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28 pages, 3469 KiB  
Review
Prostate Cancer Treatments and Their Effects on Male Fertility: Mechanisms and Mitigation Strategies
by Aris Kaltsas, Nikolaos Razos, Zisis Kratiras, Dimitrios Deligiannis, Marios Stavropoulos, Konstantinos Adamos, Athanasios Zachariou, Fotios Dimitriadis, Nikolaos Sofikitis and Michael Chrisofos
J. Pers. Med. 2025, 15(8), 360; https://doi.org/10.3390/jpm15080360 (registering DOI) - 7 Aug 2025
Abstract
Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men worldwide. Although traditionally considered a disease of older men, the incidence of early-onset PCa (diagnosis < 55 years) is steadily rising. Advances in screening and therapy have significantly improved survival, creating [...] Read more.
Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men worldwide. Although traditionally considered a disease of older men, the incidence of early-onset PCa (diagnosis < 55 years) is steadily rising. Advances in screening and therapy have significantly improved survival, creating a growing cohort of younger survivors for whom post-treatment quality of life—notably reproductive function—is paramount. Curative treatments such as radical prostatectomy, pelvic radiotherapy, androgen-deprivation therapy (ADT), and chemotherapy often cause irreversible infertility via multiple mechanisms, including surgical disruption of the ejaculatory tract, endocrine suppression of spermatogenesis, direct gonadotoxic injury to the testes, and oxidative sperm DNA damage. Despite these risks, fertility preservation is frequently overlooked in pre-treatment counseling, leaving many patients unaware of their options. This narrative review synthesizes current evidence on how PCa therapies impact male fertility, elucidates the molecular and physiological mechanisms of iatrogenic infertility, and evaluates both established and emerging strategies for fertility preservation and restoration. Key interventions covered include sperm cryopreservation, microsurgical testicular sperm extraction (TESE), and assisted reproductive technologies (ART). Psychosocial factors influencing decision-making, novel biomarkers predictive of post-treatment spermatogenic recovery, and long-term offspring outcomes are also examined. The review underscores the urgent need for timely, multidisciplinary fertility consultation as a routine component of PCa care. As PCa increasingly affects men in their reproductive years, proactively integrating preservation into standard oncologic practice should become a standard survivorship priority. Full article
(This article belongs to the Special Issue Clinical Advances in Male Genitourinary and Sexual Health)
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31 pages, 865 KiB  
Review
Beneficial Effects of Resveratrol on Testicular Functions: Focus on Its Antioxidant Properties
by Adele Chimento, Arianna De Luca, Massimo Venditti, Francesca De Amicis and Vincenzo Pezzi
Cells 2025, 14(14), 1122; https://doi.org/10.3390/cells14141122 - 21 Jul 2025
Viewed by 550
Abstract
Male infertility is a pathological condition that affects many subjects and for which a progressive increase in cases has been observed in recent years. The mechanisms underlying male reproductive system dysfunction are not fully understood and the specific drugs use has not produced [...] Read more.
Male infertility is a pathological condition that affects many subjects and for which a progressive increase in cases has been observed in recent years. The mechanisms underlying male reproductive system dysfunction are not fully understood and the specific drugs use has not produced optimal results. Therefore, the focus on developing new therapeutic options to prevent or treat this dysfunction is continuously growing. Defective sperm function has been associated with oxidative stress (OS) due to reactive oxygen species (ROS) excessive production. OS is related to mitochondrial dysfunction, lipid peroxidation, DNA damage and fragmentation, and ultimately sperm cell death. Many defense mechanisms to protect from ROS injuries have been developed; natural antioxidants, such as vitamin C and E are able to interact with oxidizing radicals, neutralizing them. Interestingly, resveratrol (RSV), a natural polyphenol with proven health-promoting actions, has been found to be an effective free radical scavenger in several in vitro and in vivo models, providing protection against OS. In this review, we discussed mechanisms related to the modulation of redox homeostasis in the testis and how the alteration of these processes can determine a damage in testicular function; particularly, we focused on the antioxidant properties of RSV that could give beneficial effects in preserving male fertility. Full article
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16 pages, 4010 KiB  
Article
Nano-Curcumin Mitigates Doxorubicin-Induced Reproductive Toxicity via Antioxidant, Anti-Apoptosis, and SIRT1-Modulating Effects in Rat Model
by Noha A. Alshuwayer, Qamraa H. Alqahtani, Marwa H. Hussein, Raeesa Mohammed, Abdulaziz Siyal and Iman H. Hasan
Toxics 2025, 13(7), 574; https://doi.org/10.3390/toxics13070574 - 8 Jul 2025
Viewed by 531
Abstract
Background: Doxorubicin (DOX) is a potent anti-cancer agent that is widely described in cancer treatment. However, its administration is often limited by its adverse effects, particularly its testicular toxicity, which can induce infertility in male patients. DOX-induced testicular damage is due to oxidative [...] Read more.
