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

Chioccarelli, Teresa; Migliaccio, Marina; Suglia, Antonio; Manfrevola, Francesco; Porreca, Veronica; Diano, Nadia; Errico, Sonia; Fasano, Silvia; Cobellis, Gilda

doi:10.3390/ijms22052540

Cited by 8 publications

(3 citation statements)

References 92 publications

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“…The Wnt/β-catenin signalling pathway is a key pathway that regulates spermatogenesis [ 23 ]. Chioccarelli et al investigated the effects of bisphenol A (BPA) on germ cells and showed that BPA increases the content of germ cells (spermatogonia), reduces the population of spermatocytes and sperm cells, accelerates the process of spermatocyte and sperm cells, and promotes the epithelial exfoliation of round and concentrated sperm cells; these phenomena are accompanied by the downregulation of β-catenin [ 24 ]. In the present study, the proliferation of rat spermatogonia is facilitated by the silencing of CAM2D .…”

Section: Discussionmentioning

confidence: 99%

Silencing CAMK2D Promotes the Proliferation of Spermatogonia in the Testis of Experimental Varicocele Rats

Tang

Yang

Ding

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Varicocele is regarded as the main factor that contributes to male infertility. This study aimed to explore the effect of CAMK2D on spermatogonia in the testis of experimental varicocele rats. The experimental varicocele model was established in rats and treated using different ligation methods. mRNA expression profile analysis was performed on the left testicular tissue isolated from different groups, and differentially expressed genes (DEGs) were analysed by bioinformatics methods and identified by qRT-PCR. The effect of CAMK2D, the screened DEG, on the proliferation of spermatogonia was evaluated by CCK-8 assay. The expression level of the c-kit was measured by the immunofluorescence assay and the expression levels of CAMKII, FOXO1, and β-catenin were detected by qRT-PCR and western blotting. Five DEGs (i.e., TMCC3, FLNB, CAMK2D, OPLAH, and EGR1) were screened using the comprehensive analysis of mRNA high-throughput sequencing data. TMCC3 and FLNB were significantly downregulated, and CAMK2D, OPLAH, and EGR1 were dramatically upregulated in the testicular tissue of varicocele rats. The target DEG CAMK2D was obtained through identification by using qRT-PCR. In vitro assays revealed that the proliferation of spermatogonia was significantly facilitated by the silencing of CAMK2D, which resulted in the downregulation of CAMKII, FOXO1, and β-catenin. In conclusion, silencing CAMK2D facilitated the proliferation of spermatogonia in the testis of experimental varicocele rats.

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Section: Discussionmentioning

confidence: 99%

Silencing CAMK2D Promotes the Proliferation of Spermatogonia in the Testis of Experimental Varicocele Rats

Tang

Yang

Ding

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Indeed, several epidemiological and experimental studies have highlighted specific male reproductive defects depending on the type of contaminant and on the exposure window ( Barakat et al , 2019 ; Campos et al , 2019 ; Selvaraju et al , 2021 ). In particular, EC exposure impairs spermatogenesis and gamete health by inducing multiple anomalies, such as: deregulation of spermatogenic cycle timing; production of reactive oxygen species (ROS); Sertoli and germ cell apoptosis; germ cell abnormal chromosomal segregation and DNA fragmentation; steroidogenesis defects; disruption of blood-testis-barrier integrity and permeability; and alteration of sperm morphology and motility ( Jeng, 2014 ; Easley et al , 2015 ; Governini et al , 2015 ; Qiu et al , 2016 ; Aydin and Erkan, 2017 ; Jia et al , 2017 ; Rodríguez et al , 2017 ; Zhang et al , 2018 ; Santoro et al , 2019 ; Maske et al , 2020 ; Chioccarelli et al , 2021b ).…”

Section: Introductionmentioning

confidence: 99%

Variation of sperm quality and circular RNA content in men exposed to environmental contamination with heavy metals in ‘Land of Fires’, Italy

