Pub Date : 2025-12-23DOI: 10.1016/j.reprotox.2025.109149
Emilie Elmelund, Marie Berg, Mikael Pedersen, Terje Svingen, Monica K. Draskau
Developmental exposure to estrogenic chemicals can cause hypospadias in mice. In rats and humans this link is less well-defined, and the causal relationship remains unclear. This likely pertains to uncertainties regarding direct and indirect effects of estrogens in the genital tubercle (GT) and inconsistent evaluations of potentially mild disruptions, especially in rats. In this study, we investigated the effects of late gestational exposure to the estrogenic chemical diethylstilbestrol (DES) in low doses on male rat penis differentiation. In an ex vivo GT culture system, DES caused subtle changes to GT morphology after 96 h in culture, but with no overt phenotype. Moreover, DES upregulated Ar and AR-responsive genes in the GT. When exposing rats in vivo from gestational day (GD) 7–21, DES did not cause genital malformations in the fetal males, but we observed slight abnormalities to GT morphology in µCT scans. Our study indicates that DES may directly modulate hormone signaling in the GT during fetal masculinization.
{"title":"Subtle morphological and molecular responses to low-dose diethylstilbestrol in the developing rat penis","authors":"Emilie Elmelund, Marie Berg, Mikael Pedersen, Terje Svingen, Monica K. Draskau","doi":"10.1016/j.reprotox.2025.109149","DOIUrl":"10.1016/j.reprotox.2025.109149","url":null,"abstract":"<div><div>Developmental exposure to estrogenic chemicals can cause hypospadias in mice. In rats and humans this link is less well-defined, and the causal relationship remains unclear. This likely pertains to uncertainties regarding direct and indirect effects of estrogens in the genital tubercle (GT) and inconsistent evaluations of potentially mild disruptions, especially in rats. In this study, we investigated the effects of late gestational exposure to the estrogenic chemical diethylstilbestrol (DES) in low doses on male rat penis differentiation. In an <em>ex vivo</em> GT culture system, DES caused subtle changes to GT morphology after 96 h in culture, but with no overt phenotype. Moreover, DES upregulated <em>Ar</em> and AR<em>-</em>responsive genes in the GT. When exposing rats <em>in vivo</em> from gestational day (GD) 7–21, DES did not cause genital malformations in the fetal males, but we observed slight abnormalities to GT morphology in µCT scans. Our study indicates that DES may directly modulate hormone signaling in the GT during fetal masculinization.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109149"},"PeriodicalIF":2.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834649","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 : 2025-12-22DOI: 10.1016/j.reprotox.2025.109147
Z.G. Yurtgezen , M. Sapmaz-Metin , D. Ercetin
Background
Titanium dioxide nanoparticles (TiO₂NPs) are widely used metal nanoparticles capable of accumulating in tissues and exerting endocrine-disrupting effects. Their impact on female reproductive physiology remains largely unclear. This study aimed to elucidate the endocrine-disrupting properties of TiO₂NPs by assessing ovarian and uterine histology, serum hormone levels, estrous cycle changes, and receptor expression patterns in both intact and ovariectomized female rats.
Methods
Thirty-two Sprague Dawley rats were randomly divided into four groups (n = 8/group): intact control, intact TiO₂NP (10 mg/kg/day, oral, 30 days), ovariectomized control (OvX), and OvX + TiO₂NP (10 mg/kg/day, oral). Vaginal cytology was monitored for 10 days. ELISA measured serum estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels. Ovarian and uterine tissues were examined histologically and immunohistochemically for estrogen-receptor alpha (ERα), estrogen-receptor beta (ERβ), luteinizing hormone receptor (LHR), and follicle-stimulating hormone receptor (FSHR) expression.
Results
TiO₂NP exposure elevated estradiol levels in both intact and ovariectomized rats. While ovariectomy significantly increased LH and FSH, TiO₂NP treatment normalized these levels in OvX rats. Ovarian changes included an increase in atretic follicles and a reduction in hormone receptor expression, whereas uterine tissues showed greater gland number, endometrial thickness, and receptor positivity. Estrous cycles were absent in OvX rats but reappeared with prolonged length and estrus frequency in the OvX + TiO₂NP group.