Background: Doxorubicin (DOX) is a potent anti-cancer agent that is widely described in cancer treatment. However, its administration is often limited by its adverse effects, particularly its testicular toxicity, which can induce infertility in male patients. DOX-induced testicular damage is due to oxidative stress, apoptosis, and inflammation. Nanocurcumin (NCR) is a nano-formulated edition of curcumin with a higher therapeutic potential. NCR has demonstrated antioxidant and anti-inflammatory properties. Methods: This study is designed to inspect the potential validity of NCR on DOX-induced testicular damage in male rats. We used thirty-two Wistar albino rats (150–200 g) and divided them into four groups. NCR (80 mg/kg/ dissolved in 1% CMC) was given orally by oral gavage for 14 days. A single dose of DOX (15 mg/kg) (i.p.) was injected on the 7th day of the experiment. Results: DOX treatment reduced the sperm viability and motility rate, cellular antioxidants, and gonadal hormones; it led to higher levels of inflammatory mediators, necrosis, and sloughing in seminiferous tubules. Conversely, NCR treatment significantly alleviated these side effects by improving sperm count/motility and reducing sperm abnormalities. The testicular function recovery was likely driven by stimulating the cytoprotective SIRT1/NF-κB pathway, depressing the testicular level of oxidative indicators such as MDA, TNF-α, iNOS, IL-1β, and NO, and increasing levels of antioxidants such as GSH and SOD. In addition, NCR contradicted the apoptotic changes by downregulating the pro-apoptotic signals Bax and caspase-3, while inducing Bcl-2 upregulation. Moreover, NCR increased levels of gonadal hormones, attenuated histological abnormalities, and preserved testicular structure when compared with the DOX group. Conclusions: NCR treatment can effectively ameliorate DOX-induced testicular toxicity. Full article
(This article belongs to the Special Issue Drug and Pesticides-Induced Oxidative Stress and Apoptosis)
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13 pages, 5262 KiB  
Article
The Relationship Between Tramadol-Induced Oxidative Testis Injury and Reproductive Function Disorder and Adenosine Triphosphate
by Fevzi Bedir, Hüseyin Kocatürk, Mehmet Sefa Altay, Renad Mammadov, Bahadır Süleyman, Taha Abdulkadir Coban, Gülce Naz Yazici, Seval Bulut and Halis Süleyman
Life 2025, 15(7), 1078; https://doi.org/10.3390/life15071078 - 6 Jul 2025
Viewed by 469
Abstract
Tramadol, a central analgesic drug, is used to treat moderate to severe pain but can cause reproductive disorders. The pathogenesis of tramadol-induced reproductive damage may involve increased oxidative stress, pro-inflammatory cytokines, ATP depletion, and reduced antioxidant levels. In this study, subjects were divided [...] Read more.
