Reproductive toxicology最新文献

{"title":"Ever cannabis use and biomarkers of male fecundity – A study in the Danish National Birth Cohort","authors":"Georges Khoury ,&nbsp;Sidsel Dan Hull ,&nbsp;Cecilia Høst Ramlau-Hansen ,&nbsp;Anne Gaml Sørensen ,&nbsp;Karin Sørig Hougaard ,&nbsp;Kajsa Ugelvig Petersen ,&nbsp;Gunnar Toft ,&nbsp;Laura Deen ,&nbsp;Jens Peter Bonde ,&nbsp;Sandra Søgaard Tøttenborg","doi":"10.1016/j.reprotox.2025.109004","DOIUrl":"10.1016/j.reprotox.2025.109004","url":null,"abstract":"<div><h3>Background</h3><div>Reports of low semen quality have led to investigations of potential risk factors, including cannabis use. Cannabis affects the endocannabinoid system, which in part regulates spermatogenesis and hormonal balance, but evidence on its impact on male reproductive health remains inconsistent.</div></div><div><h3>Objective</h3><div>This study examined the associations between ever cannabis use and biomarkers of male fecundity in a large cohort of young Danish men incorporating detailed information on their concurrent health behaviors and potential confounding factors during fetal life, a key limitation of previous studies.</div></div><div><h3>Methods</h3><div>We used data from the Fetal Programming of Semen Quality cohort, a sub cohort of 1058 young men born to women enrolled in the Danish National Birth Cohort. Cannabis use was self-reported via an online questionnaire before a clinical examination. Semen samples were collected and analyzed for volume, concentration, total count, motility, morphology, and DNA fragmentation. Hormone levels were measured from venous blood samples. Testicular volume was self-assessed using a Prader Orchidometer.</div></div><div><h3>Results</h3><div>Among participants included in the analytical sample, 324 (31 %) had never used cannabis and 721 (59 %) had used cannabis at least once. We observed no association between ever cannabis use and male fecundity biomarkers, except for a slight indication of higher follicle-stimulating hormone (FSH) levels among ever cannabis users (8 % [95 % CI: −2, 20]).</div></div><div><h3>Conclusion</h3><div>While we found no associations between ever cannabis use and most biomarkers of fecundity in young men, the higher FSH levels among ever cannabis users could suggest early signs of impaired testicular function. However, this needs to be confirmed in studies with a more comprehensive assessment of cannabis exposure.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109004"},"PeriodicalIF":3.3,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691343","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":"Unravelling the potential mechanisms of nano- and microplastic toxicity to the male reproductive system: A systematic review","authors":"Paloma da Cunha de Medeiros ,&nbsp;Aline Gabrielle Gomes da Silva ,&nbsp;Ana Beatriz Silva Angelo ,&nbsp;Maria Joana Nogueira de Moura ,&nbsp;Unnikrishnan Kannan ,&nbsp;Mary Gregory ,&nbsp;Julie Dufresne ,&nbsp;Cibele dos Santos Borges ,&nbsp;Daniel G. Cyr","doi":"10.1016/j.reprotox.2025.109002","DOIUrl":"10.1016/j.reprotox.2025.109002","url":null,"abstract":"<div><div>The ever-increasing presence of microplastic and nanoplastic (MPs/NPs) particles in the natural environment, organisms, and a wide variety of health products, cosmetics, pharmaceuticals, and foods consumed by humans is a global concern. In recent years, research efforts have shifted towards identifying human exposure and risks associated with MPs/NPs, as well as unravelling the mechanisms underlying their toxicity. This systematic review examined the literature regarding the effects of MPs/NPs on the male reproductive system, focusing on the testis, epididymis, and their associated barriers. Research, conducted primarily on rodents, demonstrated that MPs/NPs of various chemical compositions can bioaccumulate in the testis and epididymis, identifying these organs as key targets of plastic particle toxicity. Several studies using rodent models reported alterations in the blood-testis barrier, a crucial structure necessary for proper spermatogenesis. Additionally, multiple studies observed increased apoptosis of germ cells, malformations of spermatozoa, and decreased sperm motility, which is typically acquired during epididymal transit. Exposure to MPs/NPs disrupted Sertoli and Leydig cell function, leading to hormone imbalance. This is likely due to a combination of oxidative stress, inflammation, and disruption of the blood-testis barrier. These effects appear to be influenced by a combination of particle characteristics, including size, shape, chemical composition, surface properties, and exposure route. Larger MPs often cause greater structural damage, while smaller NPs more readily penetrate tissues and trigger molecular disruptions. Understanding how these particles alter male reproductive functions is essential for evaluating their full impact on fertility.