Conclusion
TiO₂NPs exert estrogen-like effects and modulate gonadotropin release through the hypothalamic–pituitary axis, even without ovarian estrogen, indicating pronounced endocrine-disrupting effects on the female reproductive system.
{"title":"Endocrine-disrupting effects of titanium dioxide nanoparticles on the female reproductive system: Evidence from an ovariectomized rat model","authors":"Z.G. Yurtgezen , M. Sapmaz-Metin , D. Ercetin","doi":"10.1016/j.reprotox.2025.109147","DOIUrl":"10.1016/j.reprotox.2025.109147","url":null,"abstract":"<div><h3>Background</h3><div>Titanium dioxide nanoparticles (TiO₂NPs) are widely used metal nanoparticles capable of accumulating in tissues and exerting endocrine-disrupting effects. Their impact on female reproductive physiology remains largely unclear. This study aimed to elucidate the endocrine-disrupting properties of TiO₂NPs by assessing ovarian and uterine histology, serum hormone levels, estrous cycle changes, and receptor expression patterns in both intact and ovariectomized female rats.</div></div><div><h3>Methods</h3><div>Thirty-two Sprague Dawley rats were randomly divided into four groups (n = 8/group): intact control, intact TiO₂NP (10 mg/kg/day, oral, 30 days), ovariectomized control (OvX), and OvX + TiO₂NP (10 mg/kg/day, oral). Vaginal cytology was monitored for 10 days. ELISA measured serum estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels. Ovarian and uterine tissues were examined histologically and immunohistochemically for estrogen-receptor alpha (ERα), estrogen-receptor beta (ERβ), luteinizing hormone receptor (LHR), and follicle-stimulating hormone receptor (FSHR) expression.</div></div><div><h3>Results</h3><div>TiO₂NP exposure elevated estradiol levels in both intact and ovariectomized rats. While ovariectomy significantly increased LH and FSH, TiO₂NP treatment normalized these levels in OvX rats. Ovarian changes included an increase in atretic follicles and a reduction in hormone receptor expression, whereas uterine tissues showed greater gland number, endometrial thickness, and receptor positivity. Estrous cycles were absent in OvX rats but reappeared with prolonged length and estrus frequency in the OvX + TiO₂NP group.</div></div><div><h3>Conclusion</h3><div>TiO₂NPs exert estrogen-like effects and modulate gonadotropin release through the hypothalamic–pituitary axis, even without ovarian estrogen, indicating pronounced endocrine-disrupting effects on the female reproductive system.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109147"},"PeriodicalIF":2.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828205","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 : 2025-12-18DOI: 10.1016/j.reprotox.2025.109146
Mohammad Saroughi , Khatereh Kharazmi , Seyedeh Zahra Asghari , Akram Aminian , Seyedeh Elnaz Nazari , Elahe Eshtad , Alex Tarnava , Tyler W. LeBaron , Majid Khazaei
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.
{"title":"Influence of hydrogen-rich water on spermatogenesis and sperm parameters in experimentally induced hypothyroidism and subclinical hypothyroidism models","authors":"Mohammad Saroughi , Khatereh Kharazmi , Seyedeh Zahra Asghari , Akram Aminian , Seyedeh Elnaz Nazari , Elahe Eshtad , Alex Tarnava , Tyler W. LeBaron , 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":"2025-12-18","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}
Pub Date : 2025-12-18DOI: 10.1016/j.reprotox.2025.109145
Karin Sørig Hougaard , Monika Hezareh Rothmann , Martin Roursgaard , Sandra Goericke-Pesch , Peter Møller , Luisa Campagnolo , Ulla Vogel
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.
