Pub Date : 2025-11-19DOI: 10.1016/j.reprotox.2025.109111
Briza Castro , Jeffrey F. Dominguez Arellanes , Charles B. Shuster , Sergio A. Soto-Navarro , Craig A. Gifford , Jennifer A. Hernandez Gifford
Gram-negative bacterial release of the endotoxin lipopolysaccharide (LPS) perturbs granulosa cell signaling resulting in reduced estradiol synthesis and disrupted folliculogenesis thereby compromising fertility. While elevated LPS from clinical infections impairs female reproduction, the effects of low-level LPS from subclinical infections remain poorly defined. This study examined increasing LPS concentrations on granulosa cell growth dynamics, immune responses, and steroidogenesis. Human granulosa (KGN) cells were cultured for 48 h with vehicle or LPS (0.0001–10 µg/mL), with or without follicle-stimulating hormone (FSH). No significant LPS × FSH interaction was detected on steroidogenic gene expression (all P ≥ 0.95). LPS increased STAR mRNA abundance with the greatest expression at 10 µg/mL LPS compared to lower concentrations (P ≤ 0.04). Cells treated with FSH demonstrated decreased CTNNB1 (P = 0.0007) and increased CYP19A expression (P = 0.003), while LPS alone had no effect on either gene. Pro-inflammatory gene expression was affected by LPS. LPS dose-dependently increased IL-6, IL-8 and MCP-1 expression in KGN cells, at 1 and 10 µg/mL, while NF-κB expression was unaffected by LPS, FSH or their interaction. Media progesterone (P4; P = 0.99) and estradiol (E2: P = 0.50) concentrations were unaffected by LPS. Live imaging revealed no change in cell confluency at 0.01 µg/mL or 0.1 µg/mL LPS, while 1 µg/mL and 10 µg/mL LPS reduced confluency over 48 h (P = 0.06 and P = 0.02, respectively). KGN cells responded to low-dose LPS with elevated pro-inflammatory cytokine expression. In conclusion, higher LPS concentrations suppress granulosa cell proliferation, an effect mitigated by FSH, indicating that gonadotropic input may protect against LPS-induced ovarian dysfunction.
{"title":"Lipopolysaccharide endotoxin triggers inflammatory responses that disrupt granulosa cell function and alter cell growth dynamics","authors":"Briza Castro , Jeffrey F. Dominguez Arellanes , Charles B. Shuster , Sergio A. Soto-Navarro , Craig A. Gifford , Jennifer A. Hernandez Gifford","doi":"10.1016/j.reprotox.2025.109111","DOIUrl":"10.1016/j.reprotox.2025.109111","url":null,"abstract":"<div><div>Gram-negative bacterial release of the endotoxin lipopolysaccharide (LPS) perturbs granulosa cell signaling resulting in reduced estradiol synthesis and disrupted folliculogenesis thereby compromising fertility. While elevated LPS from clinical infections impairs female reproduction, the effects of low-level LPS from subclinical infections remain poorly defined. This study examined increasing LPS concentrations on granulosa cell growth dynamics, immune responses, and steroidogenesis. Human granulosa (KGN) cells were cultured for 48 h with vehicle or LPS (0.0001–10 µg/mL), with or without follicle-stimulating hormone (FSH). No significant LPS × FSH interaction was detected on steroidogenic gene expression (all <em>P</em> ≥ 0.95). LPS increased <em>STAR</em> mRNA abundance with the greatest expression at 10 µg/mL LPS compared to lower concentrations (<em>P</em> ≤ 0.04). Cells treated with FSH demonstrated decreased <em>CTNNB1</em> (<em>P</em> = 0.0007) and increased <em>CYP19A</em> expression (<em>P</em> = 0.003), while LPS alone had no effect on either gene. Pro-inflammatory gene expression was affected by LPS. LPS dose-dependently increased <em>IL-6</em>, <em>IL-8</em> and <em>MCP-1</em> expression in KGN cells, at 1 and 10 µg/mL, while <em>NF-κB</em> expression was unaffected by LPS, FSH or their interaction. Media progesterone (P<sub>4</sub>; <em>P</em> = 0.99) and estradiol (E<sub>2</sub>: <em>P</em> = 0.50) concentrations were unaffected by LPS. Live imaging revealed no change in cell confluency at 0.01 µg/mL or 0.1 µg/mL LPS, while 1 µg/mL and 10 µg/mL LPS reduced confluency over 48 h (<em>P</em> = 0.06 and <em>P</em> = 0.02, respectively). KGN cells responded to low-dose LPS with elevated pro-inflammatory cytokine expression. In conclusion, higher LPS concentrations suppress granulosa cell proliferation, an effect mitigated by FSH, indicating that gonadotropic input may protect against LPS-induced ovarian dysfunction.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109111"},"PeriodicalIF":2.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565002","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}
Pub Date : 2025-11-19DOI: 10.1016/j.reprotox.2025.109113
Zhilong He , Jijiao Cai , Ruitong Liu , Weici Yan , Guoqi Yang , Runxiong Yu , Lili Xin , Zhongxiao Wan
Maternal exposure to microplastics, particularly polystyrene nanoparticles (PS-NPs), is an emerging environmental threat associated with adverse pregnancy outcomes. However, the underlying mechanisms, especially the potential involvement of placental ferroptosis and gut microbiota, remain largely unexplored. This study aimed to elucidate whether and how maternal exposure to 50-nm PS-NPs disrupts pregnancy in a mouse model, with a focus on gut microbiota dysbiosis and placental ferroptosis. We found that PS-NPs exposure during pre-mating and gestation induced gut microbiota dysbiosis (e.g., increased Campylobacterota and Helicobacter) and triggered placental ferroptosis, as evidenced by iron accumulation, lipid peroxidation, and dysregulation of key proteins associated with ferroptosis. These cellular disruptions led to impaired placental barrier function, increased inflammation, and ultimately, adverse pregnancy outcomes, including elevated embryo resorption and reduced fetal weight. Crucially, correlation analysis linked specific gut microbiota alterations to ferroptosis and pregnancy loss. Furthermore, in vitro experiments confirmed that ferroptosis inhibitors alleviated PS-NPs-induced trophoblast dysfunction. These results suggest that maternal exposure to PS‑NPs may contribute to adverse pregnancy outcomes via inducing gut‑microbiota dysbiosis and placental ferroptosis, which might be potential focus for future mechanistic and therapeutic investigations.
