Pub Date : 2025-12-26DOI: 10.1016/j.reprotox.2025.109144
George Daston, Matthew Burbank, Florian Gautier, Barbara F Hales, Amer Jamalpoor, Yasunari Kanda, Susan Makris, Aldert H Piersma, Nicola Powles-Glover, Sonya Sobrian, Vicki Sutherland, Steven Van Cruchten, Ronald L Wange, Connie L Chen
{"title":"Corrigendum to \"Hypothesis-driven approach to developmental toxicity assessment: Using mechanistic information to inform testing\" [Reprod. Toxicol. 140 (2026) 109119].","authors":"George Daston, Matthew Burbank, Florian Gautier, Barbara F Hales, Amer Jamalpoor, Yasunari Kanda, Susan Makris, Aldert H Piersma, Nicola Powles-Glover, Sonya Sobrian, Vicki Sutherland, Steven Van Cruchten, Ronald L Wange, Connie L Chen","doi":"10.1016/j.reprotox.2025.109144","DOIUrl":"https://doi.org/10.1016/j.reprotox.2025.109144","url":null,"abstract":"","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":" ","pages":"109144"},"PeriodicalIF":2.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846785","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 : 2025-12-25DOI: 10.1016/j.reprotox.2025.109151
Allison M. Narizzano , Andrew G. East , Caroline L. Procell , Matthew A. Bazar , Meredith E. Bohannon , Dmitry Pervitsky , Michael J. Quinn Jr.
The combined repeated-dose and reproductive/developmental toxicity of six fire extinguishing agents were evaluated in mice: one legacy per- and polyfluoroalkyl substances (PFAS)-containing product and five PFAS-free products. For each product, up to 1,000 mg/kg-d was administered via oral gavage (n = 12/sex/group) before mating, for at least 42 days in males, and through gestation and lactation in females. First filial (F1) generation animals were exposed in utero and via lactation, and directly via oral gavage from postnatal day (PND) 22–42. No animals exhibited statistically significant reductions in reproductive function or pregnancy. Body weights of dams, litters, and weanlings were often decreased by high doses of fire extinguishing agents. The lowest concentration that impacted body weights was 320 mg/kg-d in a PFAS-free product. Perturbations to serum thyroid hormones (both generations) and immunoglobulin levels (F1) were rarely detected. Some hematological changes (e.g., red blood cell parameters) were also detected across the products. Results from these whole-product toxicity tests are consistent with studies of well-characterized ingredients of the products, which are also common ingredients of many household and consumer products. In conclusion, PFAS-free products were not linked to any of the reproductive or developmental effects commonly seen with individual PFAS exposures at the occupationally relevant concentrations tested. Of the products tested, there was only one PFAS-free fire extinguishing agent that was more toxic than the PFAS-containing product.
{"title":"Screening potential reproductive and developmental effects of PFAS-free vs. PFAS-containing fire extinguishing agents in mice","authors":"Allison M. Narizzano , Andrew G. East , Caroline L. Procell , Matthew A. Bazar , Meredith E. Bohannon , Dmitry Pervitsky , Michael J. Quinn Jr.","doi":"10.1016/j.reprotox.2025.109151","DOIUrl":"10.1016/j.reprotox.2025.109151","url":null,"abstract":"<div><div>The combined repeated-dose and reproductive/developmental toxicity of six fire extinguishing agents were evaluated in mice: one legacy per- and polyfluoroalkyl substances (PFAS)-containing product and five PFAS-free products. For each product, up to 1,000 mg/kg-d was administered via oral gavage (n = 12/sex/group) before mating, for at least 42 days in males, and through gestation and lactation in females. First filial (F1) generation animals were exposed in utero and via lactation, and directly via oral gavage from postnatal day (PND) 22–42. No animals exhibited statistically significant reductions in reproductive function or pregnancy. Body weights of dams, litters, and weanlings were often decreased by high doses of fire extinguishing agents. The lowest concentration that impacted body weights was 320 mg/kg-d in a PFAS-free product. Perturbations to serum thyroid hormones (both generations) and immunoglobulin levels (F1) were rarely detected. Some hematological changes (<em>e.g.,</em> red blood cell parameters) were also detected across the products. Results from these whole-product toxicity tests are consistent with studies of well-characterized ingredients of the products, which are also common ingredients of many household and consumer products. In conclusion, PFAS-free products were not linked to any of the reproductive or developmental effects commonly seen with individual PFAS exposures at the occupationally relevant concentrations tested. Of the products tested, there was only one PFAS-free fire extinguishing agent that was more toxic than the PFAS-containing product.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109151"},"PeriodicalIF":2.8,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846814","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 : 2025-12-24DOI: 10.1016/j.reprotox.2025.109152
Qiming Yang , Wenxin Bai , Yujun Liu , Xiuxian Huang , Bing Zou , Zubair Muhammad , Uswa Farooq , Qingfeng Zhai , Nan Liu
Mixed exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with altered male endocrine function, but age-specific susceptibility is uncertain. We analyzed 1965 males aged 6–80 years in NHANES 2013–2018, relating PFOS, PFOA, PFHxS, and PFNA to estradiol (E2) and sex hormone-binding globulin (SHBG) with survey-weighted linear models; mixture effects were assessed by weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) within age strata. Associations were strongest at ages 6–12: PFOS was associated with higher E2, whereas PFOA and PFNA were associated with lower SHBG, with supportive evidence for PFHxS. Mixture analyses identified PFOS as a main contributor and suggested nonlinear PFOS–E2 increases and monotonic SHBG suppression by PFOA/PFHxS. Juvenile mice received PFOS in drinking water for six weeks; PFOS altered hormones and induced germ-cell injury, consistent with the human window. Our findings suggest that childhood may be a sensitive period for PFAS-related endocrine disruption, warranting child-focused monitoring and mixture-aware risk assessment.
