Toxicology ReportsPub Date : 2025-07-03DOI: 10.1016/j.toxrep.2025.102082
Saba Yousaf , Muhammad Arshad , Muhammad Raza , Anmol Fatima , Khayala Mammadova
{"title":"Targeting mitochondrial damage and ER stress to inhibit ferroptosis in cadmium-induced nephrotoxicity","authors":"Saba Yousaf , Muhammad Arshad , Muhammad Raza , Anmol Fatima , Khayala Mammadova","doi":"10.1016/j.toxrep.2025.102082","DOIUrl":"10.1016/j.toxrep.2025.102082","url":null,"abstract":"<div><div>This review highlights the pivotal roles of autophagy, ferroptosis, and endoplasmic reticulum (ER) stress in mediating cadmium (Cd)-induced nephrotoxicity. Cadmium exposure results in ER stress, which in turn activates major UPR pathways such as IRE1, ATF6, and PERK. By encouraging lipid peroxidation and suppressing cellular antioxidant defence, these mechanisms worsen ferroptosis and produce a feedback mechanism that increases cellular damage. There are two roles of autophagy in Cd-induced ferroptosis, which include its action in reducing cadmium-induced cytotoxicity by breaking down damaged components, and excessive autophagy, namely ferritinophagy, which promotes ferroptosis by iron dysregulation. The rise of mitochondrial ROS (MitoROS) caused by Cd-induced mitochondrial malfunction aids ferroptosis. This, in turn, causes ER stress and autophagy. This implies that focusing on mitochondrial health could be a useful treatment strategy. Effective treatment approaches include autophagy inhibitors like chloroquine, which have been shown to effectively reduce Cd-induced ferroptosis, and promising medicines that suppress ER stress, such as TUDCA. Desferrioxamine and other iron chelators effectively lower lipid peroxidation and iron dysregulation, therefore preventing ferroptotic cell death. Additionally, a multi-targeted treatment plan is suggested that targets iron metabolism, ER stress, and autophagy. In order to create tailored treatments for Cd-induced nephrotoxicity, this review emphasizes the need for additional study into the molecular pathways of Cd-induced ferroptosis, namely the ER stress-autophagy axis. The goal of future research should be to apply these mechanistic insights to clinical settings to enhance public health outcomes and create efficient therapies for renal failure brought on by cadmium toxicity.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102082"},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicology ReportsPub Date : 2025-06-30DOI: 10.1016/j.toxrep.2025.102080
Qasim A. El-Dwairi , Karem H. Alzoubi , Rania Mahafdeh
{"title":"Sildenafil effect on testosterone-induced prostate hypertrophy and relaxation of urinary bladder neck muscles","authors":"Qasim A. El-Dwairi , Karem H. Alzoubi , Rania Mahafdeh","doi":"10.1016/j.toxrep.2025.102080","DOIUrl":"10.1016/j.toxrep.2025.102080","url":null,"abstract":"<div><h3>Background</h3><div>Previous studies have demonstrated the expression of phosphodiesterase-5 receptors in prostate tissue. In this study, we investigated the efficacy of sildenafil citrate in testosterone-induced benign prostate hyperplasia (BPH) in rabbits.</div></div><div><h3>Methods</h3><div>Prostate hyperplasia was induced using testosterone propionate for 8 weeks. Rabbits were divided into two groups: control and experimental. The experimental group was further subdivided into two subgroups: one subgroup was sacrificed after testosterone induction, while the other subgroup received sildenafil (5 mg/kg/day) via intragastric intubation for 8 weeks. The weight of the prostate and relaxation of the bladder neck muscle were assessed. Organ bath experiments evaluated the effect of sildenafil on phenylephrine-precontracted bladder neck muscle strips.</div></div><div><h3>Results</h3><div>The mean prostate weight was reduced by 65.34 % after 8 weeks of treatment with sildenafil in animals with BPH. Sildenafil induced significant smooth muscle relaxation of the phenylephrine-contracted bladder neck muscle strips. The mean relaxation value was 2.11 ± 0.13, representing a 32.8 % reduction in contraction percentage. Maximal relaxation was produced at 5.0 × 10⁻⁶ M of sildenafil. Sildenafil induced significant relaxation of the phenylephrine-contracted bladder neck muscle strips. Adding the nitric oxide synthase inhibitor L-NAME inhibited relaxation, whereas sodium nitroprusside, a nitric oxide donor, increased it. Histopathological analysis showed increased papillary projections, acinar areas, and epithelial thickness in the testosterone-treated group. Sildenafil treatment reversed the hypertrophic and hyperplastic changes.</div></div><div><h3>Conclusions</h3><div>The results indicate that sildenafil may provide a dual function in the treatment of erectile dysfunction and the relief of urinary tract complications associated with prostatic hypertrophy.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102080"},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144524247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicology ReportsPub Date : 2025-06-26DOI: 10.1016/j.toxrep.2025.102078