{"title":"Airway particle exposure and developmental toxicity: From potential link to inflammation to within-laboratory reproducibility challenges","authors":"Karin Sørig Hougaard , Monika Hezareh Rothmann , Martin Roursgaard , Sandra Goericke-Pesch , Peter Møller , Luisa Campagnolo , 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":"2025-12-18","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}
Pub Date : 2025-12-17DOI: 10.1016/j.reprotox.2025.109143
Maira Nadeem, Michelle Jojy, Margaret Meschia, Genoa R. Warner
Phthalates, a class of plasticizers, are known endocrine-disrupting chemicals that can negatively impact reproduction and development, including placental development and function. In response to growing concerns, various groups of chemicals, including but not limited to terephthalates, citrates, and cyclohexane dicarboxylic acids, have been developed as phthalate replacements. However, significant research gaps remain in understanding how these new chemicals affect humans. This review aims to synthesize existing research on how phthalate alternatives affect the placenta, a transient yet critical organ that supports fetal growth and development during pregnancy. Disruptions to placental structure and function can cause pregnancy complications and alter fetal programming. Herein, we review findings from biomonitoring, in vivo and in vitro experiments, as well as epidemiological studies to assess potential impacts. Although biomonitoring and house dust studies have identified the presence of alternative plasticizers, many identified chemical groups lack studies on their effects during pregnancy and on the placenta. Given the rising levels of these chemicals and their metabolites in urine and blood, further investigation into their mechanisms of toxicity is necessary. Notably, some alternatives may have the capability to alter pregnancy outcomes similar to traditional phthalates, such as by increasing the likelihood to develop conditions like gestational diabetes mellitus, although the majority of alternative plasticizers lack data. Understanding these impacts will inform public policy aimed at protecting maternal and fetal health, facilitate the development of safer consumer products, and prevent further emergence of regrettable replacements.
{"title":"Placental toxicity of alternative plasticizers: Current knowledge and future directions","authors":"Maira Nadeem, Michelle Jojy, Margaret Meschia, Genoa R. Warner","doi":"10.1016/j.reprotox.2025.109143","DOIUrl":"10.1016/j.reprotox.2025.109143","url":null,"abstract":"<div><div>Phthalates, a class of plasticizers, are known endocrine-disrupting chemicals that can negatively impact reproduction and development, including placental development and function. In response to growing concerns, various groups of chemicals, including but not limited to terephthalates, citrates, and cyclohexane dicarboxylic acids, have been developed as phthalate replacements. However, significant research gaps remain in understanding how these new chemicals affect humans. This review aims to synthesize existing research on how phthalate alternatives affect the placenta, a transient yet critical organ that supports fetal growth and development during pregnancy. Disruptions to placental structure and function can cause pregnancy complications and alter fetal programming. Herein, we review findings from biomonitoring, in vivo and in vitro experiments, as well as epidemiological studies to assess potential impacts. Although biomonitoring and house dust studies have identified the presence of alternative plasticizers, many identified chemical groups lack studies on their effects during pregnancy and on the placenta. Given the rising levels of these chemicals and their metabolites in urine and blood, further investigation into their mechanisms of toxicity is necessary. Notably, some alternatives may have the capability to alter pregnancy outcomes similar to traditional phthalates, such as by increasing the likelihood to develop conditions like gestational diabetes mellitus, although the majority of alternative plasticizers lack data. Understanding these impacts will inform public policy aimed at protecting maternal and fetal health, facilitate the development of safer consumer products, and prevent further emergence of regrettable replacements.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109143"},"PeriodicalIF":2.8,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794614","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 : 2025-12-17DOI: 10.1016/j.reprotox.2025.109141
Ana Karen de Carvalho Albuquerque , Solano Dantas Martins , Leiz Maria Costa Véras , Alyne Rodrigues de Araújo Nobre , Vânia Marilande Ceccatto , Valdevane Rocha Araújo
