Reproductive toxicology最新文献

{"title":"The effects of exposure to microplastics on female reproductive health and pregnancy outcomes: A systematic review and meta-analysis","authors":"Mohammad Ali-Hassanzadeh ,&nbsp;Nasir Arefinia ,&nbsp;Zohreh-Al-Sadat Ghoreshi ,&nbsp;Hedyeh Askarpour ,&nbsp;Habibeh Mashayekhi-Sardoo","doi":"10.1016/j.reprotox.2025.108932","DOIUrl":"10.1016/j.reprotox.2025.108932","url":null,"abstract":"<div><div>Microplastic pollution is one of the most important challenges to public health. The current study aimed to assess the impact of microplastic accumulation on female reproductive health and pregnancy outcomes. A comprehensive search was conducted in databases, including ISI Web of Science, PubMed, Scopus, and Google Scholar, to evaluate the effects of microplastic contamination on reproductive health and fetal outcomes. Thirteen studies met our criteria. Microplastic pollution was found in samples of placenta, meconium, amniotic fluid, and feces. In total, 10 polymers were identified, among which polystyrene, polyurethane, and polyamide polymers were the most abundant. The average size of the microplastics was 2.1–100 micrometers. The contamination rate with microplastics was measured at about an event rate of 87 % (95 % CI: 80.0–91.2). It was found that microplastic content in human reproductive tissue has nothing to do with the mode of delivery. Also, the results showed that consuming food in plastic containers increased the chance of contamination with microplastics in pregnant women (95 % CI: 1.32–21.9; OR: 5.39). The clinical elevation of microplastic accumulation with adverse pregnancy outcomes has shown a significant correlation between microplastic content in the placenta and gestational age (95 % CI: 0.03–0.22; OR: 0.89). In addition, microplastic pollution in the placenta significantly increases the risk of intrauterine growth restriction (IUGR) (95 % CI: 2.07–8.06; OR: 5.06). Microplastics may be a risk factor that contributes to human reproductive health issues and pregnancy-related outcomes; further large-scale investigations are needed to confirm the current findings.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108932"},"PeriodicalIF":3.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repair effect of adipose-derived mesenchymal stem cell-conditioned medium on cyclophosphamide-induced ovarian injury in mice","authors":"Shuangjuan Liu ,&nbsp;Weiqi Liu ,&nbsp;Yumei Liu ,&nbsp;Dongliu Luo ,&nbsp;Jingwen Feng ,&nbsp;Leyao Hou ,&nbsp;Haotong Cui,&nbsp;Yao Liu,&nbsp;Xiaoguang Chen ,&nbsp;Xuemin Zhu ,&nbsp;Lan Wei ,&nbsp;Qiongxia Lv ,&nbsp;Ziqiang Zhang","doi":"10.1016/j.reprotox.2025.108923","DOIUrl":"10.1016/j.reprotox.2025.108923","url":null,"abstract":"<div><div>The chemotherapeutic drug cyclophosphamide (CTX) may damage the ovarian tissue of females and induce premature ovarian insufficiency (POI). This study aimed to investigate the therapeutic effect of adipose-derived mesenchymal stem cell-conditioned medium (ADSC-CM) on CTX-induced POI mice, and to provide new support for the clinical use of cell-free therapy for POI. Female mice were treated with CTX intraperitoneal injection for 2 weeks, followed by ADSCs or ADSC-CM by intravenous injection for 2 weeks. At the end of the experiment, various parameters were assessed, including ovarian interstitial fibrosis, cell proliferation, follicular count, the levels of follicle-stimulating hormone (FSH) and estradiol (E₂), and the expression of gonadal hormone receptor. Additionally, we assessed the levels of oxidative stress, apoptosis, and apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) signaling pathway-related proteins and genes in ovarian tissue. The results showed that ADSCs or ADSC-CM treatment reduced ovarian interstitial fibrosis, promoted the proliferation of cells in the follicles, and increased the number of follicles and ovarian function. In addition, ADSCs and ADSC-CM also reduced the levels of ovarian oxidative stress, decreased the apoptosis of granulosa cells (GCs), and inhibited the activation of ASK1/JNK signaling pathway. In conclusion, our study confirmed that ADSC-CM, like ADSCs, could exert therapeutic effects in POI diseases, and the underlying mechanism may be related to the inhibition of oxidative stress-mediated activation of ASK1/JNK signaling pathway. This study has important implications for the development of cell-free therapies for the clinical treatment of POI diseases.