Progress and prospect of environmental factors and male reproductive damage

An exposomic approach with 138 chemical and non-chemical exposures to predict 32 biomarkers of male reproductive damages: A case study of college students in Chongqing, China

As3MT-mediated SAM consumption, which inhibits the methylation of histones and LINE1, is involved in arsenic-induced male reproductive damage

Chlorpyrifos (CPF) has been extensively utilized in recent decades due to its highly efficient insecticidal properties. However, the widespread use of pesticides has posed new challenges to male reproduction. This study aims to explore the potential molecular mechanisms of male reproductive decline induced by CPF. We employ flow cytometry, qRT-PCR, Western blot, RNA sequencing, and bioinformatics analysis to investigate the potential molecular mechanisms involved in CPF-induced male reproductive damage in GC2spd cells. Our results revealed that after 24 h of CPF treatment, the cell viability, cell cycle, apoptosis, and reactive oxygen species (ROS) accumulation of GC2spd cells were significantly affected in vitro. RNA sequencing analysis data indicated that a total of 626 genes were differentially expressed compared to the DMSO group, especially for Efcab6, Nox3, and Cmpk2. These differential genes were mainly enriched in signaling pathways such as PI3K-AKT and glutamine metabolism. In addition, further validation through qRT-PCR, Western blot, and experiments involving the inhibition of intracellular ROS generation with N-acetylcysteine collectively confirmed that CPF induces male reproductive damage through the ROS/AKT/Efcab6 pathway. These studies elucidate potential targets and molecular mechanisms underlying CPF-induced male infertility, providing a theoretical basis for the prevention of male reproductive damage caused by pesticide residues.

SIRT1/PGC-1α is involved in arsenic-induced male reproductive damage through mitochondrial dysfunction, which is blocked by the antioxidative effect of zinc

Protective effects of catalpol on diabetes mellitus-induced male reproductive damage via suppression of the AGEs/RAGE/Nox4 signaling pathway

Objectives The object of this study was to evaluate the effect of Yikgeebohyul-tang aqueous extracts (YKBHT) on the propylthiouracil (PTU)-induced rat hypothyroidism. Methods The rats were divided into 6 groups : intact vehicle control, PTU control, LT4, YKBHT 500, 250 and 125 mg/kg treated groups. Hypothyroidism was induced by daily subcutaneous treatment of PTU 10 mg/kg for 28 days. YKBHT aqueous extracts were administered once a day as an oral dose of 500, 250 and 125 mg/kg for 42 days. The changes were observed : weight of body, thyroid gland, liver, testis, epididymis and prostate, serum thyroid hormone levels, serum male sex hormone levels, serum lipid profiles, liver and testis antioxidant system. These results were compared with LT4 0.5 mg/kg intraperitoneally treated rats. Results These PTU induced hypothyroidism and related hepatic and male reproductive organ damages were favorably and dose-dependently inhibited by treatment of YKBHT 500, 250 and 125 mg/kg, and YKBHT also effectively regulated the PTU-induced abnormal antioxidant defense factor changes in the both liver and testis. Although, LT4 also inhibited PTU-induced hypothyroidism and relative liver damages. But it deteriorated the hypothyroidism related testis, epididymis and prostate damages through testicular oxidative damages. Conclusions : The result of this study suggests that YKBHT has favorable effects on the hypothyroidism and related liver and reproductive organ damages with augmentation of antioxidant defense factor in the testis and liver. YKBHT 500, 250 and 125 mg/kg dose-dependently inhibited PTU-induced hypothyroidism and related liver and male reproductive organ damages in rats.

MEHP exposure disrupts the self-renewal and differentiation of GC-1 cells by up-regulating m6A levels, leading to reproductive damage in immature rats.

