Reproductive toxicology最新文献

{"title":"Maternal coffee consumption during pregnancy and pubertal development in children: A cohort study","authors":"Julie Lyngsø ,&nbsp;Nis Brix ,&nbsp;Andreas Ernst ,&nbsp;Bodil Hammer Bech ,&nbsp;Lea Lykke Harrits Lunddorf ,&nbsp;Cecilia Høst Ramlau-Hansen","doi":"10.1016/j.reprotox.2026.109174","DOIUrl":"10.1016/j.reprotox.2026.109174","url":null,"abstract":"<div><div>It remains unsettled whether prenatal exposure to maternal coffee consumption affects human reproductive health. We investigated whether maternal coffee consumption during early pregnancy is associated with timing of pubertal development in daughters and sons. A total of 15,819 children (8123 daughters and 7696 sons) from the Puberty Cohort, born by mothers in the Danish National Birth Cohort from 2000 to 2003 were included. Mothers reported information on maternal coffee consumption during pregnancy in early second trimester. Information on the children’s pubertal development was self-recorded half-yearly from 11 to 18 years or full maturity using web-based questionnaires. Outcomes were adjusted mean differences (in months) at attaining various pubertal milestones in daughters (i.e. age at menarche and Tanner stages 2, 3, 4 and 5 for breast development and pubic hair growth) and sons (i.e. age at voice break, first ejaculation and Tanner stages 2, 3, 4 and 5 for genital development and pubic hair growth). Moreover, we estimated a combined estimate for the average age at attaining all sex-specific milestones. We observed approximately 2 months earlier age of pubertal development (combined estimate: −2.1 (95 % CI: −3.9; −0.3)) among daughters of mothers consuming 8 or more cups of coffee per day than daughters of mothers with no coffee consumption. No differences in pubertal development were found when comparing sons of mothers with a daily coffee consumption with sons of mothers with no coffee consumption. In conclusion, daughters born of mothers with a high daily coffee consumption during pregnancy might experience earlier pubertal development.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109174"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077480","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":"Micro- and nanoplastics and brain sexual differentiation: An emerging neurodevelopmental threat within the DOHaD framework","authors":"Arielle Cristina Arena ,&nbsp;Bárbara Campos Jorge ,&nbsp;Beatriz de Matos Manoel ,&nbsp;Julia Stein ,&nbsp;Cândida Aparecida Leite Kassuya ,&nbsp;Hamilton Hisano","doi":"10.1016/j.reprotox.2026.109158","DOIUrl":"10.1016/j.reprotox.2026.109158","url":null,"abstract":"<div><div>Micro- and nanoplastics (MNPs) have been increasingly detected in human tissues, including the placenta and, more recently, the brain. Their capacity to cross biological barriers such as the placenta and the blood–brain barrier raises significant concern for sexually dimorphic neurodevelopment. Brain sexual differentiation, orchestrated by steroid hormones, neuroimmune signaling, and epigenetic programming during early life, represents one of the most hormonally sensitive and developmentally critical targets of environmental disruption. In this narrative review, we synthesize evidence positioning MNPs as potential endocrine and epigenetic disruptors that may reprogram hypothalamic circuits governing reproduction and socioemotional behavior within a DOHaD framework. Evidence is stronger in animal and cellular models, implicating oxidative stress, neuroinflammation, apoptosis, and disrupted neurotransmission as central mechanisms; however, sex-specific endpoints remain underexplored and human data are still limited. This review adds a novel integrative perspective by focusing on sexually dimorphic hypothalamic nuclei and by outlining testable, sex-informed hypotheses. We highlight key methodological priorities for future research, including environmentally relevant exposures, explicit consideration of sex as a biological variable, multi-omics approaches, and longitudinal designs.