Current Research in Toxicology最新文献

{"title":"RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice","authors":"Yan Ma ,&nbsp;Honggang Chen ,&nbsp;Yuxin Jiang ,&nbsp;Diya Wang ,&nbsp;Michael Aschner ,&nbsp;Wenjing Luo ,&nbsp;Peng Su","doi":"10.1016/j.crtox.2024.100207","DOIUrl":"10.1016/j.crtox.2024.100207","url":null,"abstract":"<div><div>Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood–brain barrier (BBB), a critical regulator in maintaining central nervous system homeostasis and a contributing factor in the pathogenesis of numerous neurological disorders. However, the precise molecular mechanisms underlying Mn-induced BBB disruption and its role in facilitating neurotoxicity remain incompletely understood. The primary objectives of this study were to elucidate the mechanisms underlying the relationship between Mn exposure and BBB tight junction proteins (TJPs), and to further investigate potential neuroprotective strategies for mitigating Mn-induced cognitive impairments. In this investigation, we developed Mn exposure models utilizing both murine subjects and cell culture systems to elucidate the mechanisms underlying TJPs involvement and to assess the potential neuroprotective effects of gastrodin (GAS), a bioactive compound extracted from traditional Chinese medicine. Our findings revealed a significant reduction in TJPs expression, both <em>in vivo</em> and <em>in vitro</em>, in Mn-induced BBB disruption. The overexpression of Occludin (OCLN), a crucial component of TJPs, mitigated Mn-induced BBB damage. GAS administration effectively attenuated Mn-induced disruption of the BBB, enhanced the expression of TJPs, and mitigated Mn-induced cognitive dysfunctions, potentially through the modulation of the RhoA/ROCK2 signaling pathway. This research sought to advance our understanding of the molecular pathways involved in Mn-mediated BBB disruption and to identify novel therapeutic approaches for mitigating the deleterious effects of Mn exposure on cognitive function.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100207"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001342","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}

{"title":"Efficacy of a hydrogen–oxygen generator in treating cigarette smoke–induced chronic obstructive pulmonary disease in rats","authors":"Wan-Ting Huang ,&nbsp;Tzong-Jih Cheng ,&nbsp;Lin-Hsiang Huang ,&nbsp;Yung-Te Hou","doi":"10.1016/j.crtox.2024.100214","DOIUrl":"10.1016/j.crtox.2024.100214","url":null,"abstract":"<div><div>Current treatments for chronic obstructive pulmonary disease (COPD), a common respiratory condition, include oxygen therapy and steroids for temporary relief. In this study, we established a rat model of cigarette smoke (CS)–induced COPD and investigated the benefits of a hydrogen–oxygen generator in this model. CS–exposed rats were treated using either a hydrogen–oxygen generator or a steroid. A hydrogen–oxygen generator reduced the neutrophil, lymphocyte, and eosinophil counts compared to natural recovery, whereas steroid treatment increased the total white blood cell, neutrophil, lymphocyte, monocyte and eosinophil counts. Furthermore, the mean linear intercept and the mean alveolar number were 59.8%, and 188.3%, respectively, after treatment with the generator, compared to the values observed with natural recovery. Finally, the generator increased the tricuspid annular plane systolic excursion values by 113.1% compared with the values in natural recovery. Our findings indicate successful establishment of a rat model of CS–induced COPD and demonstrate the potential benefits of using a hydrogen–oxygen generator for COPD patients.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100214"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001850","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}

