Radiotherapy is an effective therapeutic modality for many malignant tumors; however, it poses a significant threat to male reproductive health. This study aimed to investigate the radioprotective potential of diosmin, a flavonoid with well-established antioxidant and anti-inflammatory properties, against radiation-induced testicular injury and elucidate the underlying mechanisms. Adult male Sprague-Dawley rats were randomly allocated into four experimental groups: control, diosmin-treated, irradiated, and irradiated plus diosmin-treated. Testicular injury was induced by subjecting rats to a single 10 Gy dose of γ-radiation, while diosmin was administered orally at 50 mg/kg for 14 consecutive days. Diosmin administration markedly counteracted radiation-induced decline in serum testosterone levels, sperm count, motility, and viability, as well as reduction in testicular weights. Histopathological analysis revealed preservation of testicular architecture with diosmin treatment, as evidenced by increased seminiferous tubule diameter and epithelial thickness. Moreover, diosmin improved the antioxidant capacity of irradiated testis by elevating reduced glutathione levels and enhancing catalase activity. In addition, diosmin attenuated radiation-induced testicular inflammation by inhibiting NF-κB nuclear translocation and reducing the levels of the pro-inflammatory cytokine IL-6. Subsequently, diosmin suppressed irradiation-induced activation of the JAK/STAT signaling pathway by inhibiting the phosphorylation of JAK1 and STAT3. Furthermore, diosmin modulated the expression of autophagy-related markers through downregulating Beclin-1 expression while increasing p62/SQSTM1 accumulation. In conclusion, diosmin effectively mitigates irradiation-induced testicular damage by suppressing oxidative stress and inflammation, inhibiting the activation of the p-JAK1/p-STAT3 signaling pathway, and regulating testicular autophagy. These findings highlight diosmin as a potential therapeutic agent for safeguarding testicular function during radiotherapy.

Polycystic ovary syndrome (PCOS) represents a common endocrine-metabolic disorder. Mounting evidence has demonstrated that Korean red ginseng confers therapeutic advantages in PCOS; accordingly, this investigation sought to elucidate the therapeutic potential of its bioactive constituent, ginsenoside Rg1, in this pathological condition. A DHEA-induced murine PCOS model was generated for in vivo experiments. Serum hormonal profiles and insulin sensitivity were assessed. Ovarian histomorphological alterations were evaluated through hematoxylin and eosin staining. For in vitro studies, a PCOS-mimicking cellular model was constructed by exposing KGN cells to dihydrotestosterone (DHT, 500 nM) for 24 h. Cell viability was quantified using the CCK-8 assay. Apoptotic events were characterized through flow cytometric analysis and immunoblotting of Bax and Bcl-2. Expression patterns of glycolytic enzymes, alongside the proliferation marker PCNA, were examined. Rg1 administration ameliorated PCOS-associated phenotypes in mice, manifesting as reduced body mass, partly restored serum hormone concentrations, enhanced insulin responsiveness, and improved ovarian architecture. Rg1 potentiated glycolytic and proliferative activities while suppressing apoptotic processes in both PCOS mice and DHT-challenged KGN cells. Mechanistically, Rg1 triggered PI3K/Akt/mTOR cascade activation, evidenced by elevated p-Akt and p-mTOR expression, effects that were partially reversed by LY294002, a pharmacological antagonist of this pathway. Furthermore, LY294002 co-administration attenuated the protective actions of Rg1 against PCOS in both experimental paradigms. In conclusion, ginsenoside Rg1 exerts beneficial effects on PCOS by enhancing glycolysis and proliferative activity while attenuating apoptosis in ovarian granulosa KGN cells via PI3K/Akt/mTOR pathway activation. These findings position Rg1 as a promising therapeutic candidate for PCOS management.

Due to the widespread presence of microplastics (MPs) in the environment, humans are continuously exposed to them through ingestion, inhalation, and dermal contact, both intentionally and unintentionally. Once introduced to the body, MPs can accumulate in various tissues and organs. In addition, their ability to adsorb and carry harmful substances may further contribute to adverse health effects. The female reproductive system is particularly vulnerable to the toxic effects of MPs exposure. Studies have shown that MPs can induce oxidative stress, hormonal disruption, inflammation, and ultimately apoptosis. However, the specific mechanisms related to the female reproductive system remain incompletely understood. Hence, this review aims to summarize and evaluate the existing mechanisms involved in MP-induced toxicity effects in the ovary, uterus, placenta, and during the pregnancy period. Furthermore, potential protective interventions are discussed as possible strategies to reduce the accumulation and adverse reproductive effects that MPs may exert on the body.