Tramadol, a central analgesic drug, is used to treat moderate to severe pain but can cause reproductive disorders. The pathogenesis of tramadol-induced reproductive damage may involve increased oxidative stress, pro-inflammatory cytokines, ATP depletion, and reduced antioxidant levels. In this study, subjects were divided into four groups: healthy control (HC), tramadol only (TM), ATP only (ATP), and ATP + tramadol (ATM). ATP was administered intraperitoneally at 4 mg/kg, and tramadol was administered orally at 50 mg/kg. Distilled water was given to the HC group. This regimen was repeated for three weeks. At the end of the treatment, testicular tissues from six rats in each group were analyzed biochemically and histopathologically after euthanasia. The remaining rats’ reproductive functions were evaluated. Long-term tramadol exposure resulted in oxidative stress, inflammation in testicular tissue, and reduced male reproductive capacity. Thinning of seminiferous tubule walls and thickening of basement membrane, irregularity in germ cells, increase in interstitial connective tissue, congestion in vessels, increase in Leyding cells and hyperplasia were found in the TM group. ATP treatment significantly reduced tramadol-induced increases in oxidants and pro-inflammatory cytokines, reversed the decline in antioxidants, and mitigated infertility in testicular tissue. Furthermore, ATP preserved the morphology of the testicular tissue. These findings suggest that ATP may offer therapeutic potential for tramadol-induced infertility. Full article
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13 pages, 1335 KiB  
Article
Astaxanthin Alleviates the Decline of Sperm Quality Caused by Heat Stress in Mice via Reducing Oxidative Stress
by Jing Wang, Yuchuan Luo, Yifeilong He, Wanzhen Li, Yinghe Qin and Yingjie Wu
Life 2025, 15(6), 851; https://doi.org/10.3390/life15060851 - 25 May 2025
Viewed by 1125
Abstract
Heat stress impairs spermatogenesis primarily through increased testicular oxidative stress. Astaxanthin, a potent antioxidant, has shown beneficial effects in sperm cryopreservation. However, its potential to mitigate testicular damage induced by elevated temperatures remains uninvestigated. In this study, male mice were administered astaxanthin (10 [...] Read more.
Heat stress impairs spermatogenesis primarily through increased testicular oxidative stress. Astaxanthin, a potent antioxidant, has shown beneficial effects in sperm cryopreservation. However, its potential to mitigate testicular damage induced by elevated temperatures remains uninvestigated. In this study, male mice were administered astaxanthin (10 mg/kg/d, 50 mg/kg/d, and 100 mg/kg/d) via gavage for 21 days, with heat exposure occurring during the final 14 days. Samples were collected after the last treatment or following a recovery period. Spermatozoa in the cauda epididymis were assessed using computer-aided sperm analysis (CASA) or Diff-Quik staining, and serum testosterone levels and oxidative stress markers in both serum and testis were quantified via enzyme-linked immunosorbent assay (ELISA). Heat treatment resulted in significant reductions in sperm motility, viability, and morphological integrity. However, daily supplementation of astaxanthin at 50 mg/kg and 100 mg/kg effectively alleviated these heat-induced impairments. Furthermore, astaxanthin at 50 mg/kg/d notably improved testis weight, testis index, and serum testosterone levels under heat stress. Its antioxidant capacity was validated by significant restoration of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and reduction in malondialdehyde (MDA) levels in both testis and serum. In conclusion, this study highlights the protective effects of astaxanthin against heat-induced testicular and sperm damage by reducing oxidative stress, supporting its potential use as a nutritional or nutraceutical supplement to promote male reproductive health, particularly in the context of summer subfertility in farm animals. Full article
(This article belongs to the Section Animal Science)
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15 pages, 5379 KiB  
Article
Activity of Different Types of Cactus Forage on Testicular Function and Morphology of Sheep Subjected to Environmental Heat Stress
by Giselle Woolley Cardoso da Silva, Fernanda Carolina Ribeiro Dias, Marli do Carmo Cupertino, Alluanan Adelson do Nascimento Silva, Ângela Maria Vieira Batista, Emanuel Felipe de Oliveira Filho, Francisco Fernando Ramos de Carvalho, Ana Lúcia Figueiredo Porto and Valdemiro Amaro da Silva Júnior
Vet. Sci. 2025, 12(5), 492; https://doi.org/10.3390/vetsci12050492 - 19 May 2025
Viewed by 550
Abstract
In this study, we aim to analyze whether supplementation with cactus has the potential to minimize the testicular damage caused by heat stress, assess which of the three cactuses would have the best potential, and suggest a possible pathway (oxidative or hormonal) for [...] Read more.