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108923"},"PeriodicalIF":3.3,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychosocial stress and associations with inflammation in mid-gestation maternal, fetal, and placental tissue","authors":"Neha Sehgal ,&nbsp;Lin Li ,&nbsp;Dana E. Goin ,&nbsp;Jessica Chen ,&nbsp;Unurzul Jigmeddagva ,&nbsp;Rachel Morello-Frosch ,&nbsp;Tracey J. Woodruff ,&nbsp;Stephanie L. Gaw ,&nbsp;Joshua F. Robinson ,&nbsp;Stephanie M. Eick","doi":"10.1016/j.reprotox.2025.108922","DOIUrl":"10.1016/j.reprotox.2025.108922","url":null,"abstract":"<div><h3>Background</h3><div>Inflammation has been implicated as an intermediary between psychosocial stress and adverse birth outcomes. However, prior work has mostly relied on maternal inflammation as a proxy for fetal inflammation mid-gestation or measured fetal inflammation in cord blood and placenta obtained at delivery. No studies have examined psychosocial stress in relation to fetal inflammation mid-gestation.</div></div><div><h3>Methods</h3><div>Twenty cytokines were measured in matched maternal blood, cord blood, and placenta obtained mid-gestation from a socio-demographically diverse group of pregnant participants undergoing elective second-trimester pregnancy terminations (N = 106). Corticotropin-releasing hormone, a proposed biomarker of gestational length, was measured in maternal blood. Perceived stress, and exposure to stressful life events, job strain, and social support were measured via questionnaires. We used linear regression to estimate associations between individual stressors and inflammatory biomarkers in each biomatrix and principal component analysis to assess groups of inflammatory biomarkers.</div></div><div><h3>Results</h3><div>We observed many matrix-specific associations between psychosocial stressors and inflammatory biomarkers. For example, low versus high social support was associated with significantly decreased levels of maternal blood CCL3 (β=-0.53; 95 % confidence interval [CI]=-0.98,-0.07), CCL4 (β=-0.26; 95 % CI=-0.47,-0.04), IL8 (β=-0.79; 95 % CI=-1.47,-0.11), CXCL9 (β=-0.47; 95 % CI=-0.89,-0.06), IFNγ (β=-2.28; 95 % CI=-3.60,-0.96), IL4 (β=-1.07; 95 % CI=-1.88,-0.26); and cord blood IFNγ (β=-0.83; 95 % CI=-1.52,-0.14). Social support was not associated with placental inflammation.</div></div><div><h3>Conclusions</h3><div>During mid-pregnancy, psychosocial stress─ particularly low social support─ was associated with maternal blood levels of select cytokines, suggesting a potential pathway linking social stress and inflammation. Our results indicate that the placenta may buffer these inflammatory effects on the fetus.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108922"},"PeriodicalIF":3.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunogenicity-related placental infarcts and abortions in nonhuman primate developmental and reproductive toxicity studies: Proposed mechanism and impact on study interpretation","authors":"Gary J. Chellman ,&nbsp;Rebekah I. Keesler ,&nbsp;Kristina A. York","doi":"10.1016/j.reprotox.2025.108927","DOIUrl":"10.1016/j.reprotox.2025.108927","url":null,"abstract":"<div><div>Previous analysis of 3 developmental toxicity studies (1 EFD, 2 ePPND) conducted in cynomolgus monkeys for biotherapeutics indicated an association between immunogenicity and abortions. This led to the hypothesis that immunogenic responses to biotherapeutics administered to pregnant nonhuman primates (NHPs) can cause altered placental hemodynamics and/or vascular pathology, resulting in placental infarcts and abortion secondary to compromised uteroplacental perfusion. Retrospective analysis of an additional 17 NHP developmental and reproductive toxicity (DART) studies was conducted for further support of this hypothesis. Of 366 placentas evaluated from the 20 total studies (2 EFD, 18 ePPND), 18 % (n = 66) had central placental infarctions/hematomas associated with maternal immunogenicity; these were significant enough to lead to abortion in 32/66 (48 %) of these pregnancies. Abortions in anti-drug antibody positive females with placental infarction were found in 40 % (n = 8) of the studies but accounted for only a 5 % fetal loss rate. Thus, although immunogenicity was commonly observed in these studies, its impact to study outcome/interpretation was manageable in most cases. In the event of immune-mediated responses such as formation of anti-drug antibodies and/or abnormal placental morphology (e.g., infarcts), it is imperative to take a carefully considered, weight-of-evidence approach to interpretation of direct (test article related) vs. indirect (secondary to immunogenicity) effects. In cases where the biotherapeutic being tested is expected to be highly immunogenic in an NHP DART study, with potential confounding impact to study interpretation, alternatives to NHPs should be given high priority in the strategic approach to developmental toxicity testing.