus involved in the control of reproduction via the expression and the release of Gonadotropin-Releasing Hormone. Lastly, the effects of specific lipid classes such as polyunsaturated fatty acids and of the "fattest" of all diets, commonly known as "ketogenic diets", on brain functions will also be discussed.

Conclusion: Despite the knowledge of the molecular mechanisms is still a work in progress, the clinical relevance of the manipulation of dietary fats is well acknowledged and such manipulations are in fact currently in use for the treatment of brain diseases.
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http://dx.doi.org/10.2174/1570159X15666171017102547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120115PMC
October 2018

Bisphenol A in Reproduction: Epigenetic Effects.

Curr Med Chem 2018 Feb;25(6):748-770

Dipartimento di Scienze Motorie e del Benessere, Universita di Napoli Parthenope, Napoli, Italy.

Background: Bisphenol A (BPA) is an endocrine disrupting chemical widely used in the manufacture of polycarbonate plastic and epoxy resin to produce a multitude of consumer products, food and drink containers, and medical devices. BPA is similar to estradiol in structure and thus interferes in steroid signalling with different outcomes on reproductive health depending on doses, life stage, mode, and timing of exposure. In this respect, it has an emerging and controversial role as a "reproductive toxicant" capable of inducing short and long-term effects including the modulation of gene expression through epigenetic modification (i.e. methylation of CpG islands, histone modifications and production of non-coding RNA) with direct and trans-generational effects on exposed organisms and their offspring, respectively.

Objective: This review provides an overview about BPA effects on reproductive health and aims to summarize the epigenetic effects of BPA in male and female reproduction.

Results: BPA exerts epigenetic effects in both male and female reproduction. In males, BPA affects spermatogenesis and sperm quality and possible trans-generational effects on the reproductive ability of the offspring. In females, BPA affects ovary, embryo development, and gamete quality for successful in vivo and in vitro fertilization (IVF).

Conclusion: The exact mechanisms of BPA-mediated effects in reproduction are not fully understood; however, the environmental exposure to BPA - especially in fetal and neonatal period - deserves attention to preserve the reproductive ability in both sexes and to reduce the epigenetic risk for the offspring.
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http://dx.doi.org/10.2174/0929867324666171009121001DOI Listing
February 2018

Kisspeptin regulates steroidogenesis and spermiation in anuran amphibian.

Reproduction 2017 10;154(4):403-414

Dipartimento di Scienze Motorie e del BenessereUniversità di Napoli Parthenope, Napoli, Italy

Kisspeptin (Kp) system has a recognized role in the control of gonadotropic axis, at multiple levels. Recently, a major focus of research has been to assess any direct activity of this system on testis physiology. Using the amphibian anuran, , as animal model, we demonstrate - for the first time in non-mammalian vertebrate - that testis expresses both Kiss-1 and Gpr54 proteins during the annual sexual cycle and that 17B-estradiol (E, 10 M) increases both proteins over control group. Since the interstitium is the main site of localization of both ligand and receptor, its possible involvement in the regulation of steroidogenesis has been evaluated by treatment of testis pieces with increasing doses of Kp-10 (10-10 M). Treatments have been carried out in February - when a new wave of spermatogenesis occurs - and affect the expression of key enzymes of steroidogenesis inducing opposite effects on testosterone and estradiol intratesticular levels. Morphological analysis of Kp-treated testes reveals higher number of tubules with spermatozoa detached from Sertoli cells than control group and the expression of connexin 43, the main junctional protein in testis, is deeply affected by the treatment. In spite of the effects on spermatozoa observed , administration of Kp-10 has been unable to induce sperm release in cloacal fluid. In conclusion, we demonstrate Kp-10 effects on steroidogenesis with possible involvement in the balance between testosterone and estradiol levels, and report new Kp-10 activities on spermatozoa-Sertoli cell interaction.
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http://dx.doi.org/10.1530/REP-17-0030DOI Listing
October 2017

Bisphenol A induces hypothalamic down-regulation of the the cannabinoid receptor 1 and anorexigenic effects in male mice.

Pharmacol Res 2016 11 15;113(Pt A):376-383. Epub 2016 Sep 15.

Department of Experimental Medicine, Sez. Bottazzi, II University of Naples, 80138, Napoli, Italy.

