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Frontiers in Bioscience (Landmark... Jul 2023Hydroxychloroquine (HCQ) toxicity can adversely affect vital organs, cause pathologic ocular damage, and can have direct cardiovascular effects. This study aims to...
BACKGROUND
Hydroxychloroquine (HCQ) toxicity can adversely affect vital organs, cause pathologic ocular damage, and can have direct cardiovascular effects. This study aims to identify the biochemical, hematological, and histological alterations of the vital organs associated with the effects of HCQ.
METHODS
Male albino rats were exposed to the equivalent of HCQ therapeutic doses given to human patients being affected by malaria, lupus erythematosus, and COVID-19. The animal blood samples were subjected to hematological analysis, biochemical analysis, liver function tests, kidney function tests, and cardiac biomarkers. Liver, kidney, heart, spleen, and testis biopsies were subjected to histological examination.
RESULTS
HCQ significantly lowered the values of erythrocytes, hemoglobin, hematocrit, platelets, leucocytes, and lymphocytes but significantly increased the values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, alkaline phosphatase, lactate dehydrogenase, cholesterol, and chlorine ions. The renal tissues of HCQ-treated animals demonstrated glomerular fragmentation, partial atrophy degeneration, renal tubules hydropic degeneration, hyaline cast formation, and interstitial edema formation. Additionally, the heart exhibited myofiber necrosis, myolysis, wavy appearance, disorganization, and disarray. The testicular tissues also demonstrated spermatocyte degeneration, spermatogenic cell sloughing, testicular interstitial edema, and occasional spermatogenic arrest. Additionally, the spleen showed a decrease in the number and size of the white pulp follicles, a decrease in the number of apoptotic activity, and a decline in the number of T-rich cells. However, the red pulp demonstrated a diffuse decline in B rich-lymphocytes and macrophages. The liver was also the least affected but showed Kupffer cell hyperplasia and occasional hepatocyte dysplasia.
CONCLUSIONS
The results indicate that chronic exposure to HCQ could alter the structures and functions of the vital organs.
Topics: Rats; Animals; Humans; Male; Hydroxychloroquine; COVID-19; COVID-19 Drug Treatment; Liver; Necrosis
PubMed: 37525906
DOI: 10.31083/j.fbl2807137 -
PloS One 2020Lamin C2 (LMN C2) is a short product of the lamin a gene. It is a germ cell-specific lamin and has been extensively studied in male germ cells. In this study, we...
Lamin C2 (LMN C2) is a short product of the lamin a gene. It is a germ cell-specific lamin and has been extensively studied in male germ cells. In this study, we focussed on the expression and localization of LMN C2 in fully-grown germinal vesicle (GV) oocytes. We detected LMN C2 in the fully-grown germinal vesicle oocytes of various mammalian species with confirmation done by immunoblotting the wild type and Lmnc2 gene deleted testes. Expression of LMN C2 tagged with GFP showed localization of LMN C2 to the nuclear membrane of the oocyte. Moreover, the LMN C2 protein notably disappeared after nuclear envelope breakdown (NEBD) and the expression of LMN C2 was significantly reduced in the oocytes from aged females and ceased altogether during meiotic maturation. These results provide new insights regarding LMN C2 expression in the oocytes of various mammalian species.
Topics: Animals; Female; Gene Expression Regulation, Developmental; Germ Cells; Laminin; Male; Meiosis; Mice; Mice, Knockout; Nuclear Envelope; Oocytes; Oogenesis; Ovary; RNA, Messenger; Spermatocytes; Testis
PubMed: 32343699
DOI: 10.1371/journal.pone.0229781 -
Molecular Biology of the Cell May 2022Homologous recombination (HR) is an essential meiotic process that contributes to the genetic variation of offspring and ensures accurate chromosome segregation....
Homologous recombination (HR) is an essential meiotic process that contributes to the genetic variation of offspring and ensures accurate chromosome segregation. Recombination is facilitated by the formation and repair of programmed DNA double-strand breaks. These DNA breaks are repaired via recombination between maternal and paternal homologous chromosomes and a subset result in the formation of crossovers. HR and crossover formation is facilitated by synapsis of homologous chromosomes by a proteinaceous scaffold structure known as the synaptonemal complex (SC). Recent studies in yeast and worms have indicated that polo-like kinases (PLKs) regulate several events during meiosis, including DNA recombination and SC dynamics. Mammals express four active PLKs (PLK1-4), and our previous work assessing localization and kinase function in mouse spermatocytes suggested that PLK1 coordinates nuclear events during meiotic prophase. Therefore, we conditionally mutated in early prophase spermatocytes and assessed stages of HR, crossover formation, and SC processes. mutation resulted in increased RPA foci and reduced RAD51/DMC1 foci during zygonema, and an increase of both class I and class II crossover events. Furthermore, the disassembly of SC lateral elements was aberrant. Our results highlight the importance of PLK1 in regulating HR and SC disassembly during spermatogenesis.