This study investigated the cytotoxicity of different concentrations of aqueous extract of cigarette smoke (AECS) during in vitro maturation (IVM) of bovine oocytes, evaluating the potential synergy among its various compounds, including nicotine. The AECS was evaluated by liquid chromatography to identify nicotine amount and by atomic force microscopy (AFM) to analyze the morphology of particles. To IVM, bovine ovaries (n = 30) were collected in local slaughterhouse and submitted to slicing. Only oocytes that exhibited homogeneous cytoplasm, diameter higher than 110 µm, and surrounded by, at least, two layers of compact cumulus cells were selected. Cumulus-oocyte complex (COCs) were matured in groups under mineral oil in TCM-199 + alone (CTRL) or TCM-199 + supplemented with 1, 2.5 or 5 % of AECS, at 38,5°C in a humidified atmosphere containing 5 % CO2 in air for 24 h. After IVM period, oocytes were denuded and evaluated to chromatin configuration by Hoechst, and ROS and mitochondrial potential by H2DCFDA and JC-1, respectively. The data distribution was assessed using the Shapiro-Wilk test for homogeneity and ANOVA One-way with post hoc of Tukey considering P < 0.05. The results revelated high nicotine levels (158.40 µg/mL) in the AECS and nanoparticles with 14,66 ± 4,08 nm of diameter. Regardless of AECS concentration used, high chromatin degenerated rates of oocytes after IVM, and an increase of ROS levels and a reduction of mitochondrial (P < 0,05) was observed. Thus, it can be concluded that AECS exhibits significant cytotoxic properties towards bovine oocytes, particularly due to the presence of elevated concentrations of nicotine.
{"title":"Aqueous cigarette smoke extract reduces mitochondrial potential and increases nuclear degeneration in bovine oocytes matured in vitro","authors":"Ana Karen de Carvalho Albuquerque , Solano Dantas Martins , Leiz Maria Costa Véras , Alyne Rodrigues de Araújo Nobre , Vânia Marilande Ceccatto , Valdevane Rocha Araújo","doi":"10.1016/j.reprotox.2025.109141","DOIUrl":"10.1016/j.reprotox.2025.109141","url":null,"abstract":"<div><div>This study investigated the cytotoxicity of different concentrations of aqueous extract of cigarette smoke (AECS) during in vitro maturation (IVM) of bovine oocytes, evaluating the potential synergy among its various compounds, including nicotine. The AECS was evaluated by liquid chromatography to identify nicotine amount and by atomic force microscopy (AFM) to analyze the morphology of particles. To IVM, bovine ovaries (n = 30) were collected in local slaughterhouse and submitted to slicing. Only oocytes that exhibited homogeneous cytoplasm, diameter higher than 110 µm, and surrounded by, at least, two layers of compact cumulus cells were selected. Cumulus-oocyte complex (COCs) were matured in groups under mineral oil in TCM-199 + alone (CTRL) or TCM-199 + supplemented with 1, 2.5 or 5 % of AECS, at 38,5°C in a humidified atmosphere containing 5 % CO2 in air for 24 h. After IVM period, oocytes were denuded and evaluated to chromatin configuration by Hoechst, and ROS and mitochondrial potential by H2DCFDA and JC-1, respectively. The data distribution was assessed using the Shapiro-Wilk test for homogeneity and ANOVA One-way with post hoc of Tukey considering P < 0.05. The results revelated high nicotine levels (158.40 µg/mL) in the AECS and nanoparticles with 14,66 ± 4,08 nm of diameter. Regardless of AECS concentration used, high chromatin degenerated rates of oocytes after IVM, and an increase of ROS levels and a reduction of mitochondrial (P < 0,05) was observed. Thus, it can be concluded that AECS exhibits significant cytotoxic properties towards bovine oocytes, particularly due to the presence of elevated concentrations of nicotine.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109141"},"PeriodicalIF":2.8,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794646","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}
This study investigates the protective effects of total flavonoids of Epimedium (TFE) against obesity-induced testicular damage in mice. The potential pharmacological mechanisms were predicted using network pharmacology, molecular docking and molecular dynamics simulation. In vivo experiments were conducted in mice randomly assigned to five groups: a normal diet group, a high-fat diet (HFD) group, two TFE groups, and a positive control group. Biomarkers including dihydrotestosterone and testosterone were measured to evaluate testicular function, while lipid profiles were assessed. Oxidative stress was determined through glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) assays, and protein expression of heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1) was analysed. Network pharmacology identified 29 flavonoids and 288 key targets. Molecular docking revealed that 22 active components exhibited strong binding activity, with PLCZ1–isoginkgetin/bilobetin showing the most stable conformation. TFE treatment significantly improved testicular function and mitigated obesity-induced male infertility. It enhanced sperm quality, reversed HFD-induced reductions in sperm count and motility, decreased malformation rates, normalized serum testosterone and dihydrotestosterone levels, ameliorated oxidative stress by enhancing antioxidant enzyme activity (GSH) and reducing lipid peroxidation (MDA), and improved lipid profiles by lowering triglycerides (TG) while increasing high-density lipoprotein cholesterol (HDL-C). Mechanistically, TFE upregulated Nrf2 pathway components (HO-1, NQO1) and modulated Keap1 expression. Collectively, these findings establish that the protective effects of TFE against obesity-induced testicular damage are mediated by the coordinated regulation of oxidative stress and key testicular targets.