Grazia Mele,

Chioccarelli,

Diano

et al. 2024

Human Reproduction

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STUDY QUESTION Can illegal discharge of toxic waste into the environment induce a new condition of morpho-epigenetic pathozoospermia in normozoospermic young men? SUMMARY ANSWER Toxic environmental contaminants promote the onset of a new pathozoospermic condition in young normozoospermic men, consisting of morpho-functional defects and a sperm increase of low-quality circular RNA (circRNA) cargo, tightly linked to contaminant bioaccumulation in seminal plasma. WHAT IS KNOWN ALREADY Epidemiological findings have reported several reproductive anomalies depending on exposure to contaminants discharged into the environment, such as germ cell apoptosis, steroidogenesis defects, oxidative stress induction, blood–testis barrier dysfunctions, and poor sperm quality onset. In this scenario, a vast geographical area located in Campania, Italy, called the ‘Land of Fires’, has been associated with an excessive illegal discharge of toxic waste into the environment, negatively impacting human health, including male reproductive functions. STUDY DESIGN, SIZE, DURATION Semen samples were obtained from healthy normozoospermic men divided into two experimental groups, consisting of men living in the ‘Land of Fires’ (LF; n = 80) or not (CTRL; n = 80), with age ranging from 25 to 40 years. The study was carried out following World Health Organization guidelines. PARTICIPANTS/MATERIALS, SETTING, METHODS Quality parameters of semen from CTRL- and LF-normozoospermic men were evaluated by computer-assisted semen analysis; high-quality spermatozoa from CTRL and LF groups (n = 80 for each experimental group) were obtained using a 80–40% discontinuous centrifugation gradient. Seminal plasma was collected following centrifugation and used for the dosage of chemical elements, dioxins and steroid hormones by liquid chromatography with tandem mass spectrometry. Sperm morpho-functional investigations (cellular morphology, acrosome maturation, IZUMO1 fertility marker analysis, plasma membrane lipid state, oxidative stress) were assessed on the purified high-quality spermatozoa fraction by immunochemistry/immunofluorescence and western blot analyses. Sperm circRNA cargo was evaluated by quantitative RT-PCR, and the physical interaction among circRNAs and fused in sarcoma (FUS) protein was detected using an RNA-binding protein immunoprecipitation assay. Protein immunoprecipitation experiments were carried out to demonstrate FUS/p-300 protein interaction in sperm cells. Lastly, in vitro lead (Pb) treatment of high-quality spermatozoa collected from normozoospermic controls was used to investigate a correlation between Pb accumulation and onset of the morpho-epigenetic pathozoospermic phenotype. MAIN RESULTS AND THE ROLE OF CHANCE Several morphological defects were identified in LF-spermatozoa, including: a significant increase (P < 0.05 versus CTRL) in the percentage of spermatozoa characterized by structural defects in sperm head and tail; and a high percentage (P < 0.01) of peanut agglutinin and IZUMO1 null signal cells. In agreement with these data, abnormal steroid hormone levels in LF seminal plasma suggest a premature acrosome reaction onset in LF-spermatozoa. The abnormal immunofluorescence signals of plasma membrane cholesterol complexes/lipid rafts organization (Filipin III and Flotillin-1) and of oxidative stress markers [3-nitrotyrosine and 3-nitrotyrosine and 4-hydroxy-2-nonenal] observed in LF-spermatozoa and associated with a sperm motility reduction (P < 0.01), demonstrated an affected membrane fluidity, potentially impacting sperm motility. Bioaccumulation of heavy metals and dioxins occurring in LF seminal plasma and a direct correlation between Pb and deregulated circRNAs related to high- and low-sperm quality was also revealed. In molecular terms, we demonstrated that Pb bioaccumulation promoted FUS hyperacetylation via physical interaction with p-300 and, in turn, its shuttling from sperm head to tail, significantly enhancing (P < 0.01 versus CTRL) the endogenous backsplicing of sperm low-quality circRNAs in LF-spermatozoa. LIMITATIONS, REASONS FOR CAUTION Participants were interviewed to better understand their area of origin, their eating habits as well as their lifestyles, however any information incorrectly communicated or voluntarily omitted that could potentially compromise experimental group determination cannot be excluded. A possible association between seminal Pb content and other heavy metals in modulating sperm quality should be explored further. Future investigations will be performed in order to identify potential synergistic or anti-synergistic effects of heavy metals on male reproduction. WIDER IMPLICATIONS OF THE FINDINGS Our study provides new findings regarding the effects of environmental contaminants on male reproduction, highlighting how a sperm phenotype classified as normozoospermic may potentially not match with a healthy morpho-functional and epigenetic one. Overall, our results improve the knowledge to allow a proper assessment of sperm quality through circRNAs as biomarkers to select spermatozoa with high morpho-epigenetic quality to use for ART. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by ‘Convenzione Azienda Sanitaria Locale (ASL) Caserta, Regione Campania’ (ASL CE Prot. N. 1217885/DIR. GE). The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER N/A.

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“…By looking at the content of reproductive research, it was possible to determine its trends. Among the selected papers, about half were related to male reproduction, e.g., testis and sperm, [1][2][3][4][5][6][7][8][9][10][11][12], and the other half were associated with female reproduction, e.g., oocytes, as well as embryos and their implantation, including three reviews [13][14][15][16][17][18][19][20][21][22][23][24][25].…”

mentioning

confidence: 99%

The Development, Differentiation, and Toxicity in Reproduction

Kim

Choi

2022

IJMS

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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

Cited by 8 publications

References 92 publications

Silencing CAMK2D Promotes the Proliferation of Spermatogonia in the Testis of Experimental Varicocele Rats

Silencing CAMK2D Promotes the Proliferation of Spermatogonia in the Testis of Experimental Varicocele Rats

Variation of sperm quality and circular RNA content in men exposed to environmental contamination with heavy metals in ‘Land of Fires’, Italy

The Development, Differentiation, and Toxicity in Reproduction

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