Topics: Animals; Cell Cycle Proteins; Chromosome Pairing; DNA; Homologous Recombination; Male; Mammals; Meiosis; Mice; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Spermatogenesis; Synaptonemal Complex; Polo-Like Kinase 1
PubMed: 35274968
DOI: 10.1091/mbc.E21-03-0115 -
Cell Death and Differentiation Nov 2019Lethal (3) malignant brain tumor like 2 (L3MBTL2) is a member of the MBT-domain proteins, which are involved in transcriptional repression and implicated in chromatin...
Lethal (3) malignant brain tumor like 2 (L3MBTL2) is a member of the MBT-domain proteins, which are involved in transcriptional repression and implicated in chromatin compaction. Our previous study has shown that L3MBTL2 is highly expressed in the testis, but its role in spermatogenesis remains unclear. In the present study, we found that L3MBTL2 was most highly expressed in pachytene spermatocytes within the testis. Germ cell-specific ablation of L3mbtl2 in the testis led to increased abnormal spermatozoa, progressive decrease of sperm counts and premature testicular failure in mice. RNA-sequencing analysis on L3mbtl2 deficient testes confirmed that L3MBTL2 was a transcriptional repressor but failed to reveal any significant changes in spermatogenesis-associated genes. Interestingly, L3mbtl2 deficiency resulted in increased γH2AX deposition in the leptotene spermatocytes, subsequent inappropriate retention of γH2AX on autosomes, and defective crossing-over and synapsis during the pachytene stage of meiosis I, and more germ cell apoptosis and degeneration in aging mice. L3MBTL2 interacted with the histone ubiquitin ligase RNF8. Inhibition of L3MBTL2 reduced nuclear RNF8 and ubH2A levels in GC2 cells. L3mbtl2 deficiency led to decreases in the levels of the RNF8 and ubH2A pathway and in histone acetylation in elongating spermatids, and in protamine 1 deposition and chromatin condensation in sperm. These results suggest that L3MBTL2 plays important roles in chromatin remodeling during meiosis and spermiogenesis.
Topics: Acetylation; Animals; Apoptosis; Chromatin; Chromatin Assembly and Disassembly; Histones; Male; Meiotic Prophase I; Mice; Mice, Knockout; Nuclear Proteins; Pachytene Stage; Polycomb-Group Proteins; Sperm Count; Spermatocytes; Spermatogenesis; Testis; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 30760872
DOI: 10.1038/s41418-019-0283-z -
Cell & Bioscience Aug 2022As a member of RNA-binding protein, CDKN2AIP has been shown to play a critical role in stem cell pluripotency and somatic differentiation. Recent studies indicate that...
BACKGROUND
As a member of RNA-binding protein, CDKN2AIP has been shown to play a critical role in stem cell pluripotency and somatic differentiation. Recent studies indicate that Cdkn2aip is essential for spermatogonial self-renewal and proliferation through the activating Wnt-signaling pathway. However, the mechanisms of how Cdkn2aip regulate spermatogenesis is poorly characterized.
RESULTS
We discovered that the CDKN2AIP was expressed in spermatocyte as well as spermatids and participated in spermiogenesis. Cdkn2aip mice exhibited multiple sperm head defects accompanied by age dependent germ cell loss that might be result of protamine replacement failure and impaired SUN1 expression. Loss of Cdkn2aip expression in male mice resulted in synapsis failure in 19% of all spermatocytes and increased apoptosis due to damaged DNA double-strand break (DSB) repair and crossover formation. In vitro, knockdown of Cdkn2aip was associated with extended S phase, increased DNA damage and apoptosis.
CONCLUSIONS
Our findings not only identified the importance of CDKN2AIP in spermiogenesis and germ cell development, but also provided insight upon the driving mechanism.
PubMed: 35989335
DOI: 10.1186/s13578-022-00861-z -
Journal of Hazardous Materials Nov 2020Recent researches have demonstrated that many nanoparticles are harmful to spermatogenesis. However, the reported nanoparticles -elicited testicular pathologies have...