In this study, we aim to analyze whether supplementation with cactus has the potential to minimize the testicular damage caused by heat stress, assess which of the three cactuses would have the best potential, and suggest a possible pathway (oxidative or hormonal) for the action of cactus on the testicular parameter alterations caused by heat stress. Thirty-two male lambs, of the Santa Inês type, not castrated, approximately six months old, and averaging 21.0 ± 2.0 kg body weight, were divided into four groups, as follows: G1, which was fed an elephant grass hay diet (control); G2, with a diet with partial replacement using small cactus forage (Opuntia cochenillifera) (SMALL); G3, which was fed Mexican elephant ear (Opuntia stricta Haw) (MEE); and G4, which was fed IPA Sertania (Nopalea cochenillifera Salm Dyck) (IPA) for 63 days. After slaughter, blood and testicles were removed. The right testicles were fixed for histological analyses, and the left testicles were stored in the freezer for oxidative stress analyses. Serum testosterone, T3, and T4 levels were analyzed. The body weight of animals treated with cactus forage was higher than in the control group. However, the gonadosomatic index did not differ among experimental groups. Heat stress triggered the degradation of testis tissue in all experimental groups. The testicular degeneration process was characterized by tubular atrophy, reduction in germ epithelium height, germ cell vacuolization and necrosis, Sertoli cell vacuolization, germ cell scaling of the tubular fire, and increased intertubular space. The three different cactus forages used in this study had different weaknesses regarding their antioxidant defenses, hormonal levels, and histopathology. However, it is important to highlight that the IPA group had lower qualitative changes in the intertubular areas than the other experimental groups. The testosterone level increased in MEE (Opuntia stricta) and IPA groups, while T3 and T4 increased in SMALL (Opuntia cochenillifera) and IPA groups. The malondialdehyde, an important marker of lipid peroxidation, was reduced only in the IPA group. The testosterone level increased in MEE and IPA groups, while T3 and T4 increased in SMALL and IPA groups. In conclusion, heat stress triggers several histopathologies in testis tissue, and IPA cactus (Nopalea cochenillifera) was the most appropriate supplementation for reducing the damages, compared with an elephant grass hay diet or small cactus forage and Mexican elephant ear supplementation. Full article
(This article belongs to the Section Anatomy, Histology and Pathology)
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18 pages, 4023 KiB  
Article
Lactobacillus brevis GKJOY Supplementation Ameliorates Oxidative Stress and Reproductive Dysfunction in Male Rats with Polystyrene Microplastics-Induced Reproductive Toxicity
by Yi-Yuh Hwang, Sabri Sudirman, Yu-Chen Hsu, Chin-Chu Chen, Fanbin Kong, Deng-Fwu Hwang and Zwe-Ling Kong
Int. J. Mol. Sci. 2025, 26(10), 4533; https://doi.org/10.3390/ijms26104533 - 9 May 2025
Viewed by 703
Abstract
The growing demand for plastic products has led to an increase in human exposure to microplastics (MPs). MPs have been shown to have detrimental effects on reproductive function, while probiotics have demonstrated promise in enhancing fertility. This study aimed to determine the protective [...] Read more.
The growing demand for plastic products has led to an increase in human exposure to microplastics (MPs). MPs have been shown to have detrimental effects on reproductive function, while probiotics have demonstrated promise in enhancing fertility. This study aimed to determine the protective effects of Lactobacillus brevis GKJOY against reproductive damage induced by polystyrene microplastics (PS-MPs) in male rats. In the cell study, LC540 cells were treated with L. brevis GKJOY postbiotic (PGK), gamma-aminobutyric acid (GABA), and PS-MPs to evaluate their effects on cell viability and reactive oxygen species (ROS) production. In the animal experiment, rats were treated with a low dose of L. brevis GKJOY (GK1X, 50 mg/kg), a medium dose (GK2X, 100 mg/kg), or a high dose (GK4X, 200 mg/kg). The results showed that PGK and GABA reduced the levels of ROS and protected against oxidative stress. In contrast, PS-MPs increased ROS levels and had harmful effects on cell viability. In the animal study, testicular injuries caused by PS-MPs led to disruption of the hypothalamic–pituitary–gonadal (HPG) axis and a decrease in reproductive hormone levels. However, treatment with L. brevis GKJOY reduced oxidative stress and pro-inflammatory cytokine levels, restored hormonal imbalances, and led to significant improvements. L. brevis GKJOY effectively mitigated reproductive damage in male rats due to its dual function as a probiotic and neurotransmitter modulator. In conclusion, L. brevis GKJOY, which functions as both a probiotic and a GABA producer, may offer superior protection against male reproductive damage. Full article
(This article belongs to the Section Molecular Pharmacology)
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7 pages, 1772 KiB  
Communication
Nonerythroid Hemoglobin Present in Porcine Testes
by Jeffrey Li, Barbara Jean Nitta and Trish Berger
Animals 2025, 15(10), 1352; https://doi.org/10.3390/ani15101352 - 8 May 2025
Viewed by 321
Abstract
The presence of hemoglobin beta mRNA and protein in the female gonad suggests that hemoglobin beta may be present in the male gonad as well. The frequent occurrence of hemoglobin beta in nonerythroid tissues with hypoxic environments further underscores a potential role for [...] Read more.