Tripterygium Glycosides Tablets has good anti-inflammatory and immunomodulatory activities,but its reproductive damage is significant. Previous studies of the research group have found that Cuscutae Semen flavonoids can improve spermatogenic cell damage caused by Tripterygium Glycosides Tablets by regulating spermatogenic cell cycle,apoptosis and related protein expression,but the mechanism of action at the gene level is still unclear. In this study,Illumina high-throughput sequencing platform was applied in transcriptional sequencing of spermatogenic cells of rats after the intervention of Cuscutae Semen flavonoids and Tripterygium Glycosides Tablets. Differentially expressed genes were screened out and the GO enrichment and KEGG pathway analysis of differentially expressed genes were conducted to explore the mechanism of Cuscutae Semen flavonoids in improving reproductive injury caused by Tripterygium Glycosides Tablets. The results showed that 794 up-regulated genes and 491 down-regulated genes were screened in Tripterygium Glycosides Tablets group compared with the blank group. Compared with Tripterygium Glycosides Tablets,440 up-regulated genes and 784 down-regulated genes were screened in the Cuscutae Semen flavonoids+Tripterygium Glycosides Tablets group. Among them,the gene closely related to reproductive function is DNMT3 L. Analysis of GO function and KEGG signaling pathway enrichment showed that the above differentially expressed genes were mainly enriched in cell,cell process,catalytic activity,binding,ovarian steroid synthesis,thyroid hormone and other functions and pathways. The thyroid hormone signaling pathway was the common enrichment pathway of the two control groups. In a word,Cuscutae Semen flavonoids has a good treatment effect on male reproductive damage caused by Tripterygium Glycosides Tablets. The mechanism may be closely related to up-regulation of DNMT3 L genes and intervention of thyroid hormone signaling pathway. At the same time,the discovery of many different genes provides valuable information for study on the mechanism of Cuscutae Semen flavonoids and Tripterygium Glycosides Tablets compatibility decreasing toxicity and increasing efficiency.

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.

Objectives: This study was to evaluate the effect of Jaeumkanghwa-tang (JEKHT) on the propylthiouracil (PTU)-induced rat hypothyroidism. Methods: Six groups, each of 8 rats per group were used in the present study - intact vehicle control, PTU control, Levothyroxine (<TEX>$LT_4$</TEX>), JEKHT 500, 250 and 125 mg/kg treated groups. JEKHT were administered once a day for 42 days as an oral dose of 500, 250 and 125 mg/kg, and hypothyroidism was induced by daily subcutaneous treatment of PTU 10 mg/kg for 28 days. The changes on the body and organ weight, serum hormone and lipid profiles, liver and testis antioxidant defense factors were observed with histopathology of organs. Results were compared with <TEX>$LT_4$</TEX> 0.5 mg/kg intraperitoneally treated rats in this experiment. Results: PTU treatment, marked decrease of body weight, increases of thyroid weight, decreases of liver, testis, epididymis and prostate weights, decreases of serum Tri-iodothyronine (<TEX>$T_3$</TEX>), and Thyroxine (<TEX>$T_4$</TEX>) level with increase of serum Thyroid-stimulating hormone (TSH) level, decreases of serum testosterone and dihydrotestosterone (DHT) level with increases of serum Follicular stimulating hormone (FSH) level, increases of serum High density lipoprotein (HDL), decrease of triglyceride content, increase of serum Aspartate aminotransferase (AST) level, decreases of liver and testis antioxidant defense factors were observed. In addition, marked hyperplasia of follicular cells with decreases of follicular colloid contents and diameters was additionally demonstrated with the decrease of hepatocyte numbers per unit area due to hypertrophy of hepatocytes related to lipid droplet depositions, increase of a/oligospermatic epididymal tubules with epididymal atrophic changes, seminiferous tubular atrophy with decrease of stage I~II seminiferous tubules in testis, prostate tubular atrophic changes at histopathological inspections. However, these PTU induced hypothyroidism and related hepatic and male reproductive organ damages were favorably and dose-dependently inhibited by treatment of JEKHT 500, 250 and 125 mg/kg, and JEKHT also effectively regulated the PTU-induced abnormal antioxidant defense factor changes in the both liver and testis. Conclusions: JEKHT 500, 250 and 125 mg/kg dose-dependently inhibited PTU-induced hypothyroidism and related liver and male reproductive organ damages in rats.