Bisphenol A is an environment-polluting industrial chemical able to interfere with the endocrine system. An obesogenic effect in perinatally exposed rodents has been described as estrogenic activity. We exposed male mice to Bisphenol A during fetal-perinatal period (from 10 days post coitum to 31 days post partum) and investigated the effects of this early-life exposure at 78 days of age. Body weight, food intake, fat mass, and hypothalamic signals related to anorexigenic control of food intake were analyzed. Results show that Bisphenol A exposure reduced body weight and food intake. In addition, the exposure decreased epididymal fat mass and adiposity, acting negatively on adipocyte volume. At hypothalamic level, Bisphenol A exposure reduced the expression of the cannabinoid receptor 1 and induced gene expression of cocaine and amphetamine-regulated transcript-1. This observation suggests that Bisphenol A induces activation of anorexigenic signals via down-regulation of the hypothalamic cannabinoid receptor 1 with negative impact on food intake.
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http://dx.doi.org/10.1016/j.phrs.2016.09.005DOI Listing
November 2016

Kisspeptins, Estrogens and Male Fertility.

Curr Med Chem 2016 ;23(36):4070-4091

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, Via Medina 40, 80133 Napoli, Italy.

Background: The control of male fertility requires accurate endocrine, paracrine and autocrine communications along the hypothalamus-pituitary-gonad (HPG) axis. In this respect, the possible interplay between upcoming/classical modulators of reproductive functions deserves attention in that may be a successful tool for the future exploitation of new potential therapeutic targets in the treatment of fertility disorders.

Methods: In this review we will discuss upcoming data concerning the role of kisspeptins, the products of the Kiss1 gene, and estrogens - classically considered as female hormones - as well as their possible interplay in testis.

Results: Kisspeptins, via the activation of kisspeptin receptor Gpr54 represent the main gatekeeper of the hypothalamic Gonadotropin Releasing Hormone (GnRH) centrally modulating the onset and maintaining reproductive functions. As a consequence, the loss of kisspeptin signalling causes hypogonadotrophic hypogonadism in humans and animal models. In spite of the well recognized functions at hypothalamic levels, recent data strongly support direct production and activity of kisspeptin in testis and its involvement in the control of Leydig cells, germ cells progression and sperm functions. Similarly, estrogens exhibit high impact on proliferative/apoptotic/differentiative events in testis, thus resulting as local key modulators for the production - but also for the release, transport and maturation - of high quality spermatozoa.

Conclusion: This review summarizes the upcoming data from experimental models and humans concerning the testicular activity of kisspeptins and estrogens to preserve male fertility. Mutual enhancement of kisspeptin and estradiol signalling for the progression of spermatogenesis has also been discussed.
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http://dx.doi.org/10.2174/0929867323666160902155434DOI Listing
February 2017

Effects of Neuroendocrine CB1 Activity on Adult Leydig Cells.

Front Endocrinol (Lausanne) 2016 3;7:47. Epub 2016 Jun 3.

Dipartimento di Medicina Sperimentale, Seconda Università di Napoli , Napoli , Italy.

Endocannabinoids control male reproduction acting at central and local level via cannabinoid receptors. The cannabinoid receptor CB1 has been characterized in the testis, in somatic and germ cells of mammalian and non-mammalian animal models, and its activity related to Leydig cell differentiation, steroidogenesis, spermiogenesis, sperm quality, and maturation. In this short review, we provide a summary of the insights concerning neuroendocrine CB1 activity in male reproduction focusing on adult Leydig cell ontogenesis and steroid biosynthesis.
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http://dx.doi.org/10.3389/fendo.2016.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891325PMC
July 2016

Anandamide acts via kisspeptin in the regulation of testicular activity of the frog, Pelophylax esculentus.

Mol Cell Endocrinol 2016 Jan 14;420:75-84. Epub 2015 Nov 14.