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108927"},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling lamotrigine-induced reprotoxicity in porcine endometrial organoids: Integrated multi-platform profiling","authors":"Mariam M. Abady ,&nbsp;Islam M. Saadeldin ,&nbsp;Ayeong Han ,&nbsp;Seonggyu Bang ,&nbsp;Heejae Kang ,&nbsp;Dong Wook Seok ,&nbsp;Ha-Jeong Kwon ,&nbsp;Jongki Cho ,&nbsp;Ji-Seon Jeong","doi":"10.1016/j.reprotox.2025.108926","DOIUrl":"10.1016/j.reprotox.2025.108926","url":null,"abstract":"<div><div>Lamotrigine, a newer generation anti-epileptic drug aimed at addressing reproductive complications, requires thorough evaluation of its effects on the endometrium. Using the three-dimensional endometrial organoid (EO) model provides a distinct advantage in modeling lamotrigine-induced toxicity, offering a more relevant physiological system. In this study, a porcine EO model was used and treated with lamotrigine to mimic and analyze drug-induced toxicity. Porcine uteri were processed and digested with collagenase, then combined with Matrigel and incubated with 5 % CO₂ environment, at 38°C. During passaging, cells were dissociated, treated with trypsin-EDTA, and subcultured, with the medium renewed every 2–3 days. Different analytical methods were employed to evaluate lamotrigine's impact on the endometrial organoids, covering aspects such as cell viability, morphology, replication, steroidogenesis, and metabolic changes. The results showed significant alterations in cell morphology with a decrease in number and size. Metabolite analysis revealed metabolic shifts in some amino acids, glucose and galactose, ranging from approximately 1.5 to 5 times, (<em>p</em> &lt; 0.05), when compared to the control groups. Molecular assays indicated increased oxidative stress, activation of apoptotic pathway, and disrupted steroidogenesis, revealing lamotrigine as an active endocrine disruptor. Moreover, lamotrigine induced changes in specific miRNAs that regulate implantation, and epithelial-mesenchymal transition pathways. In conclusion, our study highlights the potential diverse impact of lamotrigine on the endometrial microenvironment, emphasizing the need for further investigations into its implications on reproductive health and embryo implantation.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108926"},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the safety profile of rosuvastatin in pregnant Wistar rats: Bridging gaps in reproductive safety data","authors":"Diego dos Santos Reis ,&nbsp;Graziele Alícia Batista Caixeta ,&nbsp;João Pedro Monteiro Barbosa ,&nbsp;Júlio César Gonçalves Guimarães dos Reis ,&nbsp;Monatha Nayara Guimarães Teófilo ,&nbsp;Camila Cristina Alves Machado ,&nbsp;Ricardo Silva Tavares ,&nbsp;Jorge Radif Rassi Filho ,&nbsp;Clayson Moura Gomes ,&nbsp;Wilson de Melo Cruvinel ,&nbsp;Eduardo José de Almeida Araújo ,&nbsp;Vanessa Cristiane Santana Amaral","doi":"10.1016/j.reprotox.2025.108920","DOIUrl":"10.1016/j.reprotox.2025.108920","url":null,"abstract":"<div><div>Rosuvastatin, a statin used to treat hypercholesterolemia, inhibits the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HGM-CoA reductase), reducing cholesterol synthesis. Beyond its lipid-lowering effects, rosuvastatin has pleiotropic effects, such as anti-inflammatory and antioxidant properties, with potential application in pre-eclampsia treatment. However, its safety during pregnancy remains controversial. This study evaluated whether prenatal treatment with rosuvastatin calcium induces maternal toxicity and possible embryotoxic, fetotoxic, and teratogenic effects in Wistar rats. Pregnant females received 10, 20, or 40 mg/kg/day of rosuvastatin or a vehicle (saline) by gavage from gestational day 0–20. Maternal toxicity was assessed through weight gain, food and water intake, biochemical markers, histopathology, and myenteric plexus neuron analysis. Fetal evaluations included external, visceral, and skeletal analyses. No significant differences were observed between groups in maternal weight gain, food and water intake, or biochemical parameters. Histopathological analysis showed no dose-dependent abnormalities in the liver, kidneys, heart, or uterus. Enteric neurons exhibited atrophy of nitrergic neurons at 10 and 40 mg/kg, while hypertrophy of total neuronal soma area was observed at 20 mg/kg. Cholinergic neurons were unaffected. Fetal evaluations revealed no significant external, visceral, or skeletal abnormalities attributable to rosuvastatin exposure. These findings suggest that rosuvastatin induces selective vulnerability of nitrergic neurons involved in nitric oxide-mediated adaptations to physiological changes during gestation, likely influenced by the tested exposure levels. Although no maternal or fetal toxicity was observed, alterations in the enteric nervous system underscore the need for further studies to investigate the underlying mechanisms and their potential implications for reproductive health.