{"title":"Polystyrene nanoparticles induced adverse pregnancy outcomes via the activation of placental ferroptosis and gut microbiota dysfunction","authors":"Zhilong He , Jijiao Cai , Ruitong Liu , Weici Yan , Guoqi Yang , Runxiong Yu , Lili Xin , Zhongxiao Wan","doi":"10.1016/j.reprotox.2025.109113","DOIUrl":"10.1016/j.reprotox.2025.109113","url":null,"abstract":"<div><div>Maternal exposure to microplastics, particularly polystyrene nanoparticles (PS-NPs), is an emerging environmental threat associated with adverse pregnancy outcomes. However, the underlying mechanisms, especially the potential involvement of placental ferroptosis and gut microbiota, remain largely unexplored. This study aimed to elucidate whether and how maternal exposure to 50-nm PS-NPs disrupts pregnancy in a mouse model, with a focus on gut microbiota dysbiosis and placental ferroptosis. We found that PS-NPs exposure during pre-mating and gestation induced gut microbiota dysbiosis (e.g., increased <em>Campylobacterota</em> and <em>Helicobacter</em>) and triggered placental ferroptosis, as evidenced by iron accumulation, lipid peroxidation, and dysregulation of key proteins associated with ferroptosis. These cellular disruptions led to impaired placental barrier function, increased inflammation, and ultimately, adverse pregnancy outcomes, including elevated embryo resorption and reduced fetal weight. Crucially, correlation analysis linked specific gut microbiota alterations to ferroptosis and pregnancy loss. Furthermore, <em>in vitro</em> experiments confirmed that ferroptosis inhibitors alleviated PS-NPs-induced trophoblast dysfunction. These results suggest that maternal exposure to PS‑NPs may contribute to adverse pregnancy outcomes via inducing gut‑microbiota dysbiosis and placental ferroptosis, which might be potential focus for future mechanistic and therapeutic investigations.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109113"},"PeriodicalIF":2.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565078","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}
Pub Date : 2025-11-16DOI: 10.1016/j.reprotox.2025.109112
Anna-Patricia Iversen , Jessica Bruun , Lars Christian Lund , Sarah Bakkær Munk Andreasen , Þórhallur Ingi Halldórsson , Anders Juul , Hanne Frederiksen , Anna-Maria Andersson , Casper P. Hagen , Flemming Nielsen , Marianne Skovsager Andersen , Tina Kold Jensen , Helle Raun Andersen
Background
Pesticides are widespread in the environment and suspected endocrine disruptors that may interfere with sex hormones. Following the chlorpyrifos ban in 2020, use of alternative pesticides has increased; 2,4-Dichlorophenoxyacetic acid (2,4-D) remains widely used. This study examined the association between maternal pesticide exposure and pituitary, gonadal, and adrenal hormones in offspring during infancy.
Methods
We recruited pregnant women from 2010 to 2012 in the Odense Child Cohort, including 489 mother-child pairs. Maternal urinary concentrations of the generic pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA), the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPY), and the herbicide 2,4-D were measured at gestational week 28. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), estrone (E1), estradiol (E2), 17-hydroxyprogesterone (17-OHP), Androstenedione (Adione), and Dehydroepiandrosterone sulfate (DHEAS) were assessed in infancy. Associations between prenatal pesticide exposure and offspring reproductive hormones (expressed as age- and sex-specific standard deviation (SD) scores) were assessed using multivariate linear regression.