Phthalate exposure during pregnancy may affect placental and renal biology, but the biological interpretation of urinary exposure and effect biomarkers remains challenging. McNell et al. provide an important longitudinal framework by relating early-pregnancy urinary phthalate metabolites to urinary biomarkers related to placental angiogenesis and renal biology measured across gestation. Their study also highlights two interpretive issues. First, an exposure biomarker obtained in early pregnancy and a biological-response trajectory extending into late pregnancy represent different temporal processes. Second, urine serves simultaneously as the matrix for exposure assessment and for assessment of renal biological responses, while the kidney itself may be a toxicological target. Thus, urinary phthalate-protein associations should not automatically be interpreted as direct evidence of organ toxicity. Future studies integrating repeated exposure measurements, complementary biological matrices, direct functional measures, and longitudinal trajectory analyses may provide a more mechanistic framework for understanding reproductive toxicity.

Despite extensive investigation on the efficacy of stem cell transplantation in repairing diabetic complications, stable repair has not yet been achieved. This study aimed to investigate whether bone marrow mesenchymal stem cells with inhibited NLRP3 inflammasome (BMSCsLV-shNLRP3) exhibit enhanced repair of high-glucose-induced damage to testicular Sertoli cells in vitro.

Numerous chemicals have been reported to be detrimental to human and animal health, particularly to the female reproductive system. Chemical exposure can lead to reproductive disorders by disrupting the hypothalamic-pituitary-gonadal axis and affecting the endocrine system, ovaries, follicular fluid, and germ cells. In addition, chemical exposure can impair female reproduction by directly affecting oocyte maturation, which is completed within the follicular fluid before ovulation. Therefore, evaluating the toxic effects of these chemicals on oocyte maturation has become increasingly important. In vitro maturation (IVM) of oocytes is an essential platform for elucidating the mechanisms underlying oocyte maturation. In particular, IVM of porcine oocytes may be a more suitable model for studying human oocyte maturation because pigs share greater physiological and genetic similarities with humans than other commonly used animal models do. Moreover, because porcine oocyte IVM uses immature oocytes obtained from ovaries collected as slaughterhouse by-products, this system avoids the use of experimental animals, offering both ethical and practical advantages. Despite the growing number of reproductive toxicology studies using porcine oocyte IVM, comprehensive summaries of the indicators used for porcine oocyte quality assessment remain limited. Therefore, this review aims to summarize the methods for assessing porcine oocyte quality, along with their underlying principles and applications, thereby providing an integrative overview to advance the use of porcine IVM as a model for reproductive toxicity evaluation.

Male infertility contributes to around 40-50% of the infertility cases worldwide. Emerging environmental pollutants (microplastics, engineered nanoparticles, radiofrequency electromagnetic radiation (RF-EMR), pharmaceuticals and personal care products (PPCPs)) have received significant attention because of their environmental persistence and potential adverse effects on male reproductive health. This review critically synthesizes evidences from experimental, epidemiological and systematic studies, with emphasis on mechanistic pathways. Micro- and nanoplastics are now detected in human blood, testes and semen, act as carriers that alter the transport and bio-availability of co-contaminants.Results from animal studies reported that emerging pollutants impair male reproductive function via interconnected mechanisms namely, oxidative stress, enhanced reactive oxygen species, mitochondrial dysfunction, DNA damage, chronic inflammation, endocrine disruption, blood-testis barrier impairment and apoptosis. Chronic RF-EMR exposure perturbs testicular homeostasis via oxidative injury, calcium channel modulation, hormonal imbalance, and disruption of the blood-testis barrier. Engineered nanoparticles readily cross biological barriers and accumulate in reproductive tissues. PPCPs particularly endocrine-disrupting contaminants cause impairment of steroidogenesis and hormonal homeostasis, resulting in impaired male fertility. Collectively, these pollutants converge on interconnected mechanism that affect sperm count, motility, morphology, viability and fertilization capacity. While animal studies provide evidence of reproductive toxicity, longitudinal human studies with biomonitoring, semen analysis, hormonal profiling and molecular endpoints are required to propose safe exposure thresholds, establish casual relationship and determine the effects of mixture pollutants. These emerging pollutants thus represent a major yet potentially preventable risk for male infertility.