Recent researches have demonstrated that many nanoparticles are harmful to spermatogenesis. However, the reported nanoparticles -elicited testicular pathologies have been mostly confined to hormone levels and sperm quality and quantity, the detail mechanism is still largely unknown and the strategies to reduce the toxicity of nanoparticles on testis are lacking. Here, we found that CdSe/ZnS quantum dots (QDs) exposure impair double-strand break (DSB) repair in spermatocyte, leading to the disruption of meiotic progression and thus cell apoptosis and decreased sperm production. Furthermore, we found that QDs exposure elevates the autophagy. Crucially, both in vitro and in vivo studies indicated that elevated autophagy could down-regulate the expression of the genes responsible for homologous recombination, which is the main pathway for DSB repair during meiosis, indicating that spermatogenesis impairment by CdSe/ZnS QDs is mediated by autophagy. Consequently, injection of autophagy inhibitor (3-MA) restore DSB repair in spermatocytes, resulting in prevention of spermatocyte apoptosis and recovery of spermatogenesis. Our studies strongly indicate that autophagy is key for eliciting the spermatogenesis dysfunction after nanoparticle exposure, and autophagy inhibition can be used as a potential clinical remedy for alleviating the male reproductive toxicity of nanoparticles.
Topics: Autophagy; Cadmium Compounds; Male; Quantum Dots; Selenium Compounds; Spermatogenesis; Sulfides; Zinc Compounds
PubMed: 32454327
DOI: 10.1016/j.jhazmat.2020.122327 -
PloS One 2020Cattleyak are the hybrid offspring between cattle and yak and combine yak hardiness with cattle productivity. Much attempt has been made to examine the mechanisms of...
BACKGROUND
Cattleyak are the hybrid offspring between cattle and yak and combine yak hardiness with cattle productivity. Much attempt has been made to examine the mechanisms of male sterility caused by spermatogenic arrest, but yet there is no research systematically and precisely elucidated testis gene expression profiling between cattleyak and yak.
METHODS
To explore the higher resolution comparative transcriptome map between the testes of yak and cattleyak, and further analyze the mRNA expression dynamics of spermatogenic arrest in cattleyak. We characterized the comparative transcriptome profile from the testes of yak and cattleyak using high-throughput sequencing. Then we used quantitative analysis to validate several differentially expressed genes (DEGs) in testicular tissue and spermatogenic cells.
RESULTS
Testis transcriptome profiling identified 6477 DEGs (2919 upregulated and 3558 downregulated) between cattleyak and yak. Further analysis revealed that the marker genes and apoptosis regulatory genes for undifferentiated spermatogonia were upregulated, while the genes for differentiation maintenance were downregulated in cattleyak. A majority of DEGs associated with mitotic checkpoint, and cell cycle progression were downregulated in cattleyak during spermatogonial mitosis. Furthermore, almost all DEGs related to synaptonemal complex assembly, and meiotic progression presented no sign of expression in cattleyak. Even worse, dozens of genes involved in acrosome formation, and flagellar development were dominantly downregulated in cattleyak.
CONCLUSION
DEGs indicated that spermatogenic arrest of cattleyak may originate from the differentiation stage of spermatogonial stem cells and be aggravated during spermatogonial mitosis and spermatocyte meiosis, which contributes to the scarcely presented sperms in cattleyak.
Topics: Animals; Azoospermia; Cattle; Chimera; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Infertility, Male; Male; Meiosis; Spermatocytes; Spermatogenesis; Spermatogonia; Spermatozoa; Testis; Transcriptome
PubMed: 32092127
DOI: 10.1371/journal.pone.0229503 -
Bioscience Reports Jun 2021To facilitate temperature adjustments, the testicles are located outside the body cavity. In most mammals, the temperature of the testes is lower than the body... (Review)
Review
To facilitate temperature adjustments, the testicles are located outside the body cavity. In most mammals, the temperature of the testes is lower than the body temperature to ensure the normal progression of spermatogenesis. Rising temperatures affect spermatogenesis and eventually lead to a decline in male fertility or even infertility. However, the testes are composed of different cell types, including spermatogonial stem cells (SSCs), spermatocytes, spermatozoa, Leydig cells, and Sertoli cells, which have different cellular responses to heat stress. Recent studies have shown that using different drugs can relieve heat stress-induced reproductive damage by regulating different signaling pathways. Here, we review the mechanisms by which heat stress damages different cells in testes and possible treatments.
Topics: Animals; Blood-Testis Barrier; Fertility; Fertility Agents, Male; Heat-Shock Proteins; Heat-Shock Response; Hot Temperature; Humans; Infertility, Male; Leydig Cells; Male; Risk Factors; Sertoli Cells; Signal Transduction; Spermatocytes; Spermatogonia; Testis
PubMed: 34060622
DOI: 10.1042/BSR20210443 -
Frontiers in Endocrinology 2021Fine particulate matter (PM)-induced male reproductive toxicity arouses global public health concerns. However, the mechanisms of toxicity remain unclear. This study...
Analysis by Metabolomics and Transcriptomics for the Energy Metabolism Disorder and the Aryl Hydrocarbon Receptor Activation in Male Reproduction of Mice and GC-2spd Cells Exposed to PM.