Results
In girls, higher maternal urinary TCPY and 2,4-D concentrations were associated with lower LH (-0.07 SD, 95 % CI: − 0.13; − 0.01 and − 0.06 SD, 95 % CI: − 0.11; − 0.02, per 1 µg/L increase, respectively); there were trends towards associations between 3-PBA, TCPY, 2,4-D and lower LH, FSH, E1 and E2, respectively. No associations were seen in boys.
Conclusion
In this low-exposed cohort, prenatal exposure to chlorpyrifos and 2,4-D may affect the reproductive hormones in girls, but not boys, during minipuberty, which may have long-term implications. This is of public health concern given the fact that > 90 % of participants were exposed.
{"title":"Prenatal exposure to the pesticides chlorpyrifos and 2,4-Dichlorophenoxyacetic acid is associated with circulating levels of reproductive hormones in healthy infant girls","authors":"Anna-Patricia Iversen , Jessica Bruun , Lars Christian Lund , Sarah Bakkær Munk Andreasen , Þórhallur Ingi Halldórsson , Anders Juul , Hanne Frederiksen , Anna-Maria Andersson , Casper P. Hagen , Flemming Nielsen , Marianne Skovsager Andersen , Tina Kold Jensen , Helle Raun Andersen","doi":"10.1016/j.reprotox.2025.109112","DOIUrl":"10.1016/j.reprotox.2025.109112","url":null,"abstract":"<div><h3>Background</h3><div>Pesticides are widespread in the environment and suspected endocrine disruptors that may interfere with sex hormones. Following the chlorpyrifos ban in 2020, use of alternative pesticides has increased; 2,4-Dichlorophenoxyacetic acid (2,4-D) remains widely used. This study examined the association between maternal pesticide exposure and pituitary, gonadal, and adrenal hormones in offspring during infancy.</div></div><div><h3>Methods</h3><div>We recruited pregnant women from 2010 to 2012 in the Odense Child Cohort, including 489 mother-child pairs. Maternal urinary concentrations of the generic pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA), the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPY), and the herbicide 2,4-D were measured at gestational week 28. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), estrone (E1), estradiol (E2), 17-hydroxyprogesterone (17-OHP), Androstenedione (Adione), and Dehydroepiandrosterone sulfate (DHEAS) were assessed in infancy. Associations between prenatal pesticide exposure and offspring reproductive hormones (expressed as age- and sex-specific standard deviation (SD) scores) were assessed using multivariate linear regression.</div></div><div><h3>Results</h3><div>In girls, higher maternal urinary TCPY and 2,4-D concentrations were associated with lower LH (-0.07 SD, 95 % CI: − 0.13; − 0.01 and − 0.06 SD, 95 % CI: − 0.11; − 0.02, per 1 µg/L increase, respectively); there were trends towards associations between 3-PBA, TCPY, 2,4-D and lower LH, FSH, E1 and E2, respectively. No associations were seen in boys.</div></div><div><h3>Conclusion</h3><div>In this low-exposed cohort, prenatal exposure to chlorpyrifos and 2,4-D may affect the reproductive hormones in girls, but not boys, during minipuberty, which may have long-term implications. This is of public health concern given the fact that > 90 % of participants were exposed.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109112"},"PeriodicalIF":2.8,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550124","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}
Pub Date : 2025-11-15DOI: 10.1016/j.reprotox.2025.109110
Sadık Küçükgünay , Halime Tozak Yildiz , Oya Korkmaz , Memiş Bolacali , Mustafa Numan Bucak , Hasan Ali Çay , Şöhret Güler
Docetaxel (DTX), a widely used chemotherapeutic agent, is known for its effectiveness in cancer treatment but also for its toxic effects on healthy tissues, particularly the male reproductive system. This study aimed to investigate the protective role of rutin, a natural flavonoid with known antioxidant and anti-apoptotic properties, against DTX-induced testicular damage in rats. Thirty-six adult male Wistar rats were randomly divided into six groups: Control, Rutin 50 mg/kg (R50), Rutin 100 mg/kg (R100), DTX, DTX+R50, and DTX+R100. A single dose of DTX (30 mg/kg, i.p.) was administered, while rutin was given orally for 7 days. On day eight, all animals were sacrificed. Sperm parameters (concentration, motility, morphology, chromatin integrity), serum testosterone and inhibin B levels, and testicular MDA and SOD levels were assessed. Histological evaluations were conducted using hematoxylin-eosin staining, Johnsen scoring, and tubule diameter measurements. Immunohistochemical analysis of Caspase-3, Bax, Bcl-2, mTOR, ULK1, and Atg13 was performed. Data were analyzed, and p < 0.05 was considered statistically significant. DTX significantly impaired sperm motility and hormone levels, increased oxidative stress, and caused histological damage in the testes (p < 0.001). Rutin, especially at 100 mg/kg, ameliorated these effects, restoring sperm function, hormonal balance, and testicular architecture. Furthermore, rutin reduced DTX-induced apoptosis and autophagy marker expression while preserving Bcl-2 levels (p < 0.001). DTX induces structural and functional impairments in testicular tissue via oxidative stress, apoptosis, and autophagy. Rutin demonstrated a dose-dependent protective effect, suggesting its potential as a supportive agent against chemotherapy-induced gonadotoxicity.