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109002"},"PeriodicalIF":3.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668209","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":"Transgenerational effects and mechanisms of nano-SiO2 on pulmonary","authors":"Jiangliang Chu ,&nbsp;Chengzhi Liu ,&nbsp;Shuang Chen ,&nbsp;Yifan Yang ,&nbsp;Keyu Zhang ,&nbsp;Yiping Fu ,&nbsp;Beilei Yuan ,&nbsp;Zhe Wang","doi":"10.1016/j.reprotox.2025.109003","DOIUrl":"10.1016/j.reprotox.2025.109003","url":null,"abstract":"<div><div>Nanomaterials, such as nano-SiO₂, have been extensively studied and applied in various fields. However, little is known about the transgenerational effects of nano-SiO₂. The purpose of this study was to investigate the transgenerational effects and mechanisms of paternal nano-SiO₂ exposure on the lung of male offspring. Male C57BL/6 mice were exposed to nano-SiO₂, which were then mated with unexposed females to produce F1 and F2 generations. The effects of nano-SiO₂ were evaluated over two generations (F0 and F2) by determining pulmonary function, lung tissue pathology, and analyzing the imprinted gene expression and DNA methylation profile in lung tissues. The results showed that tidal volume (VT), 1/2 tidal volume flow (EF50), peak expiratory flow (PEF), peak inspiratory flow (PIF), and minute ventilation (MV) increased significantly in both the F0 and F2 generations. Moreover, HE staining of lung tissues showed inflammation of the F0. PCR results of lung tissues imply a significant change in the expression of Dlk1 and Dio3. Furthermore, nano-SiO₂ exposure increased the methylation levels of Dlk1 and Dio3 across generations F0 and F2. Overall, nano-SiO₂ exposure detrimentally impacts lung respiratory function in male mice by modulating the epigenetic regulation of Dlk1-Dio3 imprinted genes, potentially leading to transgenerational risks. However, further studies are needed to determine the long-term physiological consequences in adulthood.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109003"},"PeriodicalIF":3.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668197","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":"Cell-free circulating epigenomic signatures: Non-invasive biomarkers of pregnancy-related outcomes associated with plasticizer exposure","authors":"Aneha K. Rajan ,&nbsp;Aiswarya Mohanty ,&nbsp;Priyadarshinee Swain ,&nbsp;Rajnarayan Tiwari ,&nbsp;Vikas Gurjar ,&nbsp;Rupesh K. Srivasatava ,&nbsp;Pradyumna Kumar Mishra","doi":"10.1016/j.reprotox.2025.109000","DOIUrl":"10.1016/j.reprotox.2025.109000","url":null,"abstract":"<div><div>Globally, plastics have revolutionized industrial and societal advancements, but their durability and low degradability have led to significant environmental pollution. Plasticizers, such as bisphenol A (BPA) and phthalates, are widely used to enhance the flexibility and durability of plastics; however, they are also recognized as endocrine-disrupting chemicals (EDCs) with severe health implications. These chemicals are associated with reproductive toxicity, developmental disruptions, and multigenerational health effects. Recent research has highlighted the impact of plasticizers on irreversible epigenetic modifications, which influence abnormal gene expression patterns without altering the DNA sequence. Histone alterations, DNA methylation, and non-coding RNA regulation are essential pathways. Exposure to BPA and phthalates disrupts these epigenetic processes, leading to long-term reproductive health issues, including infertility, implantation failures, preterm birth, and pregnancy complications such as gestational diabetes and preeclampsia. Cell-free circulating nucleic acids are promising non-invasive biomarkers for the early detection of pregnancy complications, such as preeclampsia, with the potential to predict sensitivity and track gestational age and underlying pathophysiological processes. Combining circulating nucleic acid analysis with evaluations of plasticizer exposure may aid in stratifying high-risk pregnancies. Here, we examined the mechanisms by which plasticizers induce epigenetic alterations, their impact on reproductive health and pregnancy outcomes, and potential biomarkers for identifying these changes to facilitate tailored management of pregnancy complications and assess reproductive health risks.