Maternal nicotine exposure during pregnancy is associated with placental dysfunction, oxidative stress, and impaired fetal development. Ellagic acid (EA), a naturally occurring polyphenolic compound with potent antioxidant properties, may protect placental tissues against nicotine-induced damage. This study investigated the protective effects of EA on placental histomorphometric alterations, oxidative stress, and apoptosis-related gene expression in nicotine-exposed pregnant rats. Twenty-four pregnant Wistar rats were randomly assigned to four groups (n = 6): control, EA (60 mg/kg), nicotine (1 mg/kg), and nicotine + EA. Treatments were administered orally from gestation day (GD) 0 to GD20. The H&E and PAS staining were used to evaluate placental architecture, trophoblast giant cells, and glycogen cell distribution. Oxidative stress biomarkers including MDA, CAT, TAC, SOD, and GPx were assessed. Expression levels of caspase-3, Bax, Bcl-2, and p53 genes were quantified using real-time PCR. Nicotine exposure significantly decreased the placental weight, diameter, and thickness characterized by disrupted placental architecture, changes in the thickness of placental layers, and the number of trophoblast giant cells (P < 0.05). These changes were accompanied by increased lipid peroxidation, reduced antioxidant defense capacity, and dysregulation of apoptosis-related genes, including upregulation of caspase-3, Bax, and p53 and downregulation of Bcl-2. Co-administration of EA significantly attenuated these adverse effects by improving placental structural integrity, oxidative stress, and apoptosis-related genes expression (P < 0.05). EA exerts significant protective effects against nicotine-induced placental injury, likely through its antioxidant and anti-apoptotic activities. These findings suggest that EA may represent a promising therapeutic strategy for mitigating placental toxicity associated with maternal nicotine exposure.

Trifluoroacetic acid (TFA) is considered a per- and polyfluoroalkyl substance (PFAS) by the European Chemicals Agency, yet its potential reproductive toxicity remains poorly understood. Here, we investigated the testicular effects and underlying mechanisms of TFA exposure in adolescent male mice. Based on environmental and potential dietary exposure levels, available toxicological and risk-assessment information, and the findings of our preliminary experiment, mice were orally administered TFA at 0.0042, 0.042, 0.42, or 4.2 mg/kg/day for 21 days, followed by a 7-day recovery period. Residual TFA remained detectable in the serum and testes after the recovery period, and doses ≥ 0.042 mg/kg/day induced Leydig cell and spermatogenic cell damage, accompanied by reduced testosterone levels. TFA exposure also increased testicular oxidative stress (OS) and activated the ribotoxic stress response (RSR) and NLRC5-PANoptosome-related signaling. These cellular stress responses were associated with activation of PANoptosis-related pathways, involving pyroptosis, apoptosis, and necroptosis, and ultimately contributed to testicular tissue injury and impaired testicular function. Collectively, our findings demonstrate that TFA exposure at environmentally and risk-assessment-relevant levels induces testicular injury in adolescent male mice and identify a potential mechanistic link between OS, RSR, NLRC5-PANoptosome-related signaling, and PANoptosis. These findings provide new insights into the reproductive toxicity of TFA and highlight the need for further evaluation of its potential health risks.