{"title":"Protective effects of rutin against docetaxel-induced testicular damage in rats: Effects on antioxidant defence, apoptosis and autophagy","authors":"Sadık Küçükgünay , Halime Tozak Yildiz , Oya Korkmaz , Memiş Bolacali , Mustafa Numan Bucak , Hasan Ali Çay , Şöhret Güler","doi":"10.1016/j.reprotox.2025.109110","DOIUrl":"10.1016/j.reprotox.2025.109110","url":null,"abstract":"<div><div>Docetaxel (DTX), a widely used chemotherapeutic agent, is known for its effectiveness in cancer treatment but also for its toxic effects on healthy tissues, particularly the male reproductive system. This study aimed to investigate the protective role of rutin, a natural flavonoid with known antioxidant and anti-apoptotic properties, against DTX-induced testicular damage in rats. Thirty-six adult male Wistar rats were randomly divided into six groups: Control, Rutin 50 mg/kg (R50), Rutin 100 mg/kg (R100), DTX, DTX+R50, and DTX+R100. A single dose of DTX (30 mg/kg, i.p.) was administered, while rutin was given orally for 7 days. On day eight, all animals were sacrificed. Sperm parameters (concentration, motility, morphology, chromatin integrity), serum testosterone and inhibin B levels, and testicular MDA and SOD levels were assessed. Histological evaluations were conducted using hematoxylin-eosin staining, Johnsen scoring, and tubule diameter measurements. Immunohistochemical analysis of Caspase-3, Bax, Bcl-2, mTOR, ULK1, and Atg13 was performed. Data were analyzed, and p < 0.05 was considered statistically significant. DTX significantly impaired sperm motility and hormone levels, increased oxidative stress, and caused histological damage in the testes (p < 0.001). Rutin, especially at 100 mg/kg, ameliorated these effects, restoring sperm function, hormonal balance, and testicular architecture. Furthermore, rutin reduced DTX-induced apoptosis and autophagy marker expression while preserving Bcl-2 levels (p < 0.001). DTX induces structural and functional impairments in testicular tissue via oxidative stress, apoptosis, and autophagy. Rutin demonstrated a dose-dependent protective effect, suggesting its potential as a supportive agent against chemotherapy-induced gonadotoxicity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109110"},"PeriodicalIF":2.8,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145542390","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}
Pub Date : 2025-11-14DOI: 10.1016/j.reprotox.2025.109108
Chuhang Lin , Qian Chen , Qianqian Xie , Haiying Li , Xiaomei Wu , Xiaoxiao Lin , Lijun Wang , Xingming Zhong , Lei Tan , Chunxia Jing
The relationship between polycyclic aromatic hydrocarbons (PAHs) exposure and female infertility (FI) remains unclear, particularly regarding mixed PAH exposures. This study aimed to investigate the association between individual and mixed PAH exposures and FI by integrating epidemiological and network toxicological approaches. A case-control study was conducted involving 83 infertile patients and 272 non-infertile controls in Guangdong Province, China. Three statistical models were applied to assess the effects of eight urinary hydroxylated-PAHs (OH-PAHs) metabolites on FI. Network toxicology analysis was utilized to identify common genes, potential pathways, and key targets. After adjusting for potential confounders, 3-OHFLU and 2-OHPHE were significantly associated with an increased risk of FI, with 3-OHFLU identified as the predominant risk factor (OR [95 % CI]: 1.92 [1.42, 2.69]). Mixture analysis revealed a positive association between mixed OH-PAHs and FI risk, with 3-OHFLU contributing the most. Based on network toxicology analysis, we propose a potential mechanism: PAHs exposure may activate the TNF signaling pathway, which could trigger an inflammatory response, potentially altering AKT1 expression via the PI3K-Akt pathway. This might lead to reduced cell survival, promoted oocyte apoptosis, and ultimately contribute to FI. These findings indicate that mixed PAHs exposure increases the risk of FI, with 3-OHFLU identified as the predominant contributing factor and the TNF signaling pathway serving as a potential underlying mechanism. Further longitudinal studies are needed to validate these results.