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109000"},"PeriodicalIF":3.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662415","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":"Exploring the toxicological mechanisms of atrazine in prostate cancer by network toxicology and molecular docking","authors":"Jinwen Mi ,&nbsp;Siyuan Wang,&nbsp;Yifan Hong,&nbsp;Shengde Wu,&nbsp;Guanghui Wei","doi":"10.1016/j.reprotox.2025.109001","DOIUrl":"10.1016/j.reprotox.2025.109001","url":null,"abstract":"<div><div>Atrazine (ATZ) is the second most used herbicide against broadleaf and grassy weeds worldwide. ATZ persists in soil and water due to its long half-life, and is considered an endocrine disrupting chemical for humans. Epidemiological studies have indicated an intimate relationship between ATZ and the pathogenesis of prostate cancer (PCa). However, the underlying toxicological mechanisms remain barely elucidated. Leveraging the CTD, GeneCards, OMIM, PharmGKB, and TTD databases, we identified 154 target genes associated with ATZ exposure and PCa. Using STRING and Cytoscape tools, a PPI network was constructed, and five key genes involved in ATZ-induced PCa toxicity including TP53, JUN, AKT1, BCL2, and IL1B were extracted. Enrichment analysis of target genes highlighted the association of ATZ with pathways integral to PCa development. Expression analysis, ROC curve analysis, immune correlation analysis, and single-gene GSEA of these key genes confirmed their pivotal role in PCa biology. Furthermore, we employed Autodock Vina for molecular docking analysis, demonstrating strong binding between ATZ and the key genes. Collectively, our findings suggest that ATZ may serve as a potential environmental pollutant influencing the pathogenesis of PCa through interactions with key proteins and signaling pathways, offering a theoretical groundwork for the comprehensive prevention and medical management of PCa patients.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109001"},"PeriodicalIF":3.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656666","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":"IGF1R as a protective target in antidiabetic drug-mediated prevention of erectile dysfunction: Insights from genetics","authors":"Yuqi Li,&nbsp;Juan Wang,&nbsp;Tao Zhou,&nbsp;Zhiyu Liu,&nbsp;Chunyang Meng,&nbsp;Qingfu Deng","doi":"10.1016/j.reprotox.2025.108999","DOIUrl":"10.1016/j.reprotox.2025.108999","url":null,"abstract":"<div><h3>Background</h3><div>In recent years, antidiabetic drugs have been increasingly repurposed for conditions beyond diabetes. However, their effects on erectile dysfunction (ED) remain inadequately understood. This study utilizes Mendelian randomization (MR) analysis to investigate the potential impact of antidiabetic drug targets on the risk of ED.</div></div><div><h3>Method</h3><div>We retrieved target gene information for eight classes of antidiabetic drugs from the DrugBank and GeneCards databases and subsequently identified instrumental variables for the corresponding genes using data from the eQTLGen consortium. Following data integration, we conducted MR, meta-analysis, and summary-data-based mendelian randomization (SMR) to systematically investigate the potential causal relationship between antidiabetic drug target genes and ED. Furthermore, we performed sensitivity analyses to assess the robustness and reliability of the observed associations.</div></div><div><h3>Result</h3><div>This study investigated the potential association between 24 antidiabetic drug target genes and ED, identifying 11 positive target genes and included in subsequent analyses. Using MR, meta-analysis, and summary-data-based MR, we observed a significant negative correlation between IGF1R and ED (OR 0.907, 95 % CI 0.859–0.959, P &lt; 0.001). These findings suggest that IGF1R may exert a protective effect against ED, offering novel theoretical support for the potential repurposing of antidiabetic drugs in ED treatment.