{"title":"Childhood susceptibility to PFAS-associated endocrine disruption: NHANES age-stratified analysis and PFOS mouse model validation","authors":"Qiming Yang , Wenxin Bai , Yujun Liu , Xiuxian Huang , Bing Zou , Zubair Muhammad , Uswa Farooq , Qingfeng Zhai , Nan Liu","doi":"10.1016/j.reprotox.2025.109152","DOIUrl":"10.1016/j.reprotox.2025.109152","url":null,"abstract":"<div><div>Mixed exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with altered male endocrine function, but age-specific susceptibility is uncertain. We analyzed 1965 males aged 6–80 years in NHANES 2013–2018, relating PFOS, PFOA, PFHxS, and PFNA to estradiol (E2) and sex hormone-binding globulin (SHBG) with survey-weighted linear models; mixture effects were assessed by weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) within age strata. Associations were strongest at ages 6–12: PFOS was associated with higher E2, whereas PFOA and PFNA were associated with lower SHBG, with supportive evidence for PFHxS. Mixture analyses identified PFOS as a main contributor and suggested nonlinear PFOS–E2 increases and monotonic SHBG suppression by PFOA/PFHxS. Juvenile mice received PFOS in drinking water for six weeks; PFOS altered hormones and induced germ-cell injury, consistent with the human window. Our findings suggest that childhood may be a sensitive period for PFAS-related endocrine disruption, warranting child-focused monitoring and mixture-aware risk assessment.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109152"},"PeriodicalIF":2.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.reprotox.2025.109150
Shubhamoy Ghosh , Amit Ganguly , Tien S. Dong , Venu Lagishetty , Jonathan P. Jacobs , Sherin U. Devaskar
We investigated the impact of chronic air pollutant (AP) exposure upon intestinal microbial diversity, composition, and metagenomic inferred functional pathways in murine pregestational and late gestational adult females, and male and female postnatal offspring (P21), compared to age- and sex- matched controls (CON). Intestinal microbiome analysis was undertaken with certain phenotypic characteristics in adult non-pregnant and pregnant females and the male and female offspring. In response to AP, pooled male and female offspring displayed no difference in E19 fetal and P1 postnatal body weights. At P21, females exposed in-utero to AP were heavier with increased fat and muscle mass at one month versus CON. Males were no different at P21 and 1 month revealing decreased fat mass and hyperglycemia. In pregestational/gestational females, AP did not change microbial α- or β-diversity from the respective CON. Gestational females showed AP induced changes in taxonomic composition such as reduced Bacteroides and increased Firmicutes, Verrucomicrobia, and Akkermansia, among others. In response to intra-uterine AP exposure, the offspring intestinal microbiome revealed more compelling differences in α- and β- diversity than adult females. While certain microbial changes were common in both sexes, sex-specific differences also emerged with reduced α-diversity, decreased Bacteroides and increased Akkermansia in males only. The metagenomic inferred pathways revealed perturbations in multiple pathways. We conclude that the offspring exposed in-utero to AP revealed sex-specific changes in microbial diversity, composition and function, displaying certain similarities with distinct differences from mothers. These early life changes were associated with the subsequent emergence of pre-diabetes and adiposity.