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109158"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906508","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":"Cross-scale causal inference integrated with single-cell profiling and molecular simulations reveals a macrophage CSF1R–CD68–LYZ axis linking benzo[a]pyrene to erectile dysfunction","authors":"Zuomin Wang ,&nbsp;Guodong Ding ,&nbsp;Yiwen Chen,&nbsp;Yuantang Zhong,&nbsp;Youwei Le,&nbsp;Qing Zhang,&nbsp;Wangdong Deng","doi":"10.1016/j.reprotox.2026.109169","DOIUrl":"10.1016/j.reprotox.2026.109169","url":null,"abstract":"<div><h3>Background</h3><div>Erectile dysfunction (ED) is a common disorder with established risk factors such as cardiovascular disease, diabetes, and aging. Increasing evidence indicates that environmental exposures also contribute to its pathogenesis. Benzo[<em>a</em>]pyrene (B[<em>a</em>]P), a carcinogenic polycyclic aromatic hydrocarbon in air pollution, tobacco smoke, and charred foods, has been linked to reproductive dysfunction, yet its molecular role in ED remains unclear.</div></div><div><h3>Methods</h3><div>A multi-faceted approach combining Mendelian randomization (MR), network toxicology, molecular simulations, single-cell RNA sequencing, and virtual gene knockout was used to explore the link between B[<em>a</em>]P exposure and ED. MR assessed causal associations, network toxicology identified molecular targets, and single-cell analysis revealed cellular responses, while virtual gene knockout validated key genes in ED.</div></div><div><h3>Results</h3><div>Our integrated analysis identified CSF1R, CD68, and LYZ as central genes in B[<em>a</em>]P-induced ED. These genes regulate macrophage-driven inflammation, which contributes to endothelial dysfunction and vascular damage—critical processes in ED pathophysiology. Direct interactions between B[<em>a</em>]P and these genes were confirmed, with macrophages playing a key role in the disease mechanism. Causal relationships between B[<em>a</em>]P exposure and ED were established, and therapeutic strategies targeting macrophage-specific genes were proposed to mitigate the impact of environmental toxins on erectile function.</div></div><div><h3>Conclusions</h3><div>This study offers novel insights into the role of B[<em>a</em>]P in ED and identifies key macrophage-specific genes as therapeutic targets. These findings suggest potential strategies for addressing B[<em>a</em>]P-induced ED, with future research needed to validate these targets and explore therapies targeting macrophage-driven inflammation.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109169"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998535","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":"A method for quantitative spatial gene expression analysis of mammary gland tissue morphological changes associated with reproductive and developmental toxicity","authors":"Emily L. Duderstadt ,&nbsp;David J. Samuelson","doi":"10.1016/j.reprotox.2026.109179","DOIUrl":"10.1016/j.reprotox.2026.109179","url":null,"abstract":"<div><div>RNAscope is a novel quantitative <em>in situ</em> gene expression assay that allows single molecule visualization and preservation of spatiotemporal and cell specific information across intact tissue samples. This method has utility to measure gene expression using intact tissue; thus, allowing quantification in a spatial and cell type specific manner, which can be valuable to complement single cell sequencing approaches that use disaggregated tissue. The accurate quantitative capacity of RNAscope depends on retention of RNA integrity which can be lost with extensive or poor tissue handling procedures. This protocol outlines a method of processing and carmine staining mammary gland whole mounts, which is commonly used to identify developmental and reproductive morphologies or disease lesions, followed by excision of tissue areas of interest and RNAscope on tissue sections. This method preserves both RNA integrity and accurate quantification of the RNAscope technology, while bypassing a need for labor-intensive screening of serial sections to identify unpalpable disease lesions induced by environmental exposures at various stages of reproductive development.