{"title":"Total flavonoids of Epimedium ameliorate testicular damage via keap1–Nrf2/ARE signalling and multi-target regulation","authors":"Hongchao Yuan , Wenhao Tian , Hao Hao , Sirui Kang , Fanfan Jia , Kai Chen , Xiaoying Zhang , Chen Chen","doi":"10.1016/j.reprotox.2025.109142","DOIUrl":"10.1016/j.reprotox.2025.109142","url":null,"abstract":"<div><div>This study investigates the protective effects of total flavonoids of <em>Epimedium</em> (TFE) against obesity-induced testicular damage in mice. The potential pharmacological mechanisms were predicted using network pharmacology, molecular docking and molecular dynamics simulation. <em>In vivo</em> experiments were conducted in mice randomly assigned to five groups: a normal diet group, a high-fat diet (HFD) group, two TFE groups, and a positive control group. Biomarkers including dihydrotestosterone and testosterone were measured to evaluate testicular function, while lipid profiles were assessed. Oxidative stress was determined through glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) assays, and protein expression of heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1) was analysed. Network pharmacology identified 29 flavonoids and 288 key targets. Molecular docking revealed that 22 active components exhibited strong binding activity, with PLCZ1–isoginkgetin/bilobetin showing the most stable conformation. TFE treatment significantly improved testicular function and mitigated obesity-induced male infertility. It enhanced sperm quality, reversed HFD-induced reductions in sperm count and motility, decreased malformation rates, normalized serum testosterone and dihydrotestosterone levels, ameliorated oxidative stress by enhancing antioxidant enzyme activity (GSH) and reducing lipid peroxidation (MDA), and improved lipid profiles by lowering triglycerides (TG) while increasing high-density lipoprotein cholesterol (HDL-C). Mechanistically, TFE upregulated Nrf2 pathway components (HO-1, NQO1) and modulated Keap1 expression. Collectively, these findings establish that the protective effects of TFE against obesity-induced testicular damage are mediated by the coordinated regulation of oxidative stress and key testicular targets.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109142"},"PeriodicalIF":2.8,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782663","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 : 2025-12-13DOI: 10.1016/j.reprotox.2025.109140
Russell Hunter, Teresa Gluth, Kate Seman, Travis Goldsmith, Riley Nett, Victoria Nist, Allison Dunn, Eric Kelly, Elizabeth Bowdridge
Gestational nano titanium-dioxide (nano-TiO2) exposure causes reduced fetal size and multi-generational reproductive effects in females. The current study utilized a whole-body nano-TiO2 inhalation exposure model in pregnant Sprague-Dawley rats coupled with a high fat diet (HFD) fed to adult offspring to examine lasting effects of in-utero exposures on weight gain, metabolic function, and endocrine perturbations. Sexually dimorphic responses in weight gain were observed whereby exposed HFD males gained less weight than their air HFD counterparts (435 g ± 9.8 vs. 505 g ± 14.5; p < 0.05), but there was no weight difference between air and exposed HFD females. Males and females presented with exposure driven decreases in glucose tolerance, such that HFD exposed animals were significantly more glucose intolerant(-6985AUC±1763). Hypothalamic gene expression of the melanocortin receptor 3 was significantly increased in nano-TiO2 males (1453 %) and significantly decreased in nano-TiO2 females (29.07 %) compared to grain-based diet (GBD) controls. Hepatic mitochondrial activity was affected in sexually dependent manner, with females exhibiting changes in Complexes I, II, III, and V, and males only showing differences in Complex I activity. Finally, exposed males had smaller testicular mass (3.685 mg ± 0.0895 in GBD; 3.358 mg±0.0786 in HFD; (3.480 mg± 0.2023 in GBD, 3.380 mg± 0.0777) and reduced testosterone (7.75 µg/nl ± 1.965 in GBD; 3.62 µg/nl±2.084 in HFD; (9.943 µg/nl±1.97 in GBD, 4.28 µg/nl± 1.6845) compared to air males. Altogether, these data reflect how nanoparticulate driven differences in growth and development at birth can alter weight gain and metabolic function later in life in the face of a dietary challenge.