Pyrethroids may be related to male reproductive system damage. However, the results of many previous studies are contradictory and uncertain. Therefore, a systematic review and a meta-analysis were performed to assess the relationship between pyrethroid exposure and male reproductive system damage. A total of 72 articles were identified, among which 57 were selected for meta-analysis, and 15 were selected for qualitative analysis. Pyrethroid exposure affected sperm count (SMD= -2.0424; 95% CI, -2.4699 to -1.6149), sperm motility (SMD=-3.606; 95% CI, -4.5172 to -2.6948), sperm morphology (SMD=2.686; 95% CI, 1.9744 to 3.3976), testis weight (SMD=-1.1591; 95% CI, -1.6145 to -0.7038), epididymal weight (SMD=-1.1576; 95% CI, -1.7455 to -0.5697), and serum testosterone level (SMD=-1.9194; 95% CI, -2.4589 to -1.3798) in the studies of rats. We found that gestational and lactational exposure to pyrethroids can reduce sperm count (SMD=1.8469; 95% CI, -2.9010 to -0.7927), sperm motility (SMD=-2.7151; 95% CI, -3.9574 to -1.4728), testis weight (SMD=-1.4361; 95% CI, -1.8873 to -0.9848), and epididymal weight (SMD=-0.6639; 95% CI, -0.9544 to -0.3733) of F1 offspring. Exposure to pyrethroids can increase malondialdehyde (SMD=3.3451; 95% CI 1.9914 to 4.6988) oxide in testes and can reduce the activities of glutathione (SMD=-2.075; 95% CI -3.0651 to -1.0848), superoxide dismutase (SMD=-2.4856; 95% CI -3.9612 to -1.0100), and catalase (SMD=-2.7564; 95% CI -3.9788 to -1.5340). Pyrethroid exposure and oxidative stress could damage male sperm quality. Gestational and lactational pyrethroid exposure affects the reproductive system of F1 offspring.

ObjectiveThe CHOP combined chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) is commonly used to treat non-Hodgkin Lymphoma (NHL). While these drugs are effective for cancer treatment, they may have side effects on the reproductive system that are poorly studied. This study used a mouse model to investigate the mechanisms of reproductive function impairment induced by the CHOP regimen and developed a predictive model for assessing reproductive damage with a non-invasive procedure.MethodsFrom 2022 to 2023, we statistically analyzed the changes of reproductive function of NHL patients before and after receiving CHOP regimen in the First Affiliated Hospital of Xiamen University. The NHL mouse model was established and divided into CHOP treatment group and control group. The weight of testis and epididymis, sperm quality and motility were compared between the two groups. Histopathological examination of testicular tissue was performed to determine pathological changes. ELISA was used to measure the expression of cytokines and cytokine pathways in serum, protein expression was analyzed by immunohistochemistry, and protein and mRNA levels of cytokines and pathways were evaluated by Western blotting and qPCR. Using stepwise regression method to select important factors, a prediction model of reproductive system damage was constructed.ResultsFifty-two NHL patients included in the questionnaire showed significant reproductive system damage after CHOP regimen treatment. The weight of testis and epididymis, as well as the number and vitality of sperm in the mouse model treatment group were significantly lower than those in the control group. Serum LH, FSH, estradiol and progesterone levels decreased significantly, while inhibin B levels increased significantly. There was no significant change in testosterone or prolactin levels. Inflammatory markers such as CSF-1, IL-1, IL-6, TGF-β1 and GDNF increased significantly, while the level of SOD1 decreased significantly. Immunohistochemical staining analysis showed that CAMP, Caspase3, CSF-1, GDNF, IL-1, IL-6, PRKACB, TGF-β1 and TXNDC5 were all expressed in spermatocytes, and the expression of therapeutic histones was significantly higher than that of the control group. Western blot analysis further detected the protein expression, and QPCR detected the mRNA content. The results showed that the expression of histone and mRNA in the treatment group was significantly higher than that in the control group. Stepwise regression method determined that estradiol (E2) was the most important variable in the prediction model, and the AUC for predicting reproductive damage was 1.ConclusionsThe CHOP regimen induces male reproductive toxicity, potentially mediated through alterations in hormone levels and increased expression of inflammatory cytokines and oxidative stress. Using E2 as the sole predictor in the model accurately predicts the extent of reproductive damage, offering a non-invasive method for detecting reproductive system damage.