{"title":"Unveiling polycyclic aromatic hydrocarbons exposure and female infertility risk in southern China: An integrated epidemiologic and network toxicology approach","authors":"Chuhang Lin , Qian Chen , Qianqian Xie , Haiying Li , Xiaomei Wu , Xiaoxiao Lin , Lijun Wang , Xingming Zhong , Lei Tan , Chunxia Jing","doi":"10.1016/j.reprotox.2025.109108","DOIUrl":"10.1016/j.reprotox.2025.109108","url":null,"abstract":"<div><div>The relationship between polycyclic aromatic hydrocarbons (PAHs) exposure and female infertility (FI) remains unclear, particularly regarding mixed PAH exposures. This study aimed to investigate the association between individual and mixed PAH exposures and FI by integrating epidemiological and network toxicological approaches. A case-control study was conducted involving 83 infertile patients and 272 non-infertile controls in Guangdong Province, China. Three statistical models were applied to assess the effects of eight urinary hydroxylated-PAHs (OH-PAHs) metabolites on FI. Network toxicology analysis was utilized to identify common genes, potential pathways, and key targets. After adjusting for potential confounders, 3-OHFLU and 2-OHPHE were significantly associated with an increased risk of FI, with 3-OHFLU identified as the predominant risk factor (OR [95 % CI]: 1.92 [1.42, 2.69]). Mixture analysis revealed a positive association between mixed OH-PAHs and FI risk, with 3-OHFLU contributing the most. Based on network toxicology analysis, we propose a potential mechanism: PAHs exposure may activate the TNF signaling pathway, which could trigger an inflammatory response, potentially altering AKT1 expression via the PI3K-Akt pathway. This might lead to reduced cell survival, promoted oocyte apoptosis, and ultimately contribute to FI. These findings indicate that mixed PAHs exposure increases the risk of FI, with 3-OHFLU identified as the predominant contributing factor and the TNF signaling pathway serving as a potential underlying mechanism. Further longitudinal studies are needed to validate these results.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109108"},"PeriodicalIF":2.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534338","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}
Pub Date : 2025-11-14DOI: 10.1016/j.reprotox.2025.109109
Fang Xie , Mengzhen Hou , Yingxia Wang , Xutao Ling , Yun Yu , Qianqian Huang , Lun Zhang , Cheng Zhang , Jun Yu , Jianqing Wang
Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental pollutant, is extensively utilized in industrial, medical, and food-related applications. In our previous study, we successfully established an mice model of ICP induced by gestational di(2-ethylhexyl) phthalate (DEHP) exposure. Our findings suggested that DEHP-induced folic acid (FA) deficiency might contribute to the development of IUGR. However, the potential protective effects of FA supplementation against IUGR resulting from gestational DEHP exposure remain to be elucidated. Notably, administration of DEHP to pregnant mice resulted in a significant reduction in average placental weight and diameter, as well as fetal body weight and crown-rump length. Histological analysis using H&E staining and immunohistochemistry revealed a reduction in the area of placental blood sinuses and the density of CD34+ micro vessels. Gene expression analysis of placental nutrient transporters demonstrated significant downregulation of glucose transporter Glut1, fatty acid transporters CD36 and Fatp1, as well as amino acid transporter Snat4. Molecular docking analysis indicated that FA exhibited strong binding affinity toward the target protein STAT3. Experimental findings confirmed that FA could enhance placental angiogenesis and alleviate placental hypoplasia and nutrient transport impairments by activating the STAT3/HIF-1α/VEGFA signaling pathway, thus preventing IUGR caused by maternal DEHP exposure. These results provide a theoretical foundation for the prevention and treatment of ICP-associated IUGR.
{"title":"Folic acid alleviates fetal growth restriction induced by gestational Di (2-ethylhexyl) phthalate exposure in mice through activating the STAT3/HIF-1α/VEGFA signaling pathway","authors":"Fang Xie , Mengzhen Hou , Yingxia Wang , Xutao Ling , Yun Yu , Qianqian Huang , Lun Zhang , Cheng Zhang , Jun Yu , Jianqing Wang","doi":"10.1016/j.reprotox.2025.109109","DOIUrl":"10.1016/j.reprotox.2025.109109","url":null,"abstract":"<div><div>Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental pollutant, is extensively utilized in industrial, medical, and food-related applications. In our previous study, we successfully established an mice model of ICP induced by gestational di(2-ethylhexyl) phthalate (DEHP) exposure. Our findings suggested that DEHP-induced folic acid (FA) deficiency might contribute to the development of IUGR. However, the potential protective effects of FA supplementation against IUGR resulting from gestational DEHP exposure remain to be elucidated. Notably, administration of DEHP to pregnant mice resulted in a significant reduction in average placental weight and diameter, as well as fetal body weight and crown-rump length. Histological analysis using H&E staining and immunohistochemistry revealed a reduction in the area of placental blood sinuses and the density of CD34<sup>+</sup> micro vessels. Gene expression analysis of placental nutrient transporters demonstrated significant downregulation of glucose transporter Glut1, fatty acid transporters CD36 and Fatp1, as well as amino acid transporter Snat4. Molecular docking analysis indicated that FA exhibited strong binding affinity toward the target protein STAT3. Experimental findings confirmed that FA could enhance placental angiogenesis and alleviate placental hypoplasia and nutrient transport impairments by activating the STAT3/HIF-1α/VEGFA signaling pathway, thus preventing IUGR caused by maternal DEHP exposure. These results provide a theoretical foundation for the prevention and treatment of ICP-associated IUGR.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109109"},"PeriodicalIF":2.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534261","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}