Dipartimento di Medicina Sperimentale sez "F. Bottazzi", Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy. Electronic address:

In the frog Pelophylax esculentus, the endocannabinoid anandamide (AEA) modulates Gonadotropin Releasing Hormone (GnRH) system in vitro and down-regulates steroidogenic enzymes in vivo. Thus, male frogs were injected with AEA ± SR141716A, a cannabinoid receptor 1 (CB1) antagonist, to evaluate possible effects on GnRH and Kiss1/Gpr54 systems, gonadotropin receptors and steroid levels. In frog diencephalons, AEA negatively affected both GnRH and Kiss1/Gpr54 systems. In testis, AEA induced the expression of gonadotropin receptors, cb1, gnrh2 and gnrhr3 meanwhile reducing gnrhr2 mRNA and Kiss1/Gpr54 proteins. Furthermore, aromatase (Cyp19) expression increased in parallel to testosterone decrease and estradiol increase. In vitro treatment of testis with AEA revealed direct effects on Cyp19 and induced the expression of the AEA-degrading enzyme Faah. Lastly, AEA effects on Faah were counteracted by the antiestrogen ICI182780, indicating estradiol mediated effect. In conclusion, for the first time we show in a vertebrate that AEA regulates testicular activity through kisspeptin system.
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http://dx.doi.org/10.1016/j.mce.2015.11.011DOI Listing
January 2016

Expression analysis of gnrh1 and gnrhr1 in spermatogenic cells of rat.

Int J Endocrinol 2015 12;2015:982726. Epub 2015 Mar 12.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, Via Medina 40, 80133 Napoli, Italy.

Hypothalamic Gonadotropin Releasing Hormone (GnRH), via GnRH receptor (GnRHR), is the main actor in the control of reproduction, in that it induces the biosynthesis and the release of pituitary gonadotropins, which in turn promote steroidogenesis and gametogenesis in both sexes. Extrabrain functions of GnRH have been extensively described in the past decades and, in males, local GnRH activity promotes the progression of spermatogenesis and sperm functions at several levels. The canonical localization of Gnrh1 and Gnrhr1 mRNA is Sertoli and Leydig cells, respectively, but ligand and receptor are also expressed in germ cells. Here, we analysed the expression rate of Gnrh1 and Gnrhr1 in rat testis (180 days old) by quantitative real-time PCR (qPCR) and by in situ hybridization we localized Gnrh1 and Gnrhr1 mRNA in different spermatogenic cells of adult animals. Our data confirm the testicular expression of Gnrh1 and of Gnrhr1 in somatic cells and provide evidence that their expression in the germinal compartment is restricted to haploid cells. In addition, not only Sertoli cells connected to spermatids in the last steps of maturation but also Leydig and peritubular myoid cells express Gnrh1.
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http://dx.doi.org/10.1155/2015/982726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377535PMC
April 2015

Kisspeptin drives germ cell progression in the anuran amphibian Pelophylax esculentus: a study carried out in ex vivo testes.

Gen Comp Endocrinol 2015 Jan 18;211:81-91. Epub 2014 Nov 18.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, Via Medina 40, 80133 Napoli, Italy. Electronic address:

Kisspeptin, via Gpr54 receptor, regulates puberty onset in most vertebrates. Thus, the direct involvement of kisspeptin activity in testis physiology was investigated in the anuran amphibian, Pelophylax esculentus. In this vertebrate gpr54 mRNA has been localized in both interstitial compartment and spermatogonia (SPG), whereas SPG proliferation requires the cooperation between estradiol and testicular Gonadotropin releasing hormone (Gnrh). In the pre-reproductive period, dose response curve to assess the effects of Kisspeptin-10 (Kp-10) was carried out in vitro (dose range: 10(-9)-10(-6)M; incubation times: 1 and 4h); proliferative activity and germ cell progression were evaluated by expression analysis of proliferating cell nuclear antigen (pcna), estrogen receptor beta (erβ), Gnrh system (gnrh1, gnrh2, gnrhr1, r2, r3) and by the count of empty, mitotic and meiotic tubules. All selected markers were up regulated at 4h Kp-10 incubation. Histological analysis also proved the increase of mitotic activity and the progression of spermatogenesis. Besides Kp-10 modulation of testicular Gnrh system, in vitro treatment with 17β-estradiol (10(-6)M) ± the antagonist ICI182-780 (10(-5)M) revealed gnrh2 and gnrhr3 estrogen dependent expression. In the reproductive period, testes were incubated for 1 and 4h with Kp-10 (10(-7)M) or Kp-10 (10(-7)M)+kisspeptin antagonist [Kp-234 (10(-6)M)]. Results obtained in the pre-reproductive period were confirmed and Kp-234 completely counteracted Kp-10 effects. In conclusion, Kp-10 modulated the expression of pcna, erβ, gnrhs and gnrhrs, inducing the progression of the spermatogenesis.
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http://dx.doi.org/10.1016/j.ygcen.2014.11.008DOI Listing
January 2015

Modulators of hypothalamic-pituitary-gonadal axis for the control of spermatogenesis and sperm quality in vertebrates.