The presence of hemoglobin beta mRNA and protein in the female gonad suggests that hemoglobin beta may be present in the male gonad as well. The frequent occurrence of hemoglobin beta in nonerythroid tissues with hypoxic environments further underscores a potential role for hemoglobin beta in the testis to facilitate the regulation of oxygen availability for the developing germ cells and Sertoli cells since they are separated from the blood supply by multiple tissues. The presence of mRNA and protein were evaluated by qPCR and immunohistochemistry, respectively. The mRNA and protein for hemoglobin were detected in juvenile and postpuberal porcine testes. The most intense immunolabelling for the protein was present in testicular interstitial cells, in contrast to previously reported ovarian labelling in close proximity to the gamete and observed in porcine ovaries in the current study. The observed decrease in mRNA expression of hemoglobin beta with age is probably due to the change in testicular composition (increase in seminiferous tubule compartment) with age. The localization of hemoglobin beta in the testis will contribute to future understanding of its potential function in facilitating oxygen availability to seminiferous tubules or reducing oxidative damage. Full article
(This article belongs to the Section Animal Reproduction)
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19 pages, 4299 KiB  
Article
Sinapic Acid Ameliorates Cadmium-Induced Hepatotoxicity: Modulation of Oxidative Stress, Inflammation, and Apoptosis
by Yomna A. Farahat, Norhan M. El-Sayed, Reem M. Hazem, Eman T. Mehanna and Asmaa Radwan
Biomedicines 2025, 13(5), 1065; https://doi.org/10.3390/biomedicines13051065 - 28 Apr 2025
Viewed by 590
Abstract
Background/Objectives: Cadmium (Cd) is a harmful metal commonly used in industry. Numerous clinical diseases, including osteomalacia, testicular damage, renal and hepatic failure, and pulmonary edema, are associated with Cd exposure. The current study evaluated the protective effect of Sinapic acid (SA) against [...] Read more.
Background/Objectives: Cadmium (Cd) is a harmful metal commonly used in industry. Numerous clinical diseases, including osteomalacia, testicular damage, renal and hepatic failure, and pulmonary edema, are associated with Cd exposure. The current study evaluated the protective effect of Sinapic acid (SA) against Cd-induced hepatotoxicity by investigating different mechanistic pathways interfering with Cd-related liver injury. Methods: Forty rats were randomly assigned to four groups as follows; group 1 served as negative control and received saline, group 2 received saline for 14 days and CdCl2 (3.5 mg/kg IP) as a single dose on day 14, groups 3 and 4 were treated with SA (20, 40 mg/kg PO), respectively, for 14 days and injected with CdCl2 (3.5 mg/kg IP) on day 14. Serum was collected to evaluate liver function. Liver samples were collected for histopathological examination and the assessment of markers related to oxidative stress, inflammation, and apoptosis. Results: Acute Cd administration elevated liver enzymes and induced pathological changes in liver specimens, with the concurrent release of inflammatory markers and reduced antioxidant capabilities. Pretreatment with SA improved liver function and Cd-induced histopathological changes and elevated the activities of antioxidant enzymes. SA ameliorated inflammation, as evidenced by decreased expression of NF-κB, TNF-α, TLR-4, and COX-2, iNOS, and IL-1β levels along with suppression of mTOR, JNK, ERK, BAX, and Bcl-2. Conclusions: The present data suggest that SA represents a promising protective agent against Cd-induced hepatic injury by attenuating oxidative stress, inflammation, and apoptosis. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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18 pages, 10852 KiB  
Article
Alpha-Lipoic Acid Alleviates Lead-Induced Testicular Damage in Roosters by Reducing Oxidative Stress and Modulating Key Pathways
by Jiahao Sun, Rahmani Mohammad Malyar, Nanwei Ye, Yueyue Wang, Quanwei Wei, Fangxiong Shi and Yansen Li
Toxics 2025, 13(5), 341; https://doi.org/10.3390/toxics13050341 - 25 Apr 2025
Viewed by 512
Abstract
(1) Background: This study aimed to detect whether alpha-lipoic acid (ALA) supplementation could reduce lead (Pb)-induced testicular toxicity in roosters. (2) Methods: A total of 48 roosters, aged 20 weeks, were selected and randomly allocated to six treatment groups: basic diet (CON); CON [...] Read more.