Pub Date : 2025-11-10DOI: 10.1016/j.reprotox.2025.109107
Linjie Yang , Rongju Liu , Kaihui Li , Siyan Chen , Lei Tan , Xijin Xu , William Au , Xia Huo
Exposure to per- and poly-fluoroalkyl substances (PFAS) has been reported to impair fertility in experimental models. However, studies on female reproductive outcomes are limited to a few legacy PFAS. This study linked exposure to various PFAS with reproductive outcomes in women undergoing IVF/ICSI. A total of 275 women were recruited, and plasma concentrations of 17 PFAS were quantified. Based on analysis using the adjusted generalized linear models, an increase in the quartile of 6:2Cl-PFESA was associated with a decrease in the number of 2PN zygotes [9.33, 95 %CI: (3.63, 15.03)] and 2PN cleavage embryos [9.20, 95 %CI: (3.57, 14.83)]. Higher quartiles of 8:2Cl-PFESA were associated with lower fertilization rate [67.44, 95 %CI: (47.91, 86.97)]. Long-chain PFAS (PFUnDA, PFTrDA, PFTeDA) were negatively correlated with oocytes quantity and embryo quality. PFHxS was associated with a reduced number of high-quality blastocysts [55.72, 95 %CI: (17.72, 93.72)]. Increased PFOA levels were associated with lower number of patients who achieved biochemical and clinical pregnancy outcomes. Quantile G-computation (QGC) showed that mixed PFAS exposures were negatively correlated with the number of oocytes retrieved, mature oocytes, 2PN zygotes, 2PN cleavage embryos, high-quality embryos, high-quality blastocysts and the number of blastocysts formed. Our results indicate that exposure to a variety of PFAS was inversely associated with the number of extracted oocytes, mature oocytes, 2PN zygotes, 2PN cleavage embryos, high-quality embryos, and high-quality blastocysts among women undergoing IVF/ICSI treatment. Our study highlights the potential reproductive toxicity of PFAS and the need for further research to determine its impact on human fertility.
{"title":"Associations between per- and polyfluoroalkyl substances and reproductive outcomes among women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment","authors":"Linjie Yang , Rongju Liu , Kaihui Li , Siyan Chen , Lei Tan , Xijin Xu , William Au , Xia Huo","doi":"10.1016/j.reprotox.2025.109107","DOIUrl":"10.1016/j.reprotox.2025.109107","url":null,"abstract":"<div><div>Exposure to per- and poly-fluoroalkyl substances (PFAS) has been reported to impair fertility in experimental models. However, studies on female reproductive outcomes are limited to a few legacy PFAS. This study linked exposure to various PFAS with reproductive outcomes in women undergoing IVF/ICSI. A total of 275 women were recruited, and plasma concentrations of 17 PFAS were quantified. Based on analysis using the adjusted generalized linear models, an increase in the quartile of 6:2Cl-PFESA was associated with a decrease in the number of 2PN zygotes [9.33, 95 %CI: (3.63, 15.03)] and 2PN cleavage embryos [9.20, 95 %CI: (3.57, 14.83)]. Higher quartiles of 8:2Cl-PFESA were associated with lower fertilization rate [67.44, 95 %CI: (47.91, 86.97)]. Long-chain PFAS (PFUnDA, PFTrDA, PFTeDA) were negatively correlated with oocytes quantity and embryo quality. PFHxS was associated with a reduced number of high-quality blastocysts [55.72, 95 %CI: (17.72, 93.72)]. Increased PFOA levels were associated with lower number of patients who achieved biochemical and clinical pregnancy outcomes. Quantile G-computation (QGC) showed that mixed PFAS exposures were negatively correlated with the number of oocytes retrieved, mature oocytes, 2PN zygotes, 2PN cleavage embryos, high-quality embryos, high-quality blastocysts and the number of blastocysts formed. Our results indicate that exposure to a variety of PFAS was inversely associated with the number of extracted oocytes, mature oocytes, 2PN zygotes, 2PN cleavage embryos, high-quality embryos, and high-quality blastocysts among women undergoing IVF/ICSI treatment. Our study highlights the potential reproductive toxicity of PFAS and the need for further research to determine its impact on human fertility.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109107"},"PeriodicalIF":2.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506526","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}
Pub Date : 2025-11-10DOI: 10.1016/j.reprotox.2025.109106
Sarah E. Amin , Eman F. Farghaly , Doaa A. Abdelmonsif , Eiman I. Zaki , Walaa Omar
Many factors contribute to infertility. Among these are chemotherapeutic drugs as they interfere with cell division and spermatogenesis. Busulfan (BU) is one of these drugs that is applied in the treatment of many malignancies. Latest studies have focused on the protective impact of medicinal plant products, such as curcumin (CU), for ameliorating tissue damage through their antioxidant properties. Nanoparticles are now used to improve drug delivery and efficacy. Our study was aimed at assessing the potential therapeutic effect of curcumin nanoemulsion (CU-NE) on busulfan-induced testicular toxicity in adult rats. Forty-eight adult male albino rats were randomly distributed in six groups, 8 rats each: Control groups; group I: negative control, II: vehicle control, III: CU-NE. Group IV: BU, group V: CU-NE+BU and group VI: spontaneous recovery. Each group was assessed regarding serum level of testosterone, tumor necrosis factor-α (TNF-α) and total antioxidant capacity (TAC). Malondialdehyde (MDA) and glutathione peroxidase (GPX) levels were measured in testicular tissue. Moreover, sperm parameters were measured, and histological examination of the testis was performed. CU-NE significantly improved all the tested parameters and ameliorated the degenerative changes found in the testis following busulfan administration. Thus, CU-NE could be a promising therapeutic agent that restores spermatogenesis and facilitates regeneration of the seminiferous epithelium after chemotherapy-induced testicular damage.