Front Endocrinol (Lausanne) 2014 18;5:135. Epub 2014 Aug 18.

Department of Experimental Medicine, Second University of Naples , Naples , Italy.

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http://dx.doi.org/10.3389/fendo.2014.00135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135230PMC
September 2014

Molecular chaperones, cochaperones, and ubiquitination/deubiquitination system: involvement in the production of high quality spermatozoa.

Biomed Res Int 2014 19;2014:561426. Epub 2014 Jun 19.

Dipartimento di Medicina Sperimentale, Sezione "F. Bottazzi", Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.

Spermatogenesis is a complex process in which mitosis, meiosis, and cell differentiation events coexist. The need to guarantee the production of qualitatively functional spermatozoa has evolved into several control systems that check spermatogenesis progression/sperm maturation and tag aberrant gametes for degradation. In this review, we will focus on the importance of the evolutionarily conserved molecular pathways involving molecular chaperones belonging to the superfamily of heat shock proteins (HSPs), their cochaperones, and ubiquitination/deubiquitination system all over the spermatogenetic process. In this respect, we will discuss the conserved role played by the DNAJ protein Msj-1 (mouse sperm cell-specific DNAJ first homologue) and the deubiquitinating enzyme Ubpy (ubiquitin-specific processing protease-y) during the spermiogenesis in both mammals and nonmammalian vertebrates.
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http://dx.doi.org/10.1155/2014/561426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089148PMC
March 2015

Intra-testicular signals regulate germ cell progression and production of qualitatively mature spermatozoa in vertebrates.

Front Endocrinol (Lausanne) 2014 8;5:69. Epub 2014 May 8.

Dipartimento di Medicina Sperimentale sez "F. Bottazzi", Seconda Università degli Studi di Napoli , Naples , Italy.

Spermatogenesis, a highly conserved process in vertebrates, is mainly under the hypothalamic-pituitary control, being regulated by the secretion of pituitary gonadotropins, follicle stimulating hormone, and luteinizing hormone, in response to stimulation exerted by gonadotropin releasing hormone from hypothalamic neurons. At testicular level, gonadotropins bind specific receptors located on the somatic cells regulating the production of steroids and factors necessary to ensure a correct spermatogenesis. Indeed, besides the endocrine route, a complex network of cell-to-cell communications regulates germ cell progression, and a combination of endocrine and intra-gonadal signals sustains the production of high quality mature spermatozoa. In this review, we focus on the recent advances in the area of the intra-gonadal signals supporting sperm development.
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http://dx.doi.org/10.3389/fendo.2014.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021137PMC
June 2014

Endocannabinoids are Involved in Male Vertebrate Reproduction: Regulatory Mechanisms at Central and Gonadal Level.

Front Endocrinol (Lausanne) 2014 15;5:54. Epub 2014 Apr 15.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope , Naples , Italy.

Endocannabinoids (eCBs) are natural lipids regulating a large array of physiological functions and behaviors in vertebrates. The eCB system is highly conserved in evolution and comprises several specific receptors (type-1 and type-2 cannabinoid receptors), their endogenous ligands (e.g., anandamide and 2-arachidonoylglycerol), and a number of biosynthetic and degradative enzymes. In the last few years, eCBs have been described as critical signals in the control of male and female reproduction at multiple levels: centrally, by targeting hypothalamic gonadotropin-releasing-hormone-secreting neurons and pituitary, and locally, with direct effects on the gonads. These functions are supported by the extensive localization of cannabinoid receptors and eCB metabolic enzymes at different levels of the hypothalamic-pituitary-gonadal axis in mammals, as well as bonyfish and amphibians. In vivo and in vitro studies indicate that eCBs centrally regulate gonadal functions by modulating the gonadotropin-releasing hormone-gonadotropin-steroid network through direct and indirect mechanisms. Several proofs of local eCB regulation have been found in the testis and male genital tracts, since eCBs control Sertoli and Leydig cells activity, germ cell progression, as well as the acquisition of sperm functions. A comparative approach usually is a key step in the study of physiological events leading to the building of a general model. Thus, in this review, we summarize the action of eCBs at different levels of the male reproductive axis, with special emphasis, where appropriate, on data from non-mammalian vertebrates.
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http://dx.doi.org/10.3389/fendo.2014.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995072PMC
June 2014

Hypothalamus-pituitary axis: an obligatory target for endocannabinoids to inhibit steroidogenesis in frog testis.