(1) Background: This study aimed to detect whether alpha-lipoic acid (ALA) supplementation could reduce lead (Pb)-induced testicular toxicity in roosters. (2) Methods: A total of 48 roosters, aged 20 weeks, were selected and randomly allocated to six treatment groups: basic diet (CON); CON + 150 mg/kg (CH3OO)2Pb (LPB); CON + 300 mg/kg (CH3OO)2Pb (HPB); CON + 300 mg/kg ALA (ALA); LPB + 300 mg/kg ALA (ALP); and HPB + 300 mg/kg ALA (AHP). (3) Results: The testicular Pb content was obviously higher in the LPB and HPB groups than in the CON group, while ALA supplementation reduced the testicular Pb content (p < 0.05). Roosters showed a significant increase in serum testosterone, sperm viability, sperm concentration, and testicular score in the AHP group compared with the HPB group. Pb exposure caused a remarkable increase in sperm abnormality and testicular malondialdehyde level, which were down-regulated by ALA supplementation (p < 0.05). RNA sequencing identified 227 differentially expressed genes (DEGs) between the HPB and CON groups and 220 DEGs between the HPB and AHP groups. (4) Conclusions: ALA supplementation mitigated Pb-induced testicular damage, suggesting its potential as a therapeutic agent for Pb toxicity in birds and potentially other species. Full article
(This article belongs to the Section Reproductive and Developmental Toxicity)
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24 pages, 1609 KiB  
Review
Interplay of Ferroptosis, Cuproptosis, Autophagy and Pyroptosis in Male Infertility: Molecular Crossroads and Therapeutic Opportunities
by Difan Cai, Junda Li, Zekang Peng, Rong Fu, Chuyang Chen, Feihong Liu, Yiwang Li, Yanjing Su, Chunyun Li and Wei Chen
Int. J. Mol. Sci. 2025, 26(8), 3496; https://doi.org/10.3390/ijms26083496 - 8 Apr 2025
Viewed by 1395
Abstract
Male infertility is intricately linked to dysregulated cell death pathways, including ferroptosis, cuproptosis, pyroptosis, and autophagy. Ferroptosis, driven by iron-dependent lipid peroxidation through the Fenton reaction and inactivation of the GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions of oxidative stress, environmental toxin exposure, or [...] Read more.
Male infertility is intricately linked to dysregulated cell death pathways, including ferroptosis, cuproptosis, pyroptosis, and autophagy. Ferroptosis, driven by iron-dependent lipid peroxidation through the Fenton reaction and inactivation of the GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions of oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis—characterized by mitochondrial dysfunction and disulfide stress due to copper overload—exacerbates germ cell apoptosis via FDX1 activation and NADPH depletion. Pyroptosis, mediated by the NLRP3 inflammasome and gasdermin D, amplifies testicular inflammation and germ cell loss via IL-1β/IL-18 release, particularly in response to environmental insults. Autophagy maintains testicular homeostasis by clearing damaged organelles and proteins; however, its dysregulation impairs sperm maturation and compromises blood–testis barrier integrity. These pathways intersect through shared regulators; reactive oxygen species and mTOR modulate the autophagy–pyroptosis balance, while Nrf2 and FDX1 bridge ferroptosis–cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise in preclinical models. However, challenges persist, including the tissue-specific roles of gasdermin isoforms, off-target effects of pharmacological inhibitors, and transgenerational epigenetic impacts of environmental toxins. This review synthesizes current molecular insights into the cell death pathways implicated in male infertility, emphasizing their interplay and translational potential for restoring spermatogenic function. Full article
(This article belongs to the Special Issue Molecular Aspects of Reproductive Medicine)
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16 pages, 9406 KiB  
Article
Transcriptome Analysis Reveals the Molecular Mechanism of Potentilla anserina L. Polysaccharides in Mitigating Zearalenone-Induced Oxidative Stress in Porcine Sertoli Cells
by Haixia Shi, Zunqiang Yan, Hong Du and Shuangbao Gun
Antioxidants 2025, 14(4), 439; https://doi.org/10.3390/antiox14040439 - 5 Apr 2025
Viewed by 574
Abstract
Zearalenone (ZEA) is a widespread mycotoxin that contaminates cereals and other animal feeds. Sertoli cells (SCs) are the main target of attack by many environmental toxins. Our previous study found that Potentilla anserina L. polysaccharides (PAP-1b) exhibited protective effects against ZEA-induced oxidative damage [...] Read more.