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108920"},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bisphenol-A-induced ovarian cancer: Changes in epithelial diversity, apoptosis, antioxidant and anti-inflammatory mechanisms","authors":"Nitin Bhardwaj ,&nbsp;Sumit Rajaura ,&nbsp;Ashutosh Singh ,&nbsp;Rambabu ,&nbsp;Nivedita ,&nbsp;Mohammad Z. Ahmed","doi":"10.1016/j.reprotox.2025.108909","DOIUrl":"10.1016/j.reprotox.2025.108909","url":null,"abstract":"<div><div>This research was designed to study the carcinogenic mechanisms of BPA on ovarian epithelial cells. For four months, mice were treated with low (LD, 1 mg/kg) and high (HD, 5 mg/kg of body weight) doses of BPA on alternate days through oral gavage; the control group was given corn oil through gavaging during 4 months. The histopathological data suggest that repeated BPA administration induces a borderline epithelial neoplasm with altered epithelial morphology with branching papillae. Various epithelial cells (ECs) in ovaries were identified by flow cytometry based on anti-mouse CD74 and podoplanin (PDPL) receptors expression. Three different populations of ovarian epithelial cells were identified: epithelial cells type 1 (PDPL⁺CD74^-,EC1), epithelial cells type 2 (PDPL^-CD74⁺_, EC2), and transition epithelial cells (PDPL⁺CD74⁺, TEC). The EC1 decreased, but EC2 was increased in BPA-exposed mice. The population of TEC was comparable to that in the control group at the low dose (LD) but decreased in the high dose (HD) BPA-treated groups. A significant increase in PDPL, CD74 receptor expression and apoptosis and necrosis in BPA-treated ovarian cells was seen. The RT-qPCR results suggest that the relative expression levels of pro-apoptotic (Bax and Casp3) and anti-apoptotic Cytc were markedly decreased, but Bcl2 expression was increased. The anti-inflammatory (IFN-γ, TNF-α, TGF-β, IL-6) gene expression was reduced, but NF-kB expression was increased. Hypoxia regulator (Hif-1α and Nrf2) and tumour suppressor genes (p53 and p21) were also decreased. Thus, BPA exposure changes EC diversity, induces mortality and alters antioxidant, apoptotic and inflammatory gene expression in ovary.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108909"},"PeriodicalIF":3.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-administration of atorvastatin with piperine induces reproductive toxicity in male Wistar rats through oxidative stress induction and downregulation of StAR, CYP11a1, 3βHSD and 17βHSD genes","authors":"Sanjib Ghosh ,&nbsp;Maharaj Biswas","doi":"10.1016/j.reprotox.2025.108919","DOIUrl":"10.1016/j.reprotox.2025.108919","url":null,"abstract":"<div><div>Atorvastatin is a statin group of medicine that inhibits biosynthesis of cholesterol and mainly prescribed for treating cardiovascular diseases. Black pepper is a one of the mostly used spices that contains an alkaloid called piperine in its fruits which is known to cause male reproductive toxicity. Both atorvastatin and black pepper (piperine) are randomly consumed by the patients of chronic hyperlipidemia and it is important to know the synergistic effects of atorvastatin and piperine on male fertility parameters. Twenty rats were taken for the study and divided into four groups each containing five rats. Group I served as a control, group II animals are treated with atorvastatin (ATR) (8 mg/kg BW), group III animals received piperine (PIP) (10 mg/kg BW) and group IV animals were co-administered with piperine (10 mg/kg BW) and atorvastatin (8 mg/kg BW). All treatments were done by using water suspension of atorvastatin and piperine and using oral gavage for consecutive 28 days and thereafter assessed for gravimetric and histomorphometry analysis, sperm motility and morphology, ROS generation, anti-oxidant enzymes, serum testosterone quantification, qRTPCR (StAR, CYP11a1, 3βHSD and 17βHSD genes) and toluidine blue staining for analyzing chromatin integrity of spermatozoa. The results showed that co-administration of ATR+PIP significantly reduced body weight, changed in GSI also found. Activities of major two antioxidant enzymes (SOD and Catalase) were found to reduce whereas levels of TBARS and ROS in testicular tissues increased significantly. The study found that combined administration of atorvastatin and piperine negatively impacted male fertility potential, causing reproductive toxicity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108919"},"PeriodicalIF":3.