{"title":"The potential ameliorative effect of curcumin nanoemulsion on busulfan-induced testicular toxicity in adult rat model","authors":"Sarah E. Amin , Eman F. Farghaly , Doaa A. Abdelmonsif , Eiman I. Zaki , Walaa Omar","doi":"10.1016/j.reprotox.2025.109106","DOIUrl":"10.1016/j.reprotox.2025.109106","url":null,"abstract":"<div><div>Many factors contribute to infertility. Among these are chemotherapeutic drugs as they interfere with cell division and spermatogenesis. Busulfan (BU) is one of these drugs that is applied in the treatment of many malignancies. Latest studies have focused on the protective impact of medicinal plant products, such as curcumin (CU), for ameliorating tissue damage through their antioxidant properties. Nanoparticles are now used to improve drug delivery and efficacy. Our study was aimed at assessing the potential therapeutic effect of curcumin nanoemulsion (CU-NE) on busulfan-induced testicular toxicity in adult rats. Forty-eight adult male albino rats were randomly distributed in six groups, 8 rats each: Control groups; group I: negative control, II: vehicle control, III: CU-NE. Group IV: BU, group V: CU-NE+BU and group VI: spontaneous recovery. Each group was assessed regarding serum level of testosterone, tumor necrosis factor-α (TNF-α) and total antioxidant capacity (TAC). Malondialdehyde (MDA) and glutathione peroxidase (GPX) levels were measured in testicular tissue. Moreover, sperm parameters were measured, and histological examination of the testis was performed. CU-NE significantly improved all the tested parameters and ameliorated the degenerative changes found in the testis following busulfan administration. Thus, CU-NE could be a promising therapeutic agent that restores spermatogenesis and facilitates regeneration of the seminiferous epithelium after chemotherapy-induced testicular damage.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109106"},"PeriodicalIF":2.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506496","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}
Pub Date : 2025-11-05DOI: 10.1016/j.reprotox.2025.109103
Karmveer Yadav , Ritu Sharma
Biomaterials for drug delivery offer significant advantages over conventional medications, including enhanced cellular uptake, improved drug stability, targeted delivery, and controlled drug release. Cutting-edge nanodrugs delivery approaches such as drugs formulations, hydrogels, films, and vaccines have been developed for diverse applications, including hormonal therapies, immunotherapy, infectious diseases, and gestational health. Tailored biomaterial systems can administer drugs for conditions such as vaginal infections, endometriosis, pregnancy disorders, reproductive cancers, and inherent messes during gestation. Designing delivery technologies for female health requires addressing unique barriers and challenges specific to the female body. Advancements in delivery technologies in other disease contexts can inform innovations in female health treatments. Delivering biomaterials and medications at the time of pregnancy may have adverse developmental consequences for the fetus, necessitating an understanding of how nanomaterials interact with reproductive systems and activate signal transduction pathways. Ensuring safety and minimizing toxicity are critical considerations, alongside developing appropriate and accessible preclinical models to facilitate clinical translation. Omics-based techniques can aid in the sustainable risk assessment and safety evaluation of nanomaterials by identifying biomolecules involved in nanotoxicity. Taking these events or exposures together with their toxicity on the female reproductive system and offspring outcomes, thus further study is required to explore, the way that nanoparticles compromise fertility and growth of embryos in humans. Long-term studies are crucial for assessing the safety of nanodrugs in pregnant female, especially concerning chronic effects from prenatal exposure. Effective development and translation of nano-drug delivery technologies for female health require collaboration among biomaterials researchers, patients, clinicians, and regulatory agencies.