Zearalenone (ZEA) is a widespread mycotoxin that contaminates cereals and other animal feeds. Sertoli cells (SCs) are the main target of attack by many environmental toxins. Our previous study found that Potentilla anserina L. polysaccharides (PAP-1b) exhibited protective effects against ZEA-induced oxidative damage in testicular SCs. However, the regulatory mechanisms remain incompletely characterized. In this study, SCs were treated with a complete medium (CON group) or medium containing 150 μg/mL PAP-1b (PAP-1b group). After 4 h, 100 μM ZEA was added to the ZEA group and PAP-1b-ZEA group, respectively. Samples were collected after the cells continued to be incubated for 48 h and subsequently subjected to transcriptome sequencing. The results showed that 1018, 7183, and 1023 differentially expressed genes (DEGs) were screened in the CON-vs.-PAP-1b, CON-vs.-ZEA, and ZEA-vs.-PAP-1b-ZEA groups, respectively. Among them, glutathione peroxidase 1 (GPX1) emerges as a key gene within this antioxidant defense mechanism. In addition, these DEGs were significantly enriched in Gene Ontology (GO) terms related to oxidative stress as well as in MAPK and PI3K-AKT signaling pathways, suggesting that PAP-1b effectively mitigated ZEA-induced oxidative damage in SCs by regulating these signaling pathways. These results provide an essential basis for the further elucidation of the role of PAP-1b in mitigating ZEA-induced oxidative damage in SCs. Full article
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35 pages, 3356 KiB  
Review
Mechanisms of Hormonal, Genetic, and Temperature Regulation of Germ Cell Proliferation, Differentiation, and Death During Spermatogenesis
by María Maroto, Sara N. Torvisco, Cristina García-Merino, Raúl Fernández-González and Eva Pericuesta
Biomolecules 2025, 15(4), 500; https://doi.org/10.3390/biom15040500 - 29 Mar 2025
Cited by 3 | Viewed by 4607
Abstract
Spermatogenesis is a complex and highly regulated process involving the proliferation, differentiation, and apoptosis of germ cells. This process is controlled by various hormonal, genetic, and environmental factors, including temperature. In hormonal regulation, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) are [...] Read more.
Spermatogenesis is a complex and highly regulated process involving the proliferation, differentiation, and apoptosis of germ cells. This process is controlled by various hormonal, genetic, and environmental factors, including temperature. In hormonal regulation, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) are essential for correct spermatogenesis development from the early stages and spermatogonia proliferation to germ cell maturation. Other hormones, like inhibin and activin, finely participate tuning the process of spermatogenesis. Genetic regulation involves various transcription factors, such as SOX9, SRY, and DMRT1, which are crucial for the development and maintenance of the testis and germ cells. MicroRNAs (miRNAs) play a significant role by regulating gene expression post-transcriptionally. Epigenetic modifications, including DNA methylation, histone modifications, and chromatin remodelling, are also vital. Temperature regulation is another critical aspect, with the testicular temperature maintained around 2–4 °C below body temperature, essential for efficient spermatogenesis. Heat shock proteins (HSPs) protect germ cells from heat-induced damage by acting as molecular chaperones, ensuring proper protein folding and preventing the aggregation of misfolded proteins during thermal stress. Elevated testicular temperature can impair spermatogenesis, increasing germ cell apoptosis and inducing oxidative stress, DNA damage, and the disruption of the blood–testis barrier, leading to germ cell death and impaired differentiation. The cellular mechanisms of germ cell proliferation, differentiation, and death include the mitotic divisions of spermatogonia to maintain the germ cell pool and produce spermatocytes. Spermatocytes undergo meiosis to produce haploid spermatids, which then differentiate into mature spermatozoa. Apoptosis, or programmed cell death, ensures the removal of defective germ cells and regulates the germ cell population. Hormonal imbalance, genetic defects, and environmental stress can trigger apoptosis during spermatogenesis. Understanding these mechanisms is crucial for addressing male infertility and developing therapeutic interventions. Advances in molecular biology and genetics continue to uncover the intricate details of how spermatogenesis is regulated at multiple levels, providing new insights and potential targets for treatment. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanism of Spermatogenesis)
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22 pages, 9271 KiB  
Article
Spermidine as a Potential Protective Agents Against Poly(I:C)-Induced Immune Response, Oxidative Stress, Apoptosis, and Testosterone Decrease in Yak Leydig Cells
by Yujun Tang, Hao Li, Yutian Zeng, Cuiting Yang, Run Zhang, Arab Khan Lund and Ming Zhang
Int. J. Mol. Sci. 2025, 26(6), 2753; https://doi.org/10.3390/ijms26062753 - 19 Mar 2025
Viewed by 777
Abstract
Viral infections of the reproductive tract and testis in male yaks, often resulting from natural mating under grazing conditions, can lead to infertility due to Leydig cell (LC) apoptosis, immune activation, oxidative stress, and reduced testosterone production. Spermidine (SPD), a potential therapeutic agent [...] Read more.