</div></div><div><h3>Conclusion</h3><div>Our findings indicate that elevated expression of IGF1R may be associated with a reduced risk of erectile dysfunction (ED). This observation implies that the rational application of insulin and its analogs could confer potential preventive benefits against ED, offering novel theoretical insights for the development of targeted therapeutic strategies.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 108999"},"PeriodicalIF":3.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637897","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":"Human umbilical cord mesenchymal stem cell-derived exosomes repair raloxifene-induced damage in endometrial stromal cells via autophagy activation","authors":"Shiling Chen ,&nbsp;Xiuying Lin ,&nbsp;Lei Liu ,&nbsp;Jianhua Fu ,&nbsp;Xiaodan Lu ,&nbsp;Chunxue Niu ,&nbsp;Qilai Wang ,&nbsp;HaiFeng Wei ,&nbsp;Mengxue Wu ,&nbsp;Munan Sun ,&nbsp;Lixin Cao ,&nbsp;Xuguang Mi ,&nbsp;Yanqiu Fang","doi":"10.1016/j.reprotox.2025.108997","DOIUrl":"10.1016/j.reprotox.2025.108997","url":null,"abstract":"<div><div>Estrogen plays a central role in promoting endometrial thickening during the menstrual cycle. In patients with a thin endometrium, endometrial cells exhibit reduced sensitivity to estrogen, contributing to female infertility. We established an endometrial stromal cell damage model using the estrogen antagonist raloxifene (RAL) and investigated the role and underlying mechanism of human umbilical cord mesenchymal stem cell–derived exosomes (hUCMSC-EXO) in repairing RAL-induced damage in human endometrial stromal cells (hEndoSCs). In this study, hEndoSCs were treated with RAL and subsequently cultured with hUCMSC-EXO. The results showed that hUCMSC-EXO restored the proliferative capacity of hEndoSCs, decreased endogenous reactive oxygen species production, and increased mitochondrial membrane potential. Mechanistic analysis indicated that hUCMSC-EXO activated intracellular autophagy, and that autophagy inhibition reversed the protective effects of hUCMSC-EXO on hEndoSCs. These findings suggest that hUCMSC-EXO may ameliorate endometrial injury associated with estrogen insensitivity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 108997"},"PeriodicalIF":3.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614873","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":"Effects of non-nutritive sweeteners on the sweet taste receptor expression and reproductive function in female guinea pigs","authors":"Shanli Zhu ,&nbsp;Ziqing Li ,&nbsp;Fangxiong Shi ,&nbsp;Junrong Li","doi":"10.1016/j.reprotox.2025.108998","DOIUrl":"10.1016/j.reprotox.2025.108998","url":null,"abstract":"<div><div>Non-nutritive sweeteners (NNS) are widely used food additives with unclear reproductive effects. This study examined how dietary NNS supplementation affects taste receptors T1R2/T1R3 expression in female guinea pig reproductive organs. Four groups of ten animals either received the control (basal diet) or basal diet supplemented with either rebaudioside A (RA, 330 mg/kg), saccharin sodium (SS, 800 mg/kg), or sucralose (TGS, 167 mg/kg) for 28 consecutive days. All NNS significantly increased serum progesterone and estradiol levels (P &lt; 0.05). RA significantly upregulated ovarian T1R2/T1R3 expression (P &lt; 0.05), while SS and TGS groups showed higher incidence of follicular cysts and structural disorganization. In uterine tissues, T1R2 expression was significantly higher in TGS and SS groups compared to control and RA groups (P &lt; 0.05), while T1R3 expression was significantly elevated in the SS group compared to all others (P &lt; 0.05). Our findings suggest that dietary NNS supplementation induces ovarian histological alterations, activates sweet taste receptors in reproductive tissues, and elevates serum P₄ and E₂ levels, indicating potential risks to female reproductive health through sweet taste receptor-mediated modulation of steroidogenesis and disruption of follicular development.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 108998"},"PeriodicalIF":3.