Toxicological Sciences最新文献

{"title":"Paternal methylphenidate exposure alters sperm miRNAs and induces intergenerational behavioral and transcriptional changes that are largely reversed by washout.","authors":"Kanata Akaike, Asuka Kaizaki-Mitsumoto, Satoshi Numazawa","doi":"10.1093/toxsci/kfag126","DOIUrl":"https://doi.org/10.1093/toxsci/kfag126","url":null,"abstract":"<p><p>Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. Methylphenidate (MPH), a first-line medication, is often used long-term and not routinely discontinued in individuals planning to have children. Guided by the Paternal Origins of Health and Disease framework, in this study, we investigated intergenerational effects of paternal MPH exposure and reversibility of sperm epigenetic changes. Male BALB/c mice received MPH (15 mg/kg) or vehicle for 28 days and were mated with untreated females immediately after treatment (F0-T1) or after a 40-day washout period (F0-T2). Behavioral tests and brain gene expression analyses were conducted in the offspring (F1), and sperm small noncoding RNA (sncRNA) profiles were examined in F0 males. Male offspring in the F0-T1-MPH group showed increased open-arm entry into the elevated plus maze and reduced expression of Maoa, Maob, and Bdnf in the medial prefrontal cortex. These changes were absent in the offspring derived from the F0-T2-MPH group. Sperm sncRNA sequencing identified 5,684 differentially expressed fragments in F0-T1-MPH mice, including marked alterations in miRNA-derived fragments, such as miR-34c-5p and miR-30e-5p. The target genes of these altered miRNAs were enriched in ADHD-related pathways, including axon guidance and Rap1 signaling. After washout, the number of differentially expressed sncRNA fragments decreased to 665, whereas the number of altered miRNA-derived fragments decreased from 383 to 7. These findings suggest that paternal MPH exposure may influence offspring behavior and brain gene expression through sperm miRNA alterations and that these effects are largely reversible following drug withdrawal.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal PFOS Exposure Impairs β‑Cell Insulin Secretion and Glucose Tolerance in Rats.","authors":"Alissa Hofmann, Pankaj Yadav, Ruolin Song, Sri Vidya Dangudubiyyam, Jay S Mishra, Sathish Kumar","doi":"10.1093/toxsci/kfag137","DOIUrl":"https://doi.org/10.1093/toxsci/kfag137","url":null,"abstract":"<p><p>Perfluorooctanesulfonic acid (PFOS) is epidemiologically linked to gestational diabetes mellitus (GDM), but the mechanisms remain undefined. We hypothesized that PFOS exposure impairs pancreatic β-cell function through mitochondrial dysfunction and deficits in ATP/cAMP signaling. Pregnant and non-pregnant rats received PFOS (50 μg/mL in drinking water) for 17 days (gestation day [GD] 4-20 in pregnant dams). PFOS-exposed pregnant dams exhibited fasting hypoinsulinemia (65% decrease) with normal fasting glucose. Glucose tolerance was impaired (31% increase in glucose AUC), with blunted insulin secretion (52% decrease in insulin AUC). In contrast, non-pregnant PFOS-exposed rats showed no changes in fasting glucose or insulin but developed glucose intolerance (25% increase in glucose AUC) with only modest early insulin suppression, revealing greater vulnerability in pregnancy. Pancreatic islet morphology and insulin content remained unchanged in PFOS-exposed dams. Isolated islets from PFOS-exposed dams and INS-1 β-cells treated with PFOS (10-100 μM) showed reduced glucose-stimulated insulin secretion despite normal Ins1 and Ins2 expression and insulin content. In INS-1 cells, PFOS selectively reduced Complex II subunits, depleted ATP (32-39%) and cAMP (57-74%), and impaired insulin secretion under low and high glucose. Co-treatment with the mitochondria-targeted antioxidant MitoQ (0.1μM) fully restored ATP, cAMP, and insulin secretion to control levels. These findings demonstrate that PFOS exposure causes gestational glucose intolerance and β-cell secretory failure, accompanied by reduced mitochondrial Complex II subunit abundance and ATP/cAMP depletion. The complete rescue by MitoQ highlights oxidative mitochondrial dysfunction as a mechanistic contributor linking PFOS exposure and GDM risk.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multiparametric in vitro strategy for small molecule drug-induced liver injury risk mitigation in early drug development.","authors":"Leah M Norona, Fjodor Melnikov, Tomomi Kiyota, Christopher Lawson, Cyrus Khojasteh, Joyce Liu, Kevin Johnson, Tony Pourmohamad, Lennart T Anger, William R Proctor, Aaron M Fullerton","doi":"10.1093/toxsci/kfag124","DOIUrl":"10.1093/toxsci/kfag124","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) remains a major cause of preclinical and clinical attrition, reflecting persistent gaps in the predictive translation of preclinical safety data to human outcomes. To address these gaps, we established a refined multiparametric framework for early DILI risk prediction using a balanced reference set of 170 drugs with established clinical outcomes. Thirty physicochemical, mechanistic endpoints, and exposure-related features were systematically evaluated to identify high-specificity predictors of intrinsic DILI risk. Cytotoxicity in primary human hepatocytes and human liver microtissues, mitochondrial toxicity (i.e. mitotoxicity), and bile salt export pump inhibition were identified as top predictive features. Incorporation of clinical exposure data to derive margins of safety substantially improved assay performance, emphasizing the importance of exposure normalization. A multiparametric, flag-based hazard framework integrating ≥2 hazard flags achieved 