Viral infections of the reproductive tract and testis in male yaks, often resulting from natural mating under grazing conditions, can lead to infertility due to Leydig cell (LC) apoptosis, immune activation, oxidative stress, and reduced testosterone production. Spermidine (SPD), a potential therapeutic agent with antioxidant and anti-aging properties, might alleviate oxidant stress, immune response, and virus infection caused by apoptosis. In this study, firstly testicular Leydig cells of yak were induced with Poly(I:C), the pathogen-associated molecular pattern of the dsRNA virus, as a pathogenic model at the cellular level. Secondly, immune response, apoptosis, oxidative stress, and testosterone synthesis were measured in LC with or without SPD culture medium. Finally, transcriptomic sequencing was utilized to investigate the molecular mechanisms underlying the protective effects of SPD. These results suggested Poly(I:C) damaged the function of Leydig cells, significantly decreased the concentration of testosterone, and induced immune response, oxidative stress, and cell apoptosis, while SPD significantly alleviated the immune response and oxidative stress, and then significantly inhibited cell apoptosis and restores testosterone production in LCs. Transcriptomic analysis revealed that SPD significantly alleviates inflammation and apoptosis induced by Poly(I:C), reducing immune response and cellular damage through the regulation of several key gene expressions. These findings suggest SPD has the potential ability to mitigate Poly(I:C)-induced immune response, oxidative stress, and apoptosis, and then restore testosterone production in Leydig cells, offering a promising strategy to protect and enhance male yak fertility after infection with dsRNA virus. Full article
(This article belongs to the Section Molecular Biology)
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16 pages, 875 KiB  
Review
Low-Dose Ionizing Radiation and Male Reproductive Immunity: Elucidating Subtle Modulations and Long-Term Health Implications
by Jiacheng Yin, Yifan Ye, Yuankai Gao, Qing Xu, Muzhe Su, Shengkui Sun, Wenhui Xu, Qian Fu, An Wang and Sumin Hu
Int. J. Mol. Sci. 2025, 26(5), 2269; https://doi.org/10.3390/ijms26052269 - 4 Mar 2025
Cited by 2 | Viewed by 1188
Abstract
Low-dose ionizing radiation (LDIR) is a prevalent environmental factor with profound impacts on male reproductive health, particularly on the testicular immune microenvironment. This review examines the multifaceted effects of LDIR, emphasizing its ability to induce genotoxic stress, oxidative damage, and epigenetic modifications in [...] Read more.
Low-dose ionizing radiation (LDIR) is a prevalent environmental factor with profound impacts on male reproductive health, particularly on the testicular immune microenvironment. This review examines the multifaceted effects of LDIR, emphasizing its ability to induce genotoxic stress, oxidative damage, and epigenetic modifications in reproductive cells. These alterations compromise DNA repair, disrupt chromatin structure, and induce immune dysregulation. Immune cells such as macrophages, T cells, natural killer cells, and dendritic cells exhibit significant functional changes under LDIR exposure, destabilizing the immune privilege critical for normal spermatogenesis. The long-term health implications of LDIR include impaired sperm quality, reduced fertility, and transgenerational risks through heritable genomic instability. This review underscores the importance of exploring the mechanisms underlying immune dysregulation and developing effective protective strategies. While LDIR’s full impact on male reproductive health remains to be elucidated, addressing the gaps in our understanding of immune microenvironmental changes is crucial for mitigating its adverse effects and improving reproductive health outcomes. Full article
(This article belongs to the Section Molecular Immunology)
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