Fine particulate matter (PM)-induced male reproductive toxicity arouses global public health concerns. However, the mechanisms of toxicity remain unclear. This study aimed to further investigate toxicity pathways by exposure to PM and through the application of metabolomics and transcriptomics. , spermatocyte-derived GC-2spd cells were treated with 0, 25, 50, 100 μg/mL PM for 48 h. , the real-world exposure of PM for mouse was established. Forty-five male C57BL/6 mice were exposed to filtered air, unfiltered air, and concentrated ambient PM in Tangshan of China for 8 weeks, respectively. The results and showed that PM exposure inhibited GC-2spd cell proliferation and reduced sperm motility. Mitochondrial damage was observed after PM treatment. Increased Humanin and MOTS-c levels and decreased mitochondrial respiratory indicated that mitochondrial function was disturbed. Furthermore, nontargeted metabolomics analysis revealed that PM exposure could disturb the citrate cycle (TCA cycle) and reduce amino acids and nucleotide synthesis. Mechanically, the aryl hydrocarbon receptor (AhR) pathway was activated after exposure to PM, with a significant increase in CYP1A1 expression. Further studies showed that PM exposure significantly increased both intracellular and mitochondrial reactive oxygen species (ROS) and activated NRF2 antioxidative pathway. With the RNA-sequencing technique, the differentially expressed genes induced by PM exposure were mainly enriched in the metabolism of xenobiotics by the cytochrome P450 pathway, of which was the most significantly changed gene. Our findings demonstrated that PM exposure could induce spermatocyte damage and energy metabolism disorder. The activation of the aryl hydrocarbon receptor might be involved in the mechanism of male reproductive toxicity.
Topics: Air Pollutants; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Citric Acid Cycle; Cytochrome P-450 Enzyme System; Energy Metabolism; Gene Expression Profiling; Male; Metabolome; Metabolomics; Mice; Mice, Inbred C57BL; Mitochondria; Particulate Matter; Reactive Oxygen Species; Receptors, Aryl Hydrocarbon; Reproduction; Sperm Motility; Spermatocytes; Transcriptome; Xenobiotics
PubMed: 35046903
DOI: 10.3389/fendo.2021.807374 -
PeerJ 2022Leptin is a 16 kDa hormone encoded by obese () gene in adipocytes. This molecule not only regulates energy metabolism but also plays a role in the reproduction of...
Leptin is a 16 kDa hormone encoded by obese () gene in adipocytes. This molecule not only regulates energy metabolism but also plays a role in the reproduction of mammals. Leptin and its receptor () have been found in male reproductive systems of human, bovine, equine and pig. The effects of leptin on sperm quality vary widely from different research findings. However, the presence of leptin and its receptor in the ram reproductive system and the effect of leptin on sperm quality have not reported yet. In the present study, we found that the was highly expressed in primary and secondary spermatocytes of the testes, was highly expressed in secondary spermatocytes of the testes. The expressions of were in stereocilia of epididymis and in columnar cells of epididymal caput and cauda, the expressions of were in columnar cells of epididymis and in stereocilia of epididymal and cauda. The presence of both and in testes, epididymis and sperm were confirmed through RT-PCR, immunolocalization and Western blot analyses. The RT-qPCR results indicated and had higher expression levels in epididymal sperm than that of the ejaculated sperm in rams. When sperm were treated with 5 ng/mL leptin, the progressive motility ( < 0.01), straight-line velocity (VSL) ( < 0.05), average path velocity (VAP) ( < 0.05), membrane mitochondrial potential (MMP) ( < 0.01) and viability ( < 0.05) significantly increased, while DNA fragmentation index (DFI) and reactive oxygen species (ROS) significantly decreased compared to the control ( < 0.01), and the other semen parameters such as acrosome integrity and acrosome reaction rate had no significant changes between groups ( > 0.05). In conclusion, this is probably the first report describing localization of leptin and its receptors in the reproductive system of rams and their effects on sperm quality parameters. Our findings suggest that 5 ng/mL leptin treatment enhanced sperm motility, viability and MMP, and decrease DFI and ROS without obvious influence on the acrosome reaction in ram sperm. The potential mechanisms may be related to leptin's ability to reduce the oxidative stress and apoptosis of sperms and improve their mitochondrial function and energy supply, therefore, to maintain the physiological homeostasis of the sperm.
Topics: Male; Animals; Sheep; Cattle; Horses; Humans; Swine; Semen; Leptin; Reactive Oxygen Species; Sperm Motility; Spermatozoa; Sheep, Domestic; Genitalia
PubMed: 36187750
DOI: 10.7717/peerj.13982