{"title":"Persistent impact of in utero nanoparticle exposure on metabolic and endocrine outcomes in adult rats fed a high-fat diet","authors":"Russell Hunter, Teresa Gluth, Kate Seman, Travis Goldsmith, Riley Nett, Victoria Nist, Allison Dunn, Eric Kelly, Elizabeth Bowdridge","doi":"10.1016/j.reprotox.2025.109140","DOIUrl":"10.1016/j.reprotox.2025.109140","url":null,"abstract":"<div><div>Gestational nano titanium-dioxide (nano-TiO<sub>2</sub>) exposure causes reduced fetal size and multi-generational reproductive effects in females. The current study utilized a whole-body nano-TiO<sub>2</sub> inhalation exposure model in pregnant Sprague-Dawley rats coupled with a high fat diet (HFD) fed to adult offspring to examine lasting effects of <em>in-utero</em> exposures on weight gain, metabolic function, and endocrine perturbations. Sexually dimorphic responses in weight gain were observed whereby exposed HFD males gained less weight than their air HFD counterparts (435 g ± 9.8 vs. 505 g ± 14.5; p < 0.05), but there was no weight difference between air and exposed HFD females. Males and females presented with exposure driven decreases in glucose tolerance, such that HFD exposed animals were significantly more glucose intolerant(-6985AUC±1763). Hypothalamic gene expression of the melanocortin receptor 3 was significantly increased in nano-TiO<sub>2</sub> males (1453 %) and significantly decreased in nano-TiO<sub>2</sub> females (29.07 %) compared to grain-based diet (GBD) controls. Hepatic mitochondrial activity was affected in sexually dependent manner, with females exhibiting changes in Complexes I, II, III, and V, and males only showing differences in Complex I activity. Finally, exposed males had smaller testicular mass (3.685 mg ± 0.0895 in GBD; 3.358 mg±0.0786 in HFD; (3.480 mg± 0.2023 in GBD, 3.380 mg± 0.0777) and reduced testosterone (7.75 µg/nl ± 1.965 in GBD; 3.62 µg/nl±2.084 in HFD; (9.943 µg/nl±1.97 in GBD, 4.28 µg/nl± 1.6845) compared to air males. Altogether, these data reflect how nanoparticulate driven differences in growth and development at birth can alter weight gain and metabolic function later in life in the face of a dietary challenge.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109140"},"PeriodicalIF":2.8,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763760","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 : 2025-12-12DOI: 10.1016/j.reprotox.2025.109138
Madison T. Stewart, Gu Zhou, Danielle P.M. LeBlanc, Annette E. Dodge, Matthew J. Meier, Andrew Williams, Alexandra S. Long, Paul A. White, Carole L. Yauk, Francesco Marchetti
{"title":"CORRIGENDUM, Long Term Exposure to Benzo[b]fluoranthene Does Not Induce Mutations in MutaMouse Male Germ Cells. Reprod Toxicol, 2025, 137:108985 http://doi.org/10.1016/j.reprotox.2025.108985","authors":"Madison T. Stewart, Gu Zhou, Danielle P.M. LeBlanc, Annette E. Dodge, Matthew J. Meier, Andrew Williams, Alexandra S. Long, Paul A. White, Carole L. Yauk, Francesco Marchetti","doi":"10.1016/j.reprotox.2025.109138","DOIUrl":"10.1016/j.reprotox.2025.109138","url":null,"abstract":"","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109138"},"PeriodicalIF":2.8,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757481","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 : 2025-12-12DOI: 10.1016/j.reprotox.2025.109139
Zhang Zhaowen , Guo Ling , Zhou Guiqiang , Lin Jiajin , Qin Tongzhou , Li Jiangyi , Li Jing , Wang Fuli , Ding Guirong