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating network toxicology and Mendelian randomization to uncover the role of AHR in linking air pollution to male reproductive health","authors":"Yuqi Li ,&nbsp;Zhiyu Liu ,&nbsp;Tao Zhou ,&nbsp;Xinyao Zhu ,&nbsp;Qilong Wu ,&nbsp;Yang Zeng ,&nbsp;Jinghong Yang ,&nbsp;Chunyang Meng ,&nbsp;Qingfu Deng","doi":"10.1016/j.reprotox.2025.108918","DOIUrl":"10.1016/j.reprotox.2025.108918","url":null,"abstract":"<div><h3>Background</h3><div>With the rapid advancement of global industrialization and urbanization, air pollution has emerged as a major public health concern. This study investigates the molecular mechanisms linking air pollutants (APs) to male reproductive health (MRH), providing a scientific foundation for disease prevention and treatment.</div></div><div><h3>Methods</h3><div>APs-disease-related genes were retrieved from multiple network databases, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A protein-protein interaction (PPI) network was constructed to elucidate potential molecular interactions. Differentially expressed genes from two external Gene Expression Omnibus (GEO) sequencing datasets were selected for validation, and intersection analysis was performed to identify key genes. Mendelian randomization (MR）was then applied to assess the causal relationships between key genes and male infertility (MIF), erectile dysfunction (ED), total testosterone levels, and testicular dysfunction. Additionally, molecular docking analysis was conducted to evaluate the binding affinity between key genes and APs.</div></div><div><h3>Results</h3><div>This study focused on seven common APs (Benzene, SO₂, NO, CO, NO₂, Toluene, and O₃) and two MRH conditions (ED and MIF). Through intersection analyses and external validation, Aryl Hydrocarbon Receptor (AHR) was identified as a key regulator. MR analysis suggested that AHR may contribute to MIF and ED by suppressing testosterone levels and impairing testicular function.</div></div><div><h3>Conclusion</h3><div>By integrating network toxicology, MR, and molecular docking analysis, this study highlights the critical role of AHR as a molecular bridge between air pollution and MRH. These findings provide novel molecular insights into the impact of Aps on MRH.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108918"},"PeriodicalIF":3.3,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protocatechualdehyde improves cyclophosphamide-induced premature ovarian insufficiency by inhibiting granulosa cell apoptosis and senescence through the SIRT1/p53 axis","authors":"Cong Feng ,&nbsp;Yue Jiang ,&nbsp;Yi Wang ,&nbsp;Yuehui Zhang ,&nbsp;Yu Liu ,&nbsp;Jia Li","doi":"10.1016/j.reprotox.2025.108903","DOIUrl":"10.1016/j.reprotox.2025.108903","url":null,"abstract":"<div><div>Premature ovarian insufficiency (POI) is a prevalent gynecological disorder. Cyclophosphamide (CP), as a chemotherapeutic drug, particularly plays an important role in inducing POI. Protocatechualdehyde (PCA) is a major phenolic acid in Chinese herb Danshen, and has been reported to have beneficial effects on anti-inflammatory, anti-apoptotic, and anti-oxidant functions. We aimed to investigate the effect of different doses of PCA on ovarian function and the underlying molecular mechanisms. PCA administration reduced estrous cycle disorders, increased ovarian weight, promoted the secretion of serum hormone levels, and improved the CP-damaged ovarian microenvironment. Importantly, the administration of PCA contributed to the recovery of ovarian function with POI by inhibiting the senescence and apoptosis of granulosa cells. <em>In vitro</em> assay further confirmed the protective effect of PCA on CP-induced senescence and apoptosis of granulosa cells. Mechanistically, both <em>in vivo</em> and <em>in vitro</em> experiments proved that PCA administration promoted activation of the Sirt1/p53 signaling cascade, ultimately improving ovarian function. In conclusion, PCA might protect against ovarian damage in CP-induced POI that might be related to its activity on senescence and apoptosis of granulosa cells by the Sirt1/p53 pathway.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"135 ","pages":"Article 108903"},"PeriodicalIF":3.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}