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109179"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126225","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":"Childhood susceptibility to PFAS-associated endocrine disruption: NHANES age-stratified analysis and PFOS mouse model validation","authors":"Qiming Yang ,&nbsp;Wenxin Bai ,&nbsp;Yujun Liu ,&nbsp;Xiuxian Huang ,&nbsp;Bing Zou ,&nbsp;Zubair Muhammad ,&nbsp;Uswa Farooq ,&nbsp;Qingfeng Zhai ,&nbsp;Nan Liu","doi":"10.1016/j.reprotox.2025.109152","DOIUrl":"10.1016/j.reprotox.2025.109152","url":null,"abstract":"<div><div>Mixed exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with altered male endocrine function, but age-specific susceptibility is uncertain. We analyzed 1965 males aged 6–80 years in NHANES 2013–2018, relating PFOS, PFOA, PFHxS, and PFNA to estradiol (E2) and sex hormone-binding globulin (SHBG) with survey-weighted linear models; mixture effects were assessed by weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) within age strata. Associations were strongest at ages 6–12: PFOS was associated with higher E2, whereas PFOA and PFNA were associated with lower SHBG, with supportive evidence for PFHxS. Mixture analyses identified PFOS as a main contributor and suggested nonlinear PFOS–E2 increases and monotonic SHBG suppression by PFOA/PFHxS. Juvenile mice received PFOS in drinking water for six weeks; PFOS altered hormones and induced germ-cell injury, consistent with the human window. Our findings suggest that childhood may be a sensitive period for PFAS-related endocrine disruption, warranting child-focused monitoring and mixture-aware risk assessment.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109152"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844279","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":"Airway particle exposure and developmental toxicity: From potential link to inflammation to within-laboratory reproducibility challenges","authors":"Karin Sørig Hougaard ,&nbsp;Monika Hezareh Rothmann ,&nbsp;Martin Roursgaard ,&nbsp;Sandra Goericke-Pesch ,&nbsp;Peter Møller ,&nbsp;Luisa Campagnolo ,&nbsp;Ulla Vogel","doi":"10.1016/j.reprotox.2025.109145","DOIUrl":"10.1016/j.reprotox.2025.109145","url":null,"abstract":"<div><div>Research within nanotoxicology has revealed inhalation of particles can interfere with fetal development. Our research group has contributed knowledge on several aspects of developmental toxicity of manufactured nanomaterials. In some cases, the same batch of particles were examined in more than one mouse study. The present review evaluates whether our findings are within-laboratory reproducible and furthermore examines the potential relationships between induced maternal lung inflammation as a potential mediator of developmental toxicity, irrespectively of particle type. Our results ranged from fully reproducible (lack of effects on gestational and litter parameters, on germline mutations in females, irrespective of particle type, and on daily sperm production in F1 males of mothers exposed to carbon black; and depression of immune system function after maternal exposure to multiwalled carbon nanotubes) to not reproducible (transplacental genotoxicity and daily sperm production in the F2 generation of mothers exposed to carbon black and behavioral measures in general). Delineation of the relationship between maternal lung inflammation and developmental effects was somewhat hampered by differences time span from exposure termination to assessment of lung inflammation. At the observed levels, lung inflammation was however not associated with changes in gestational nor litter parameters, and did not seem to play a role in transplacental genotoxicity. In conclusion, this review reveals both consistency and variability in outcomes across studies. The results underscore the complexity of effects of nanoparticle exposure in developmental toxicology and reproducibility of results and warrants future research to focus on reproducibility and elucidate specific mechanisms underlying the observed toxicological effects.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109145"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800674","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":"Influence of hydrogen-rich water on spermatogenesis and sperm parameters in experimentally induced hypothyroidism and subclinical hypothyroidism models","authors":"Mohammad Saroughi ,&nbsp;Khatereh Kharazmi ,&nbsp;Seyedeh Zahra Asghari ,&nbsp;Akram Aminian ,&nbsp;Seyedeh Elnaz Nazari ,&nbsp;Elahe Eshtad ,&nbsp;Alex Tarnava ,&nbsp;Tyler W. LeBaron ,&nbsp;Majid Khazaei","doi":"10.1016/j.reprotox.2025.109146","DOIUrl":"10.1016/j.reprotox.2025.109146","url":null,"abstract":"<div><div>Hypothyroidism, characterized by insufficient thyroid hormone production, disrupts metabolic processes and impairs reproductive function. It is suggested that oxidative stress plays a key role in mediating the deleterious effects of hypothyroidism on testicular function and because of the antioxidative and anti-inflammatory effects