{"title":"Intestinal microbiome in response to air pollutant exposure in pregestational and gestational murine females and their male and female offspring","authors":"Shubhamoy Ghosh , Amit Ganguly , Tien S. Dong , Venu Lagishetty , Jonathan P. Jacobs , Sherin U. Devaskar","doi":"10.1016/j.reprotox.2025.109150","DOIUrl":"10.1016/j.reprotox.2025.109150","url":null,"abstract":"<div><div>We investigated the impact of chronic air pollutant (AP) exposure upon intestinal microbial diversity, composition, and metagenomic inferred functional pathways in murine pregestational and late gestational adult females, and male and female postnatal offspring (P21), compared to age- and sex- matched controls (CON). Intestinal microbiome analysis was undertaken with certain phenotypic characteristics in adult non-pregnant and pregnant females and the male and female offspring. In response to AP, pooled male and female offspring displayed no difference in E19 fetal and P1 postnatal body weights. At P21, females exposed in-utero to AP were heavier with increased fat and muscle mass at one month versus CON. Males were no different at P21 and 1 month revealing decreased fat mass and hyperglycemia. In pregestational/gestational females, AP did not change microbial α- or β-diversity from the respective CON. Gestational females showed AP induced changes in taxonomic composition such as reduced Bacteroides and increased Firmicutes, Verrucomicrobia, and Akkermansia, among others. In response to intra-uterine AP exposure, the offspring intestinal microbiome revealed more compelling differences in α- and β- diversity than adult females. While certain microbial changes were common in both sexes, sex-specific differences also emerged with reduced α-diversity, decreased Bacteroides and increased Akkermansia in males only. The metagenomic inferred pathways revealed perturbations in multiple pathways. We conclude that the offspring exposed in-utero to AP revealed sex-specific changes in microbial diversity, composition and function, displaying certain similarities with distinct differences from mothers. These early life changes were associated with the subsequent emergence of pre-diabetes and adiposity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109150"},"PeriodicalIF":2.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834609","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 : 2025-12-23DOI: 10.1016/j.reprotox.2025.109148
Yanggang Hong , Tangansu Zhang , Jingxuan Zhou , Lingfei Wang , Yirong Wang , Wanyi Shu , Hongbo Wang , Haiyan Chen
Endometriosis is a chronic, estrogen-dependent disorder influenced by both genetic and environmental factors, including endocrine-disrupting chemicals (EDCs). This study aimed to identify EDC-responsive genes contributing to endometriosis risk by integrating Mendelian randomization (MR), Bayesian colocalization, and single-cell RNA sequencing (scRNA-seq). We first compiled a list of EDC-responsive genes using curated chemical-gene interaction databases. MR and Bayesian colocalization analyses were applied to integrate gene expression quantitative trait loci (eQTL) data with genome-wide association study (GWAS) data for endometriosis. We identified eight genes (PRLR, SULT1B1, DIP2B, FBXO5, CDCA2, AGPAT1, PDE5A, and VPS13B) with strong evidence for causal association and shared genetic regulation. The scRNA-seq revealed that these genes are differentially expressed across key cell types, including mesenchymal, epithelial, and smooth muscle cells. PRLR was enriched in mesenchymal cells, while PDE5A showed high expression in smooth muscle cells. The chemical-gene interaction network further highlighted specific EDCs linked to these genes, such as perfluorooctanoic acid, triphenyl phosphate, and bisphenol A. This study uncovers molecular pathways by which EDCs may influence endometriosis risk and identifies potential biomarkers and therapeutic targets. The findings also establish a scalable approach for studying gene-environment interactions in other hormone-sensitive conditions.
{"title":"Systematic analyses uncover endocrine-disrupting chemical-responsive genes linked to endometriosis","authors":"Yanggang Hong , Tangansu Zhang , Jingxuan Zhou , Lingfei Wang , Yirong Wang , Wanyi Shu , Hongbo Wang , Haiyan Chen","doi":"10.1016/j.reprotox.2025.109148","DOIUrl":"10.1016/j.reprotox.2025.109148","url":null,"abstract":"<div><div>Endometriosis is a chronic, estrogen-dependent disorder influenced by both genetic and environmental factors, including endocrine-disrupting chemicals (EDCs). This study aimed to identify EDC-responsive genes contributing to endometriosis risk by integrating Mendelian randomization (MR), Bayesian colocalization, and single-cell RNA sequencing (scRNA-seq). We first compiled a list of EDC-responsive genes using curated chemical-gene interaction databases. MR and Bayesian colocalization analyses were applied to integrate gene expression quantitative trait loci (eQTL) data with genome-wide association study (GWAS) data for endometriosis. We identified eight genes (<em>PRLR</em>, <em>SULT1B1</em>, <em>DIP2B</em>, <em>FBXO5</em>, <em>CDCA2</em>, <em>AGPAT1</em>, <em>PDE5A</em>, and <em>VPS13B</em>) with strong evidence for causal association and shared genetic regulation. The scRNA-seq revealed that these genes are differentially expressed across key cell types, including mesenchymal, epithelial, and smooth muscle cells. <em>PRLR</em> was enriched in mesenchymal cells, while <em>PDE5A</em> showed high expression in smooth muscle cells. The chemical-gene interaction network further highlighted specific EDCs linked to these genes, such as perfluorooctanoic acid, triphenyl phosphate, and bisphenol A. This study uncovers molecular pathways by which EDCs may influence endometriosis risk and identifies potential biomarkers and therapeutic targets. The findings also establish a scalable approach for studying gene-environment interactions in other hormone-sensitive conditions.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109148"},"PeriodicalIF":2.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828223","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 : 2025-12-23DOI: 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}
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