{"title":"Community-based insights into the connection between endocrine-disrupting chemicals and depressive symptoms","authors":"Yun-An Liu ,&nbsp;Heng-Jung Hsu ,&nbsp;Heng-Chih Pan ,&nbsp;Chiao-Yin Sun ,&nbsp;Yih-Ting Chen ,&nbsp;Chin-Chan Lee ,&nbsp;Feng-Chieh Su ,&nbsp;Yi-Chia Wei ,&nbsp;Cheng-Kai Hsu ,&nbsp;Chun-Yu Chen","doi":"10.1016/j.crtox.2025.100225","DOIUrl":"10.1016/j.crtox.2025.100225","url":null,"abstract":"<div><h3>Background</h3><div>The rising prevalence of depressive disorders has sparked concerns regarding environmental risk factors, particularly exposure to endocrine-disrupting chemicals (EDCs). However, the link between EDC exposure and depressive symptoms remains largely unexplored.</div></div><div><h3>Methods</h3><div>The Chang Gung Community Medicine Research Center carried out a cross-sectional study across four regions in northeastern Taiwan. Out of 887 participants, 120 subjects were chosen according to their EDC exposure scores. These participants underwent urinary EDC analysis and were evaluated for depressive symptoms through the standardized Hospital Anxiety and Depression Scale − Depression subscale (HADS-D) questionnaire.</div></div><div><h3>Results</h3><div>Participants with HADS-D scores ≥ 8 exhibited significantly higher EDC exposure score compared to those with lower scores. The correlation analyses identified a notible positive association between urinary monobenzyl phthalate (MBzP) levels and HADS-D scores (<em>r</em> = 0.244, <em>p</em> = 0.007). Multiple regression analysis revealed that MBzP was independently linked to increased HADS-D scores in a positive manner (β ± SE: 0.139 ± 0.050, <em>p</em> = 0.006). Multivariable logistic regression indicated that higher MBzP (OR: 1.150, 95 % CI: 1.036–1.278, <em>p</em> = 0.009) and methylparaben (MP) levels (OR: 1.008, 95 % CI: 1.003–1.013, p &lt; 0.001) showed a significant correlation with the likelihood of HADS-D scores ≥ 8. Receiver operating characteristic curve analysis demonstrated that elevated levels of MBzP, MP and the EDCs exposure score were associated with a greater likelihood of depressive symptoms.</div></div><div><h3>Conclusion</h3><div>Exposure to EDCs, particularly MBzP and MP, could be associated with a heightened risk of depressive symptoms.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100225"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511085","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}

{"title":"A simple, reliable and easily generalizable cell-based assay for screening potential drugs that inhibit lipid accumulation","authors":"Weili Yang,&nbsp;Qiuyue Pan,&nbsp;Qi Li,&nbsp;Sirui Zhou,&nbsp;Xi Cao","doi":"10.1016/j.crtox.2024.100213","DOIUrl":"10.1016/j.crtox.2024.100213","url":null,"abstract":"<div><div>Ectopic lipid deposition in the hepatocyte plays an important role in the development of nonalcoholic fatty liver disease (NAFLD), which has become one of the most common causes of chronic liver disease worldwide yet no approved drugs are currently available. In this study, a cell-based method was developed to screen potential drugs with low toxicity that inhibit lipid accumulation. In the same 96-well plate, cytotoxicity was measured using CCK8 assay, followed by lipid content detection using BODIPY 493/503 via fluorometry assay, a lipid droplet-specific fluorescent dye commonly used in microscopy and flow cytometry, but not previously reported in fluorometry. Lipid content was normalized to DAPI staining to control for cell number. The results of this assay were highly consistent with the fluorescence microscopy, with significantly lower intra-group variability in detecting lipid accumulation induced by free fatty acids in Huh7 cells. Validation was conducted using 10 well documented steatotic compounds and 5 negative controls, all of which were correctly identified by the assay. In addition, the inhibitory effect of ML261, a well-known inhibitor of hepatic lipid droplets formation, was also confirmed by the assay both in AML12 cells and Hepa1-6 cells. To our knowledge, this study is the first to quantify lipid droplets using BODIPY 493/503 by fluorometry assay, and to demonstrate that CCK8 does not interfere with subsequent BODIPY 493/503 staining, both of which will reduce the cost and increase the efficiency. In conclusion, the method is simple, reliable, efficient and does not rely on expensive instruments, making it an easily generalizable approach to identify potential drug candidates for NAFLD treatment.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100213"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001848","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}