With the widespread application of 5G communication technology, the potential health risks of radiofrequency radiation (RFR) have been paid much attention. Prior studies have demonstrated that the testes are highly sensitive to RFR, and notably, paternal epigenetic modifications can be transmitted to offspring, impacting their reproductive and neurobehavioral phenotypes. To investigate the intergenerational effects of paternal exposure to 5 G RFR on male offspring health, 7–8-week-old male C57BL/6 mice were randomly divided into Sham group and 4.9 GHz RFR group (16 mice per group). The mice in 4.9 GHz RFR group were exposed to 4.9 GHz RFR for 1 h/d over 42 consecutive days. Male offspring derived from exposed males and unexposed females were raised to adulthood. Anxiety and depression-like behaviors, learning and memory capabilities, sperm quality, and fertility in male offspring were assessed. Paternal testicular LRGUK gene (sperm motility-related) methylation, mRNA, and protein expression were detected. The results showed that paternal 5G RFR exposure induced anxiety-like behaviors and impaired sperm quality in F1 males, potentially associated with RFR-induced hypermethylation of paternal LRGUK gene and subsequent down regulation of its expression in offspring testes. No significant effects were observed on depression-like behaviors, cognitive performance, or fertility across F1-F2 generations. These findings indicated that paternal 5G RFR exposure induced intergenerational adverse effects on F1 males, potentially mediated by germ cell epigenetic modifications.
{"title":"Effects of paternal 5G RFR exposure on health of male offspring mice","authors":"Zhang Zhaowen , Guo Ling , Zhou Guiqiang , Lin Jiajin , Qin Tongzhou , Li Jiangyi , Li Jing , Wang Fuli , Ding Guirong","doi":"10.1016/j.reprotox.2025.109139","DOIUrl":"10.1016/j.reprotox.2025.109139","url":null,"abstract":"<div><div>With the widespread application of 5G communication technology, the potential health risks of radiofrequency radiation (RFR) have been paid much attention. Prior studies have demonstrated that the testes are highly sensitive to RFR, and notably, paternal epigenetic modifications can be transmitted to offspring, impacting their reproductive and neurobehavioral phenotypes. To investigate the intergenerational effects of paternal exposure to 5 G RFR on male offspring health, 7–8-week-old male C57BL/6 mice were randomly divided into Sham group and 4.9 GHz RFR group (16 mice per group). The mice in 4.9 GHz RFR group were exposed to 4.9 GHz RFR for 1 h/d over 42 consecutive days. Male offspring derived from exposed males and unexposed females were raised to adulthood. Anxiety and depression-like behaviors, learning and memory capabilities, sperm quality, and fertility in male offspring were assessed. Paternal testicular LRGUK gene (sperm motility-related) methylation, mRNA, and protein expression were detected. The results showed that paternal 5G RFR exposure induced anxiety-like behaviors and impaired sperm quality in F1 males, potentially associated with RFR-induced hypermethylation of paternal LRGUK gene and subsequent down regulation of its expression in offspring testes. No significant effects were observed on depression-like behaviors, cognitive performance, or fertility across F1-F2 generations. These findings indicated that paternal 5G RFR exposure induced intergenerational adverse effects on F1 males, potentially mediated by germ cell epigenetic modifications.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109139"},"PeriodicalIF":2.8,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756196","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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