{"title":"Nanodrug impact on female reproductive health and fetal development: From translation approaches to long-term safety concern","authors":"Karmveer Yadav , Ritu Sharma","doi":"10.1016/j.reprotox.2025.109103","DOIUrl":"10.1016/j.reprotox.2025.109103","url":null,"abstract":"<div><div>Biomaterials for drug delivery offer significant advantages over conventional medications, including enhanced cellular uptake, improved drug stability, targeted delivery, and controlled drug release. Cutting-edge nanodrugs delivery approaches such as drugs formulations, hydrogels, films, and vaccines have been developed for diverse applications, including hormonal therapies, immunotherapy, infectious diseases, and gestational health. Tailored biomaterial systems can administer drugs for conditions such as vaginal infections, endometriosis, pregnancy disorders, reproductive cancers, and inherent messes during gestation. Designing delivery technologies for female health requires addressing unique barriers and challenges specific to the female body. Advancements in delivery technologies in other disease contexts can inform innovations in female health treatments. Delivering biomaterials and medications at the time of pregnancy may have adverse developmental consequences for the fetus, necessitating an understanding of how nanomaterials interact with reproductive systems and activate signal transduction pathways. Ensuring safety and minimizing toxicity are critical considerations, alongside developing appropriate and accessible preclinical models to facilitate clinical translation. Omics-based techniques can aid in the sustainable risk assessment and safety evaluation of nanomaterials by identifying biomolecules involved in nanotoxicity. Taking these events or exposures together with their toxicity on the female reproductive system and offspring outcomes, thus further study is required to explore, the way that nanoparticles compromise fertility and growth of embryos in humans. Long-term studies are crucial for assessing the safety of nanodrugs in pregnant female, especially concerning chronic effects from prenatal exposure. Effective development and translation of nano-drug delivery technologies for female health require collaboration among biomaterials researchers, patients, clinicians, and regulatory agencies.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109103"},"PeriodicalIF":2.8,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469138","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}
Pub Date : 2025-11-05DOI: 10.1016/j.reprotox.2025.109105
Nora Bouftas , Anna K. Rosenmai , Eleftheria M. Panagiotou , Johanna Zilliacus , Pauliina Damdimopoulou , Anna Beronius , Majorie van Duursen , Terje Svingen
The Adverse Outcome Pathway (AOP) framework offers a structured approach to organize mechanistic knowledge of toxicological pathways. By describing biological events linking molecular initiating events (MIEs) to an adverse outcome (AO) at the organismal level, it aims to aid regulatory decision-making through predictive toxicology approaches. To serve this purpose, however, it is recognized that AOP networks are required to adequately capture complex biology. Another central feature of the AOP concept is that upstream molecular networks will be shared between numerous downstream AOs. This report focuses on steroidogenesis, a common target of endocrine disrupting chemicals, and the development of an upstream network for reduced steroidogenesis focusing on hormones and enzymes that are particularly relevant to mammalian reproduction. The AOP-Wiki was mapped for existing content related to steroidogenesis and the resulting network expanded by incorporating additional key events (KEs) and KE Relationships (KERs) not yet inventoried. All existing KEs and KERs were evaluated for completeness. Using a pragmatic approach, we developed the identified KEs and KERs by integrating evidence from recent review articles. The focus was particularly on the impact of disrupted cholesterol transport, altered enzyme activities and hormone levels. The resulting upstream AOP network serves as a foundation for developing complete AOPs linking disrupted steroidogenesis with downstream AOs. This upstream network will also contribute to identifying relevant test assays for development and understanding the predictive capabilities of existing in vitro assays, such as the OECD-validated H295R steroidogenesis assay.
{"title":"A pragmatic upstream network for disrupted steroidogenesis through reduced enzyme activity and steroid hormone production for Adverse Outcome Pathway building","authors":"Nora Bouftas , Anna K. Rosenmai , Eleftheria M. Panagiotou , Johanna Zilliacus , Pauliina Damdimopoulou , Anna Beronius , Majorie van Duursen , Terje Svingen","doi":"10.1016/j.reprotox.2025.109105","DOIUrl":"10.1016/j.reprotox.2025.109105","url":null,"abstract":"<div><div>The Adverse Outcome Pathway (AOP) framework offers a structured approach to organize mechanistic knowledge of toxicological pathways. By describing biological events linking molecular initiating events (MIEs) to an adverse outcome (AO) at the organismal level, it aims to aid regulatory decision-making through predictive toxicology approaches. To serve this purpose, however, it is recognized that AOP networks are required to adequately capture complex biology. Another central feature of the AOP concept is that upstream molecular networks will be shared between numerous downstream AOs. This report focuses on steroidogenesis, a common target of endocrine disrupting chemicals, and the development of an upstream network for reduced steroidogenesis focusing on hormones and enzymes that are particularly relevant to mammalian reproduction. The AOP-Wiki was mapped for existing content related to steroidogenesis and the resulting network expanded by incorporating additional key events (KEs) and KE Relationships (KERs) not yet inventoried. All existing KEs and KERs were evaluated for completeness. Using a pragmatic approach, we developed the identified KEs and KERs by integrating evidence from recent review articles. The focus was particularly on the impact of disrupted cholesterol transport, altered enzyme activities and hormone levels. The resulting upstream AOP network serves as a foundation for developing complete AOPs linking disrupted steroidogenesis with downstream AOs. This upstream network will also contribute to identifying relevant test assays for development and understanding the predictive capabilities of existing in vitro assays, such as the OECD-validated H295R steroidogenesis assay.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109105"},"PeriodicalIF":2.8,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469139","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}
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