{"title":"The impact of in utero tobacco exposure on smoking behaviors, cardiovascular disease risk and all-cause mortality in adulthood: A UK Biobank study","authors":"Yanxu Zheng ,&nbsp;Xinyu Xiong ,&nbsp;Jing Bao ,&nbsp;Jingyu Liu ,&nbsp;Jin Wang ,&nbsp;Fang Zou ,&nbsp;Zixi Chen ,&nbsp;Yang Guo ,&nbsp;Qingyao Wang ,&nbsp;Yixuan Qiu ,&nbsp;Zhaowei Zhu","doi":"10.1016/j.crtox.2025.100226","DOIUrl":"10.1016/j.crtox.2025.100226","url":null,"abstract":"<div><div>The knowledge regarding the negative impacts of in utero tobacco exposure (IUTE) on cardiovascular disease (CVD) was incomplete. This study aims to assess the association between IUTE and the risks of CVD incidence and all-cause mortality, discuss the inter-group difference based on genetic susceptibility and smoking behaviors after birth, and explore the potential mediating factors. Utilizing a total of 375,024 participants from the UK Biobank, the outcomes include myocardial infarction, stroke, chronic ischemic heart disease, nonrheumatic aortic valve disorders, cardiomyopathy, heart failure, atherosclerosis, aortic aneurysm and dissection, and all-cause mortality. During a median follow-up period of 14.6 years, 50,434 cases of CVD were recorded. IUTE was significantly associated with increased CVD incidence (HR 1.10, 95 % CI 1.08–1.12) and all-cause mortality (HR 1.11, 95 % CI 1.09–1.14). Interaction effects between IUTE, smoking behaviors after birth, and genetic risk scores for CVD were observed significant (P for interaction &lt; 0.005). The results of the cross-sectional study revealed a significant positive association between IUTE and smoking behaviors after birth (OR 1.08, 95 % CI 1.06–1.09). Mediation analysis indicated that smoking behaviors (Proportion = 12.40 %, P &lt; 0.001) and HDL-c levels (Proportion = 14.20 %, P &lt; 0.001) partially mediated the IUTE-CVD relationship. This study demonstrated that individuals with IUTE have a higher risk of developing CVD, and smoking behaviors after birth have multifaceted influence on this correlation. These findings underscore the importance of mothers avoiding smoking during pregnancy to mitigate adverse effects on their offspring.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100226"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511086","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}

{"title":"Developmental polychlorinated biphenyl (PCB) exposure impacts on voiding physiology persist into adulthood and influence sensitivity to bladder stimuli in mice","authors":"Monica Ridlon,&nbsp;Audrey Spiegelhoff,&nbsp;Conner L Kennedy,&nbsp;Thomas Lavery,&nbsp;Kathy Wang,&nbsp;Julia Tlapa,&nbsp;Tamryn Jordan,&nbsp;Lindsey Felth Tanaka,&nbsp;Kimberly Keil Stietz","doi":"10.1016/j.crtox.2025.100227","DOIUrl":"10.1016/j.crtox.2025.100227","url":null,"abstract":"<div><div>Polychlorinated biphenyls (PCBs) are toxicants present in the environment, foodstuff, animal and human tissues. PCBs are linked to numerous adverse health effects; however, impacts of developmental PCB exposure on lower urinary tract function are a comparatively newer area of interest. We have previously found developmental exposure (<em>in utero</em> and lactational) to a human-relevant PCB mixture in mice leads to sex- and dose- dependent changes to urinary voiding physiology at 6 weeks of age. This study expands upon previous findings to investigate if developmental PCB-induced urinary voiding phenotypes persist or shift as mice age to 12 weeks of age. Urinary voiding physiology testing through void spot assays, uroflowmetry, and cystometry demonstrated several sex- and dose- dependent effects of PCB exposure at 12 weeks of age. Further, patterns of dysfunction were either maintained, newly acquired, or reversed compared to those from younger adult mice in a previous study. Here, developmental PCB exposure decreased number of small urine spots in adult male and female mice in a dose dependent manner, and female mice had more frequent voiding events assessed by anesthetized cystometry. Mice also had PCB dose-dependent changes to urinary voiding physiology when challenged with intravesical capsaicin infusion to target transient receptor potential cation channel subfamily V member 1 (TRPV1)-mediated pathways. PCBs either blocked or exacerbated capsaicin induced responses depending on the endpoint examined, suggesting this pathway may play a role in PCB-dependent changes in voiding. PCBs also had subtle impacts on prostate wet weight, with high PCB doses reducing tissue mass compared to low PCB doses, while none differed from vehicle. This study demonstrates developmental exposure to PCBs continues to impact lower urinary tract function in adulthood to at least 12 weeks of age both during homeostatic conditions and upon challenge of capsaicin. Better understanding of how early life stressors like PCBs contribute to aging-associated voiding dysfunction are imperative as these findings may help mitigate risk or improve treatment strategies for patients suffering from lower urinary tract symptoms.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100227"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628828","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}