Mahdi Yassin Ahmed, Kamaran Abdoulrahman
{"title":"Toxic metals and bioelements: Combined oxidative stress effects on liver injury and thyroid hormone disruption in subjects from different areas of Erbil province","authors":"Mahdi Yassin Ahmed, Kamaran Abdoulrahman","doi":"10.1016/j.toxrep.2025.102078","DOIUrl":"10.1016/j.toxrep.2025.102078","url":null,"abstract":"<div><div>In Iraq, particularly in Erbil city and Gwer road are deemed environmentally disadvantaged because of industrial pollutants and refinery activities. This study conducted 143 subjects from rural, urban, and industrial areas. The sera of subjects were taken for the analysis. The toxic metals and bioelements were assessed using ICP-MS, the oxidative stress parameters were determined via ELISA. For estimation of liver test biomarkers Kenza was used, and thyroid hormones were measured by Cobas. While their relationships were statistically analyzed. The results indicated that metals concentrations were markedly significantly increased in industrial areas, particularly for Fe 599.1 (723.9) μg/L and Mn 7.534 ± 8.793 μg/L. The median level of Cu 4082 (2824) μg/L in urban subjects is significantly lower than those of other areas. Markers for oxidative stress revealed considerably higher MDA in urban participants 1917 (1085) pg/mL, while SOD and CP exhibited significantly lower level in urban and industrial participants P-value (0.0001 and <0.0001) respectively. The liver tests revealed elevated ALT in urban and industrial participants, 29.06 ± 1.723 IU/L and 21.94 ± 1.162 IU/L, respectively. The ALP levels were significantly elevated in industrial participants (P-value <0.0001). The study found that industrial workers had significantly higher levels of TSH 2.209 ± 0.1032 μIU/L and low levels of T3 1.765 ± 0.0227 nmol/l compared to the rural individuals. Fe had positive correlations with ONOO<sup>-.</sup> and TSH (r = 0.2221, r = 0.2452). Furthermore, Cu showed positively correlated with Cp (r = 0.2967; p = 0.0068), AST (r = 0.2417; p = 0.0268) and ALB (r = 0.2187; p = 0.0457). This study shows that increased levels of hazardous metals and bioelements in industrial and urban areas cause oxidative stress, which has a significant impact on public health and causes a number of health problems, including liver injury and thyroid dysfunction.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102078"},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144489873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicology ReportsPub Date : 2025-06-20DOI: 10.1016/j.toxrep.2025.102071
Laimar C. Garmo , Mackenzie K. Herroon , Shane Mecca , Alexis Wilson , David R. Allen , Abu Sayed Mohammed Sayam , Aaron J. Specht , Jennifer J. Schlezinger , Michael C. Petriello , Izabela Podgorski
{"title":"Per- and polyfluorinated substances (PFAS) promote osteoclastogenesis and bone loss through PPARα activation","authors":"Laimar C. Garmo , Mackenzie K. Herroon , Shane Mecca , Alexis Wilson , David R. Allen , Abu Sayed Mohammed Sayam , Aaron J. Specht , Jennifer J. Schlezinger , Michael C. Petriello , Izabela Podgorski","doi":"10.1016/j.toxrep.2025.102071","DOIUrl":"10.1016/j.toxrep.2025.102071","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS) are emerging as significant environmental contaminants affecting bone health, with studies linking their exposure to decreased bone mineral density (BMD), enhanced osteoclastogenesis, and disruptions in the bone marrow microenvironment. While current research highlights the effects on bone and BMD, there is a critical gap in understanding the mechanisms behind these effects. Studies presented here investigate the effects of legacy and alternative PFAS, particularly hexafluoropropylene oxide dimer acid (GenX) and perfluorohexane sulfonic acid (PFHxS), on bone health using <em>in vitro</em> and <em>in vivo</em> models. An environmentally relevant mixture of five PFAS was found to promote osteoclastic differentiation of murine bone marrow macrophages (BMMs) <em>in vitro</em>. Among the five components of the Mixture, the emerging compound, GenX, had the highest propensity to induce osteoclastogenesis. Utilizing pharmacological and genetic approaches, we identified peroxisome proliferator-activated receptor alpha (PPARα) as a potential mediator of PFAS-driven osteoclastogenesis. Furthermore, our <em>in vivo</em> mouse experiments demonstrated a decrease in trabecular and cortical bone thickness as well as altered bone mineral composition in male FVB/N mice exposed to either GenX or PFHxS (2 mg/L) for 12 weeks. Altogether, our results reveal potentially negative effects of PFAS exposure on BMD, bone mineral composition, and overall bone health and underscore the need for further research assessing the health risks associated with exposure to alternative PFAS.