Antineoplastic agents exacerbate oxidative stress and trigger inflammatory responses in the testis. Numerous studies have proposed antioxidants as a therapeutic approach to ameliorate chemotherapy-induced damage and improve reproductive outcomes. This systematic review aims to evaluate the potential therapeutic value of antioxidants in mitigating chemotherapy-induced male reproductive damage and address knowledge gaps to guide future research efforts. A comprehensive literature search was conducted in accordance with the PRISMA guidelines using the Google Scholar and Web of Science databases to identify experimental studies published between 2012 and 2025. The search strategy employed the following keywords: “antioxidant” AND “oxidative stress” AND “spermatozoa” AND “testosterone” AND “histopathology” AND (“rat” OR “mice”) AND (“chemotherapy” OR “chemotherapeutic” OR “antineoplastic”). The study design was guided by the PICO framework. Data extraction focused on reproductive histopathological changes, testosterone levels, and sperm parameters. A total of 28 studies were deemed eligible for inclusion. The methodological quality and risk of bias of the included studies were assessed using SYRCLE’s Risk of Bias tool. The majority of findings suggest that antioxidant administration mitigated male reproductive toxicity by improving sperm parameters, testicular histopathology, and testosterone levels; however, a small number of studies reported no significant effects. Additionally, a number of the included studies also presented the beneficial effects of several antioxidants on other endocrine parameters and oxidative stress markers. Current preclinical evidence suggests that antioxidants may mitigate chemotherapy-induced reproductive toxicity; however, clinical studies are required to clarify their clinical applicability, optimal dosing, and long-term safety.

Chronic excessive alcohol intake may lead to male reproductive damage. Lutein is a carotenoid compound with antioxidant activity. The purpose of this study was to observe the effect of lutein supplementation on male reproductive damage caused by excessive alcohol intake. In this study, an animal model of excessive drinking (12 mL/(kg.bw.d)) for 12 weeks was established and supplemented with different doses of lutein (12, 24, 48 mg/(kg.bw.d)). The results showed that the body weight, sperm quality, sex hormones (FSH, testosterone), and antioxidant markers (GSH-Px) decreased significantly, while MDA and inflammatory factors (IL-6, TNF-α) increased significantly in the alcohol model group when compared to the normal control group. After 12 weeks of high-dose lutein supplementation with 48mg/(kg.bw.d), the spermatogenic ability, testosterone level, and the activity of marker enzymes reflecting testicular injury were improved. In addition, high-dose lutein supplementation downregulated the NF-κB and the pro-apoptosis biomarkers (Bax, Cytc and caspase-3), whereas it upregulated the expression of Nrf2/HO-1 and the anti-apoptotic molecule Bcl-2. These findings were fully supported by analyzing the testicular histopathology and by measuring germ cell apoptosis. In conclusion, lutein protects against reproductive injury induced by excessive alcohol through its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Manganese exposure caused reproductive toxicity of male mice involving activation of GnRH secretion in the hypothalamus by prostaglandin E2 receptors EP1 and EP2.