of hydrogen-rich water (HRW), this study aimed to evaluate the effects of HRW on spermatogenesis in rats with hypothyroidism and subclinical hypothyroidism. Thirty male Wistar rats were divided into control, hypothyroidism (hypo), hypo+HRW, subclinical hypothyroidism (sub hypo), and sub hypo+HRW groups. Hypothyroidism was induced using propylthiouracil. After induction of models and four weeks of treatment with HRW (twice daily, drinking water), serum levels of thyroid hormones, LH (luteinizing hormone), FSH (follicle-stimulating hormone), and testosterone were measured. Testicular and epididymal weights, sperm parameters, and oxidative stress markers were evaluated. Hypothyroid rats exhibited significantly lower serum testosterone, with trends toward lower LH, and FSH, compared to controls. HRW treatment significantly increased serum LH and testosterone in the hypothyroid group. Histological analysis revealed reduced epithelial height in seminiferous tubules and lower Sertoli and Leydig cell counts in hypothyroid animals, HRW significantly improved Leydig cell counts and showed a nonsignificant upward trend in Sertoli cells. Sperm count and motility decreased in the hypothyroid group, while sperm motility decreased in both hypothyroid and subclinical hypothyroid groups. HRW administration enhanced these parameters. Additionally, HRW reduced MDA (malondialdehyde) levels and increased SOD (superoxide Dismutase) and catalase activities, indicating improved oxidative stress balance. HRW demonstrates potential as a therapeutic strategy for mitigating reproductive impairments associated with hypothyroidism and subclinical hypothyroidism by restoring oxidative stress balance, improving sperm count and enhancing hormonal profiles.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109146"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800703","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":"Caffeine enhances migration, invasion, and tube formation by upregulating MMP-2 in EVT-like HTR-8/SVneo cells","authors":"Jeonghyeon Lee ,&nbsp;Ki-Young Ryu ,&nbsp;Jihyun Keum ,&nbsp;Jaesook Roh","doi":"10.1016/j.reprotox.2025.109157","DOIUrl":"10.1016/j.reprotox.2025.109157","url":null,"abstract":"<div><div>Caffeine is consumed widely during pregnancy, yet its effects on cellular processes relevant to early placental development, particularly on extravillous trophoblast (EVT) function, remain incompletely understood. This study examined the impact of caffeine on EVT-like HTR-8/SVneo cells, focusing on key cellular processes including migration, invasion, and matrix-interactive behaviors relevant to trophoblast function. Treatment with 1 mM caffeine enhanced cell motility and tube formation in EVT-like cells without affecting cell viability or inducing apoptosis. These functional changes were associated with a selective upregulation of MMP-2 expression and activity, while MMP-9 remained unchanged. Pharmacological inhibition of MMP-2 abolished caffeine-induced increases in migration, invasion, and tube formation, supporting a functional role for MMP-2 in these responses. At the signaling level, caffeine-induced MMP-2 upregulation was attenuated by inhibition of PI3K/Akt signaling, with a minor contribution from PKA, whereas MEK1/2 inhibition had minimal effect, supporting the involvement of distinct signaling pathway in EVT-like cells. The observed trophoblast-specific response contrasts with the inhibitory effects of caffeine reported in cancer and endothelial cells. Collectively, these findings identify a previously uncharacterized mechanism by which caffeine modulates signaling and matrix-remodeling−associated behaviors in EVT-like cells in vitro.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109157"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884300","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":"β-caryophyllene mitigates metabolic dysfunction in the testes of gerbils perinatally exposed to BPA","authors":"Stella Bicalho-Silva ,&nbsp;Ana D. Martins ,&nbsp;Rúben J. Moreira ,&nbsp;Thalles F.R. Ruiz ,&nbsp;Vitor Grigio ,&nbsp;Pedro F. Oliveira ,&nbsp;Sebastião R. Taboga ,&nbsp;Patrícia S.L. Vilamaior ,&nbsp;Marco G. Alves","doi":"10.1016/j.reprotox.2025.109155","DOIUrl":"10.1016/j.reprotox.2025.109155","url":null,"abstract":"<div><div>Bisphenol A (BPA) is a persistent environmental pollutant harmful to male reproductive health. Although linked to testicular disorders, the underlying