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102071"},"PeriodicalIF":0.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144481171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Determination of nitrofuran metabolites in sausage casings and crawfish using LC-Q-Orbitrap HRMS: Method development and validation","authors":"Omar Khaled , Lamia Ryad , Nermine Gad , Fawzy Eissa","doi":"10.1016/j.toxrep.2025.102076","DOIUrl":"10.1016/j.toxrep.2025.102076","url":null,"abstract":"<div><div>This study developed and validated an analytical method for determining four nitrofuran (NF) metabolites in sausage casings and crawfish matrices. The method utilizes liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry (LC-Q-Orbitrap HRMS) to analyze these metabolites. The validation of the developed method was carried out in accordance with the Commission Implementing Regulation (CIR) EU 2021/808, using three concentration levels ranging from 0.25 to 0.75 μg/kg. The recoveries ranged from 77 % to 109 %, while both repeatability and reproducibility remained consistently below 15 %. The calibration curves exhibited good linearity, with correlation coefficients (R) exceeding 0.9978. The limits of detection (LOD) ranged from 0.0218 to 0.0596 μg/kg, while the limits of quantification (LOQ) ranged from 0.0719 to 0.1966 μg/kg. The decision limit (CCα) and detection capability (CCβ) values ranged from 0.30 to 0.39 μg/kg and 0.29–0.35 μg/kg, respectively. Out of 30 crawfish samples collected from local markets in Egypt, 16.66 % contained NF metabolites residues, whereas sausage casings showed no NF metabolite residues. The reliability of the method was further demonstrated through successful participation in two proficiency testing (PT) rounds.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102076"},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicology ReportsPub Date : 2025-06-19DOI: 10.1016/j.toxrep.2025.102077
Amjad Z. Alrosan , Tahani Alwidyan , Ghaith B. Heilat , Aseel O. Rataan , Khaled Alrosan
{"title":"Pre-treatment red cell index and metastasis status as independent predictors of overall survival in Jordanian breast cancer patients receiving chemotherapy","authors":"Amjad Z. Alrosan , Tahani Alwidyan , Ghaith B. Heilat , Aseel O. Rataan , Khaled Alrosan","doi":"10.1016/j.toxrep.2025.102077","DOIUrl":"10.1016/j.toxrep.2025.102077","url":null,"abstract":"<div><div>Breast cancer (BC) poses a global health challenge, necessitating accessible prognostic biomarkers. Systemic inflammatory markers from complete blood counts, such as neutrophil-to-lymphocyte ratio (NLR) and red cell index (RCI), have shown prognostic potential. This retrospective study evaluated the prognostic significance of pre-treatment NLR and RCI for overall survival (OS) in 144 Jordanian BC patients (KAUH, 2011–2025) undergoing chemotherapy. Kaplan-Meier analysis revealed that high pre-treatment NLR (≥ 4.25) and high RCI (≥ 0.02) were significantly associated with shorter OS. Multivariate Cox regression identified elevated pre-treatment RCI (≥ 0.02) and metastasis at diagnosis as independent predictors of increased mortality and worse OS. A significant association between high NLR and RCI values was also observed, suggesting a link between systemic inflammation and erythrocytic dysregulation. In conclusion, pre-treatment RCI and metastasis are strong independent predictors of OS in this cohort, with RCI demonstrating substantial prognostic value.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102077"},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicology ReportsPub Date : 2025-06-17DOI: 10.1016/j.toxrep.2025.102073
Odera R. Umeh , Eziafakaego M. Ibo , Chima I. Eke , Hilda C. Afeku-Amenyo , Duke U. Ophori
{"title":"A review of the sidelined pollutant: Reviving the fight against heavy metal contamination in an era of emerging contaminants","authors":"Odera R. Umeh , Eziafakaego M. Ibo , Chima I. Eke , Hilda C. Afeku-Amenyo , Duke U. Ophori","doi":"10.1016/j.toxrep.2025.102073","DOIUrl":"10.1016/j.toxrep.2025.102073","url":null,"abstract":"<div><div>Groundwater contamination by heavy metals (HMs) remains a pressing global concern, presenting substantial risks to humans, animals, plants, and the environment. Although emerging pollutants have received increasing attention, the adverse impacts of HM have not been adequately resolved. This comprehensive review examines the current state of knowledge regarding HM in groundwater, addressing sources, global trends, transport, fate, sampling techniques, modeling, quality control, toxicity, treatment, sustainable measures, and vital research gaps. HM research has continued to dwindle since 2022, these chemicals infiltrate groundwater systems through various pathways, and their mobility and bioavailability are affected by changes in climate, geological heterogeneity, and