Gen Comp Endocrinol 2014 Sep 22;205:88-93. Epub 2014 Feb 22.

Dipartimento di Scienze Motorie e del Benessere, Università di Napoli Parthenope, Italy.

Endocannabinoids - primarily anandamide (AEA) and 2-arachidonoylglycerol (2-AG) - are lipophilic molecules that bind to cannabinoid receptors (CB1 and CB2). They affect neuroendocrine activity inhibiting gonadotropin releasing hormone (GnRH) secretion and testosterone production in rodents, through a molecular mechanism supposed to be hypothalamus dependent. In order to investigate such a role, we choose the seasonal breeder, the anuran amphibian Rana esculenta, an experimental model in which components of the endocannabinoid system have been characterized. In February, at the onset of a new spermatogenetic wave, we carried out in vitro incubations of frog testis with AEA, at 10(-9)M dose. Such a treatment had no effect on the expression of cytochrome P450 17alpha hydroxylase/17,20 lyase (cyp17) nor 3-β-hydroxysteroid dehydrogenase/Δ-5-4 isomerase (3β-HSD), key enzymes of steroidogenesis. To understand whether or not the functionality of the hypothalamus-pituitary axis could be essential to support the role of endocannabinoids in steroidogenesis, frogs were injected with AEA, at 10(-8)M dose. Differently from in vitro experiment, the in vivo administration of AEA reduced the expression of cyp17 and 3β-HSD. Whereas the effect on 3β-HSD was counteracted by SR141716A (Rimonabant) - a selective antagonist of CB1, thus indicating a CB1 dependent modulation - the effect on cyp17 was not, suggesting a possible involvement of receptors other than CB1, probably the type-1 vanilloid receptor (TRPV1), since AEA works as an endocannabinoid and an endovanilloid as well. In conclusion our results indicate that endocannabinoids, via CB1, inhibit the expression of 3β-HSD in frog testis travelling along the hypothalamus-pituitary axis.
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http://dx.doi.org/10.1016/j.ygcen.2014.02.010DOI Listing
September 2014

Estrogens and spermiogenesis: new insights from type 1 cannabinoid receptor knockout mice.

Int J Endocrinol 2013 12;2013:501350. Epub 2013 Nov 12.

Dipartimento di Medicina Sperimentale, Sez. Bottazzi, Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.

Spermatogenesis is a complex mechanism which allows the production of male gametes; it consists of mitotic, meiotic, and differentiation phases. Spermiogenesis is the terminal differentiation process during which haploid round spermatids undergo several biochemical and morphological changes, including extensive remodelling of chromatin and nuclear shape. Spermiogenesis is under control of endocrine, paracrine, and autocrine factors, like gonadotropins and testosterone. More recently, emerging pieces of evidence are suggesting that, among these factors, estrogens may have a role. To date, this is a matter of debate and concern because of the agonistic and antagonistic estrogenic effects that environmental chemicals may have on animal and human with damaging outcome on fertility. In this review, we summarize data which fuel this debate, with a particular attention to our recent results, obtained using type 1 cannabinoid receptor knockout male mice as animal model.
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http://dx.doi.org/10.1155/2013/501350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845505PMC
June 2014

Endocannabinoids and endovanilloids: a possible balance in the regulation of the testicular GnRH signalling.

Int J Endocrinol 2013 29;2013:904748. Epub 2013 Aug 29.

Dipartimento di Medicina Sperimentale Sezione "F. Bottazzi," Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.

Reproductive functions are regulated both at central (brain) and gonadal levels. In this respect, the endocannabinoid system (eCS) has a very influential role. Interestingly, the characterization of eCS has taken many advantages from the usage of animal models different from mammals. Therefore, this review is oriented to summarize the main pieces of evidence regarding eCS coming from the anuran amphibian Rana esculenta, with particular interest to the morphofunctional relationship between eCS and gonadotropin releasing hormone (GnRH). Furthermore, a novel role for endovanilloids in the regulation of a testicular GnRH system will be also discussed.
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http://dx.doi.org/10.1155/2013/904748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773452PMC
June 2014