Benzene is a ubiquitous environmental pollutant and a human hematotoxicant and carcinogen. Increasing epidemiological and experimental evidence links in utero benzene exposure to adverse pregnancy outcomes, altered fetal development, and increased childhood leukemia risk. Benzene toxicity is initiated through metabolism into reactive intermediates, primarily by cytochrome P450 2E1 (CYP2E1) and myeloperoxidase. These enzymes are expressed not only in the maternal liver but also in the placenta and fetal liver, indicating that multiple compartments may contribute to benzene toxicity during pregnancy. Despite these observations, the mechanisms linking maternal exposure to fetal hematotoxicity remain incompletely understood, as existing studies have largely examined maternal, placental, and fetal effects independently, with the placenta often treated as a passive barrier rather than an active regulator of developmental toxicity. We propose the maternal-placental-fetal liver axis as a mechanistic framework for understanding in utero benzene developmental hematotoxicity, and discuss three biologically plausible bioactivation routes across this axis: maternal hepatic metabolism, placental bioactivation, and direct fetal liver metabolism. We further examine how fetal injury may arise through complementary mechanisms: direct toxicity from transplacental transfer of benzene and its reactive metabolites, and indirect toxicity, whereby benzene-induced placental dysfunction alters the intrauterine environment and may drive secondary fetal injury. We suggest a model where placental dysfunction may amplify, rather than independently drive, fetal benzene toxicity. The maternal-placental-fetal liver axis integrates maternal metabolism, placental biology, and fetal susceptibility, providing a mechanistic framework for understanding the pathways underlying benzene-induced developmental hepatotoxicity and its potential contribution to childhood leukemia.

Haloacetamides are nitrogen-containing disinfection byproducts formed during conventional water disinfection processes that are not currently regulated in drinking water standards. Their potential health risks have attracted increasing attention. Among them, 2-bromoacetamide (BAcAm) is particularly concerning due to its relatively high occurrence in disinfected water and potent toxicity. While BAcAm exposure has been reported to disrupt oocyte meiotic maturation in mice and humans, its effects on preimplantation embryonic development remain poorly understood. Here, we investigated the impact of BAcAm on mouse preimplantation embryonic development. Mouse preimplantation embryos were collected and cultured in vitro with different concentrations of BAcAm, and developmental progression was assessed. To characterize molecular changes associated with BAcAm exposure, 2-cell embryos were subjected to transcriptome sequencing, immunofluorescence and live-cell fluorescence assays. BAcAm exposure induced dose-dependent developmental arrest, predominantly at the 2-cell stage. Transcriptomic analysis revealed changes in the expression of genes related to the maternal-to-zygotic transition. BAcAm exposure was accompanied by altered mitochondrial features (increased ATP levels and a downward trend in mitochondrial membrane potential), elavated reactive oxygen species (ROS) levels and increased DNA damage. Supplementation with N-acetylcysteine attenuated both the developmental arrest and ROS elevation. BAcAm also altered histone modification profiles, with a significant decrease in me2H3K27 and downward trends in acH3K27 and me3H3K9. Collectively, BAcAm disrupted mouse preimplantation embryonic development and was associated with mitochondrial alterations, oxidative stress and altered histone modifications. These data revealed the toxic effects of BAcAm on early embryonic development and emphasized its potential adverse impacts on female reproductive health.

The rapid expansion of wireless technologies has raised concerns regarding the biological effects of radiofrequency radiation on reproductive health. This study evaluated the impact of radiofrequency electromagnetic radiation from mobile phones (4 G) and a signal generator operating at 1800 MHz and 2450 MHz for 15-120 min on mitochondrial function in TM3 Leydig cells. Flow cytometry with JC-1 dye revealed frequency- and time-dependent mitochondrial membrane potential (Δψm) depolarization. Corresponding adenosine triphosphate (ATP) assay indicated impaired mitochondrial bioenergetics after 30 min of irradiation across all exposure conditions. Pharmacological modulation revealed frequency-dependent variations in oxidative stress responses. DPI significantly reduced ROS under mobile phone and 2450 MHz exposure but showed no significant effect on superoxide levels, suggesting a comparatively limited contribution of NOX-derived oxidative stress. In contrast, Mito-TEMPO significantly reduced ROS levels across all exposure conditions and reduced superoxide levels under mobile phone and 2450 MHz exposure, while significant restoration of Δψm was observed only under 2450 MHz exposure, suggesting mitochondria as a predominant source of oxidative stress in RF-EMR-exposed Leydig cells. Rapamycin partially stabilized Δψm, whereas bafilomycin A1 and hydroxychloroquine aggravated mitochondrial depolarization, suggesting possible involvement of autophagy-associated mitochondrial quality control pathways. Collectively, these findings demonstrate that short-term RF-EMR exposure induces frequency-dependent mitochondrial dysfunction in TM3 Leydig cells through mechanisms involving oxidative stress and possible alterations in autophagy-associated cellular responses.