chemical properties. Moreover, HM may interact with other emerging contaminants to enhance migration and toxicity; however, little or no research has been conducted to fully understand cocktail migration mechanisms and impacts in groundwater systems. Despite the existence of various treatment techniques, no single approach has been universally accepted as the sole solution for completely removing HM from drinking water systems. There is a pressing need for standardized and advanced sampling methods, stringent quality control measures, and the incorporation of cutting-edge technologies such as smart water sensors that can detect both charged and uncharged contaminants, and nanotechnology for effective management. The increasing toxicity of HM and their harmful effects on human health and ecosystems emphasize the need for continuous and novel research involving sustainable remedial strategies, as the battle against metal contamination in groundwater systems requires constant dedication, innovative research, and a shared commitment to protecting our environment.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102073"},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Toxicology ReportsPub Date : 2025-06-17DOI: 10.1016/j.toxrep.2025.102072
Sivaselvakumar Muthusamy , Ramanujam Narayanan
{"title":"Transgenerational toxicity of Aroclor 1232 by inhalational route in mouse model","authors":"Sivaselvakumar Muthusamy , Ramanujam Narayanan","doi":"10.1016/j.toxrep.2025.102072","DOIUrl":"10.1016/j.toxrep.2025.102072","url":null,"abstract":"<div><h3>Background</h3><div>Aroclor 1232 is a commercial mixture of polychlorinated biphenyls with inhalational toxicological implications as it contains semi-volatile congeners like PCB 77, along with highly lipophillic ones like PCB 180. We aimed to assess the trans-generational behavioral toxicities of this complex mixture in mice by inhalational dosing chamber. We also aimed to evaluate the penetrability of PCBs across placental and lactational routes in mice in this study.</div></div><div><h3>Methods</h3><div>We assessed the probable route of penetration in the first generation of litters using behavioral scores as surrogate markers of developmental toxicity. We also quantified plasma concentrations of key PCBs and anthropometric parameters for trans-generational comparability.</div></div><div><h3>Results</h3><div>PCBs are responsible for behavioral toxicities across one generation of mice by hazardous exposures via the inhalational route. Behavioral scores of F1 and F2generation mice indicated as surrogate endpoints that PCBs are concentrated in lactating milk more than placental route in the next generation of mice. No significant lethality or effects on anthropometrical parameters were detected across one generation although the congeners were detected in plasma of the litters when they were 12–14 weeks age.</div></div><div><h3>Conclusion</h3><div>PCBs may pose both indoor and outdoor volatile hazard by inhalational routes and cause behavioral deficits across one generation by transfer via lactational routes. PCB 77 is more evident of penetrating trans-generationally and produces behavioral toxicities in subsequent generations. They definitely carry inhalational hazard in workplaces and outdoor as environmental pollutants and neuroendocrine disruptors.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102072"},"PeriodicalIF":0.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Sub-acute polyethylene microplastic inhalation exposure induced pulmonary toxicity in wistar rats through inflammation and oxidative stress.","authors":"Athaya Rahmanardi Muhammad, Muhammad Reva Aditya, Bayu Lestari, Hikmawan Wahyu Sulistomo","doi":"10.1016/j.toxrep.2025.102067","DOIUrl":"10.1016/j.toxrep.2025.102067","url":null,"abstract":"<p><p>Plastic waste, particularly polyethylene (PE) plastic bags and bottles, poses a significant environmental problem and health risk when degraded into microplastics. Recent atmospheric microplastic pollution increases inhalation exposure, necessitating a study on toxicity in the lungs. However, the inhalation toxicology of PE microplastics is poorly understood. This study used Wistar rats that are divided into control and PE group. The PE groups were exposed to PE microplastic through inhalation for 28 days with the daily dose of 15 mg/m<sup>3</sup>. Inflammatory marker such as Inflammatory exudate, Alveolar thickening, and NF-κB were in PE group increased significantly compared to control group. the increment of MDA and decrement of SOD in PE group revealed the oxidative stress occurred. These results suggest that sub-acute PE microplastic inhalation may contribute to inflammation pathogenesis via the NF-κB pathway as a result of oxidative stress.</p>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"14 ","pages":"102067"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}