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604569","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":"Maternal exposure to polystyrene nanoplastics leads to ovotoxicity in female mouse offspring","authors":"Huage Liu","doi":"10.1016/j.reprotox.2025.108996","DOIUrl":"10.1016/j.reprotox.2025.108996","url":null,"abstract":"<div><div>Polystyrene nanoplastics (nPS) have been involved in male reproductive health by inducing testicular damage in offspring. However, whether nPS exposure affects reproductive development in female offspring remains poorly understood. Here, we investigated the effects of maternal nPS exposure on ovarian development in offspring. 31 ICR mice were orally administered normal drinking water (control group) or nPS at concentrations of 0.1 µg/ml, 1 µg/ml, and 10 µg/ml in normal drinking water for 11 consecutive weeks, encompassing the pre-mating, mating, pregnancy, and lactation periods. The results showed that there were no significant changes in litter size and live litter rate when exposed female mice were delivered. Notably, maternal nPS exposure significantly reduced ovarian weight and follicle number in offspring, suggesting the adverse effects of nPS on ovarian development in female offspring. Additionally, <em>Sod1</em> and <em>Gpx1</em> mRNA expressions were dramatically downregulated in nPS-exposed offspring, suggesting an increased risk of oxidative damage to the ovaries. This study indicated that maternal nPS exposure exhibited ovotoxic effects on female offspring, and provided a theoretical foundation for investigating nPS-induced damage to female reproductive health. Furthermore, these findings will offer valuable insights into the field of environmental health.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 108996"},"PeriodicalIF":3.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597297","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 methylenetetrahydrofolate 677C > T variant in murine models following valproic acid exposure","authors":"Man Yang ,&nbsp;Yinchao Li ,&nbsp;Lei Lei ,&nbsp;Shangnan Zou ,&nbsp;Huanling Lai ,&nbsp;Yue Xing ,&nbsp;Yubao Fang ,&nbsp;Qihang Zou ,&nbsp;Yaqian Zhang ,&nbsp;Xiaofeng Yang ,&nbsp;Liemin Zhou","doi":"10.1016/j.reprotox.2025.108995","DOIUrl":"10.1016/j.reprotox.2025.108995","url":null,"abstract":"<div><div>The teratogenic effects of valproic acid (VPA) can lead to abnormal fetal development, which may be related to abnormal maternal one-carbon metabolism. Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme involved in one-carbon metabolism. Variations in <em>MTHFR</em>, particularly 677 C&gt;T, are associated with susceptibility to teratogenicity. However, the current research is limited to clinical practice. Therefore, an <em>Mthfr</em>^{<em>677C&gt;T</em>} mouse model was constructed to explore whether the 677 C &gt; T polymorphism increases the teratogenic susceptibility to VPA. Pregnant wild type and <em>Mthfr</em>^{<em>677C&gt;T</em>} mice were exposed to a single teratogenic dose of 400 mg/kg VPA or saline via intraperitoneal injection on day 7.5 of gestation (E7.5), and fetuses were harvested on E18.5. Resorbed fetuses, malformations, including neural tube defects (NTDs) increased in the VPA-treated group. Consistent with the clinical data, <em>Mthfr</em>^{<em>677C&gt;T</em>} mice also showed lower liver MTHFR enzymatic activity and elevated serum homocysteine (Hcy) levels. No abnormalities were observed in the saline-treated groups. Therefore, intraperitoneal injected VPA significantly increased the malformation rate of CT and TT heterozygote and homozygote mice, respectively, compared to that of CC mice (P &lt; 0.05). In this study, an association between the 677 C &gt; T polymorphism of <em>MTHFR</em> and susceptibility to VPA-induced teratogenesis in mice, especially in TT mice, was found. This may be related to changes in Hcy metabolism. Collectively, these data have important implications for exploring the different responses of individuals to drug-induced teratogenesis, which may help guide the adjustment of drug selection during pregnancy.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 108995"},"PeriodicalIF":3.3,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611818","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}