{"title":"Fit for purpose testing and independent GMP validation of the monocyte activation test","authors":"Ruth Daniels ,&nbsp;Wim Van der Elst ,&nbsp;Chi K. So ,&nbsp;Liesbeth Voeten ,&nbsp;Philip Breugelmans ,&nbsp;Marijke W.A. Molenaar-de Backer ,&nbsp;Stephen Poole ,&nbsp;Mehul Patel","doi":"10.1016/j.crtox.2024.100206","DOIUrl":"10.1016/j.crtox.2024.100206","url":null,"abstract":"<div><div>The present study describes the “fit for purpose” testing and the independent product-specific GMP validation of the monocyte activation test (MAT) to detect pyrogenic and pro-inflammatory contaminants, MAT Method A, Quantitative Test (<span><span>European Pharmacopoeia, Ph. Eur. chapter 2.6.30, 2017</span></span>). A fit for purpose study was carried out to ensure that the chosen MAT set-up (cryopreserved PBMC, IL-6 detection) can reliably discriminate between batches of product containing pyrogenic contaminants below the contaminants limit concentration, CLC, from batches containing pyrogenic contaminants above the CLC. Such testing is carried out once, before the chosen MAT set-up is used for subsequent product testing to show that the incidence of false positives (pyrogen-negative (&lt;CLC) batches testing as pyrogen-positive (&gt;CLC) batches) and – especially – false negatives (pyrogen-positive (&gt;CLC) testing as pyrogen-negative (&lt;CLC)) is low. This study also afforded the opportunity to collect an independent body of validation data for comparison with that obtained previously (<span><span>Daniels et al., 2022</span></span>) to evaluate the robustness of MAT Method A and its fitness to replace the rabbit pyrogen test (RPT) where this has not already happened.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100206"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970094","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}

{"title":"A computational dynamic systems model for in silico prediction of neural tube closure defects","authors":"Job H. Berkhout ,&nbsp;James A. Glazier ,&nbsp;Aldert H. Piersma ,&nbsp;Julio M. Belmonte ,&nbsp;Juliette Legler ,&nbsp;Richard M. Spencer ,&nbsp;Thomas B. Knudsen ,&nbsp;Harm J. Heusinkveld","doi":"10.1016/j.crtox.2024.100210","DOIUrl":"10.1016/j.crtox.2024.100210","url":null,"abstract":"<div><div>Neural tube closure is a critical morphogenetic event during early vertebrate development. This complex process is susceptible to perturbation by genetic errors and chemical disruption, which can induce severe neural tube defects (NTDs) such as spina bifida. We built a computational agent-based model (ABM) of neural tube development based on the known biology of morphogenetic signals and cellular biomechanics underlying neural fold elevation, bending and fusion. The computer model functionalizes cell signals and responses to render a dynamic representation of neural tube closure. Perturbations in the control network can then be introduced synthetically or from biological data to yield quantitative simulation and probabilistic prediction of NTDs by incidence and degree of defect. Translational applications of the model include mechanistic understanding of how singular or combinatorial alterations in gene-environmental interactions and animal-free assessment of developmental toxicity for an important human birth defect (spina bifida) and potentially other neurological problems linked to development of the brain and spinal cord.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100210"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403139","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}