mechanisms and potential therapeutic agents to mitigate their adverse effects need to be fully explored. We investigated the impacts of perinatal BPA exposure and the therapeutic potential of β-caryophyllene (BCP) in the testes of adult Mongolian gerbils (<em>Meriones unguiculatus</em>). Pregnant females were exposed to a historically relevant and realistic dose of BPA (50 μg/kg/day) during gestation and lactation. The F1 male offspring were maintained until adulthood and received a 30-day treatment with BCP (50 mg/kg/day). We assessed the biometric, hormonal, sperm motility, oxidative markers, and metabolic testicular parameters. BPA-exposed gerbils showed decreased progressive sperm motility, as well as increased non-progressive sperm movement. ¹H-NMR metabolomics revealed testicular metabolic reprogramming, including deficits in central energy metabolism (e.g., acetate), nucleoside biosynthesis (adenosine, IMP), vitamin metabolism (pyridoxine, taurine), and phospholipid integrity (ethanolamine, O-phosphoethanolamine). Pathway analysis revealed disturbances in pyruvate metabolism/gluconeogenesis, purine metabolism, and glycerophospholipid metabolism, confirming altered testicular homeostasis. Notably, the BCP consumption rescues sperm motility and mitigates BPA-induced metabolic dysfunction by restoring testicular contents of acetate, adenosine, inosine, IMP, ethanolamine, and O-phosphoethanolamine. Perinatal exposure to BPA programs latent testicular dysfunction through the establishment of a toxic metabolic memory that manifests in adulthood. However, the 30-day BCP intervention mitigated BPA-induced testicular metabolic dysfunctions. This study provides novel descriptive insights into BPA-induced testicular toxicity and highlights BCP as a promising therapeutic agent to counteract the long-term reproductive consequences of early-life exposures.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109155"},"PeriodicalIF":2.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145884301","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":"Uncovering the molecular network of nicotine induced erectile dysfunction through network toxicology and mendelian randomization","authors":"Zhiqiang Dai,&nbsp;Boyi Wang,&nbsp;Hailin Yin,&nbsp;Qiang Zhang","doi":"10.1016/j.reprotox.2025.109114","DOIUrl":"10.1016/j.reprotox.2025.109114","url":null,"abstract":"<div><h3>Background</h3><div>In recent years, smoking has been recognized as a major risk factor for erectile dysfunction (ED). However, the specific harmful constituents of tobacco and their underlying molecular mechanisms remain poorly understood. This study aimed to systematically elucidate the potential targets and pathways of nicotine, the principal addictive component of cigarettes, in the development of ED using an integrative multi omics approach.</div></div><div><h3>Methods</h3><div>Potential nicotine and ED related targets were identified via SEA, TargetNet, and SwissTargetPrediction databases, followed by intersection and enrichment analyses. PPI networks, GO, and KEGG analyses were used to identify key biological pathways. Transcriptomic datasets from rat ED models were integrated for differential expression and receiver operating characteristic (ROC) curve analyses. Mendelian randomization (MR) assessed causal relationships between gene expression and ED risk, while molecular docking validated ligand–receptor binding.</div></div><div><h3>Results</h3><div>Thirty-four overlapping nicotine-ED related genes were identified, mainly enriched in dopaminergic and serotonergic signaling pathways. Four hub genes CNR1, HTR2A, HTR3A, and SLC6A4 were screened, with HTR3A showing the strongest association with ED. MR analysis revealed that higher HTR3A expression was significantly associated with reduced ED risk (OR = 0.607, 95 % CI: 0.454–0.811, <em>p</em> = 0.001). Molecular docking confirmed stable binding between nicotine and the HTR3A orthosteric pocket (binding energy = −6.8 kcal/mol).</div></div><div><h3>Conclusions</h3><div>HTR3A acts as a potential protective target in nicotine-induced ED. The proposed nicotine–HTR3A–serotonin signaling axis provides new mechanistic insights into smoking-related ED and suggests novel directions for precision prevention and therapeutic intervention.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109114"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569439","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}