{"title":"Evaluation of the endocrine disrupting potential of Di-isononyl phthalate","authors":"I.A. Lea ,&nbsp;A.N. Buerger ,&nbsp;D. Feifarek ,&nbsp;A. Mihalchik ,&nbsp;M.M. Heintz ,&nbsp;L.C. Haws ,&nbsp;H. Nyambego ,&nbsp;K. Goyak ,&nbsp;C. Palermo ,&nbsp;S.J. Borghoff","doi":"10.1016/j.crtox.2025.100220","DOIUrl":"10.1016/j.crtox.2025.100220","url":null,"abstract":"<div><div>Low molecular weight <em>ortho</em>-phthalate compounds have been implicated in disruption of androgen pathways when exposure occurs during the masculinization programming window. Di-isononyl phthalate (DINP) is a high molecular weight phthalate and a high production volume chemical. To understand the potential for DINP and its metabolites to disrupt endocrine pathways, a weight of evidence assessment was conducted according to the European Chemicals Agency (ECHA)/ European Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). Toxicological data related to estrogen (E), androgen (A), thyroid (T), or steroidogenesis (S) pathways was assessed. Literature searches returned 110 articles from which data were extracted and assessed in conjunction with 105 high-throughput assays. An <em>in-silico</em> assessment of the EATS activity for DINP metabolites also was conducted. Based on the available evidence, DINP did not elicit thyroid- or estrogen-related apical outcomes <em>in vivo.</em> There were no studies evaluating thyroid hormone levels <em>in vivo</em> which, according to the ECHA/EFSA guidance, constitutes a data gap and prevents a conclusion being drawn on the T-pathway. The E, A, and S-pathways were sufficiently assessed to conclude on the endocrine disrupting potential of DINP. Based on the lack of apical outcomes, DINP did not disrupt the E-pathway. For the A and S-pathways, there was limited evidence to support adverse apical outcomes, so a mode of action assessment using a structured adverse outcome pathway (AOP) framework was performed. No biologically plausible link could be established between the key events in the hypothesized AOP that lead to adverse outcomes. Further, no dose or temporal concordance for A- and S-mediated findings were identified. Therefore, DINP does not meet the ECHA/EFSA criteria to be considered an endocrine disruptor.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100220"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510178","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}

{"title":"Evaluation of a hypothesized Sertoli cell-based adverse outcome pathway for effects of diisononyl phthalate on the developing testis","authors":"J.M. Rogers ,&nbsp;A.N. Buerger ,&nbsp;M.M. Heintz ,&nbsp;C.M. Palermo ,&nbsp;L.C. Haws ,&nbsp;I.A. Lea","doi":"10.1016/j.crtox.2025.100219","DOIUrl":"10.1016/j.crtox.2025.100219","url":null,"abstract":"<div><div>Exposure of pregnant rats to some phthalates during the masculinization programming window (MPW) can lower fetal testis testosterone production and adversely affect development of the fetal male reproductive tract. Some of the effects in rats are androgen-dependent, while others also occur in mice without lower testosterone production. An adverse outcome pathway (AOP) network has been proposed for these developmental effects that includes both androgen-dependent and androgen-independent pathways, the latter of which includes a short list of putative molecular initiating events (MIEs) including peroxisome proliferator activated receptor (PPAR) activation, and effects on Sertoli cells in the developing testes as early key events (KEs) (PMID 34314370). Data from peer-reviewed literature, publicly cited toxicology reports, and EPA’s Toxicity Forecaster (ToxCast) were evaluated in the context of this hypothesized Sertoli cell-based AOP and exposure to diisononyl phthalate (DINP). Each of the fifteen identified studies underwent a risk of bias (RoB) assessment, which revealed a high risk of bias for all but one study endpoint. <em>In vitro</em> evidence in kidney, liver, and fibroblast-like cell lines indicates that the DINP metabolites mono-isononyl phthalate (MINP) and mono-hydroxyisononyl phthalate (MHINP) activate PPARα/γ and that mouse PPARα/γ are more sensitive than human PPARα/γ. However, DINP did not activate PPARα-related genes in rat fetal testes at high maternal dosages (PMID 22112501), and it remains unknown whether PPARs are expressed in fetal Sertoli cells. Overall, there is insufficient evidence to evaluate whether PPAR activation in the developing male reproductive tract is causally linked to the KEs in the hypothesized AOP. Regarding the KEs, no <em>in vivo</em> studies were identified that examined the effects of DINP on Sertoli cell proliferation or cytoskeleton; a single <em>in vitro</em> study found no effect of DINP on Sertoli cell proliferation. There was limited and conflicting evidence for the effects of DINP on tubulogenesis, but strong <em>in vivo</em> evidence for increased multinucleated germ (MNG) cells. No evidence was found concerning germ cell apoptosis. For the adverse outcomes (AOs), there was limited <em>in vivo</em> evidence for testicular dysgenesis following altered tubulogenesis, and impaired spermatogenesis following increased MNGs. There was strong evidence against reduced fertility, but this is not a sensitive endpoint in rats given their robust sperm production and excess capacity. In conclusion, following <em>in utero</em> DINP exposure, while PPAR activation (MIE) is plausible, linkage to effects on Sertoli cells and downstream AOPs is lacking. The sparse evidence currently available is insufficient to support the applicability of the hypothesized Sertoli cell-based AOP to DINP.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100219"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563253","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}