98% specificity and a positive likelihood ratio of 18, providing a pragmatic approach for early compound triage and confidence in early decision-making. Random Forest models further enhanced predictive performance, identifying exposure, predicted lipophilicity (e.g. cLogD), mitotoxicity, cytotoxicity, and hepatic clearance as major contributors to DILI risk, with exposure-informed models achieving a balanced accuracy of 0.72. Application of the framework to contemporary Genentech portfolio molecules demonstrated translational utility in refining risk categorization, particularly for compounds with borderline or 0-1 hazard flags. Collectively, this work establishes a mechanistically informed and machine learning-enabled platform that combines interpretability, specificity, and practicality to guide safer molecule design in drug discovery and reduce hepatotoxicity-related attrition in clinical development.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"209 10","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A high-throughput method to computationally develop candidate adverse outcome pathways in humans: a proof of concept with insecticides and Parkinson's Disease.","authors":"Dorian Rollin, Chenyu Shen, Ksenia Groh, Marissa B Kosnik","doi":"10.1093/toxsci/kfag122","DOIUrl":"10.1093/toxsci/kfag122","url":null,"abstract":"<p><p>Adverse outcome pathways (AOPs) describe stressor-non-specific sequences of events between a first molecular trigger (molecular initiating event, MIE), causally linked key events (KEs), and an adverse outcome (AO). AOPs are intended to aid in chemical toxicity testing as a new approach methodology. However, commonly used AOP development methods depend on manual curation, which is labor-intensive. As a result, there are still relatively few AOPs, and a huge number of toxicity mechanisms and possible AOs remain undescribed. Therefore, systematic and high-throughput approaches to predict new AOPs are needed. Here, we developed and implemented a data integration-based framework to generate new candidate AOPs using insecticides and Parkinson's Disease as a proof of concept. We integrated and statistically linked disconnected databases (e.g. Comparative Toxicogenomics Database, Human Protein Atlas, and Gene Ontology) to form MIE-KE (cell level)-KE (tissue level)-AO candidate AOPs. Through this systematic process, we generated 562,117 candidate AOPs, which we then scored using a weight-of-evidence (WoE) approach and prioritized 12,756 AOPs with a WoE >0.5. The prioritized AOPs describe varied mechanisms of toxicity related to e.g. MAPK, PTEN, and FGFR signaling pathways, with \"increases phosphorylation of MAPK1\" as the most frequent MIE. Through analysis of 100 random prioritized AOPs, we found 70% had external literature supporting their biological plausibility, and only 15% represented identifiably implausible associations. Our AOP-generating approach yields consistently structured AOPs and can complement existing and emerging development methods to expand AOP coverage across different stressors and outcomes.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated single-cell and epigenomic analysis reveals cellular specificity of CYP2E1 in human alcohol-related liver disease.","authors":"Lukas Neckermann, Eleusa Karavasili, Anne Dropmann, Seddik Hammad","doi":"10.1093/toxsci/kfag128","DOIUrl":"10.1093/toxsci/kfag128","url":null,"abstract":"<p><p>Cytochrome P450 2E1 (CYP2E1) is a key hepatic xenobiotic metabolizing enzyme classically localized to pericentral hepatocytes. However, its cellular specificity and regulatory landscape in human alcohol-related liver disease (ALD) remain incompletely defined. We aimed to delineate the spatial, cellular, and epigenetic determinants of CYP2E1 expression in health and in ALD. We integrated cross-species immunohistochemistry (human, mouse, rat, pig) with bulk RNA sequencing (human), single-cell RNA sequencing, and paired single-nucleus RNA and ATAC sequencing. Healthy controls and patients with ALD, including alcoholic hepatitis and cirrhosis, were analyzed to define CYP2E1 localization, zonation, and regulatory features across hepatocyte and non-parenchymal cell (NPC) populations. In healthy liver, CYP2E1 protein and transcript expression were predominantly localized to zone 3 hepatocytes across species and platforms. Apparent CYP2E1 signals in NPC populations were not accompanied by CYP2E1-linked chromatin accessibility and were consistent with hepatocyte-derived ambient RNA or technical contamination rather than bona fide NPC expression. In human ALD, CYP2E1 expression is reduced in alcoholic hepatitis and cirrhosis, particularly in the pericentral compartment, and is associated with increased AST levels and impaired metabolic zonation. These findings contrast with ethanol-induced CYP2E1 upregulation during active exposure and suggest that advanced ALD is characterized by loss of CYP2E1 expression linked to hepatocyte dysfunction. CYP2E1 is a predominantly hepatocytic enzyme that, in the healthy liver, exhibits strong pericentral enrichment. In chronic ALD, CYP2E1 expression appears to reflect pericentral hepatocyte integrity rather than ethanol responsiveness, highlighting the importance of rigorous cell-type validation in liver disease studies.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to di(2-ethylhexyl) phthalate and diisononyl phthalate alters the aryl hydrocarbon receptor signaling pathway in the ovary throughout reproductive aging in mice.","authors":"Angela E Dean, Ramsés Santacruz-Márquez, Adira M Safar, Mary J Laws, Taylor A Seaton, Estella Miller, Justin Huff, Lydia M Hall, Jodi A Flaws","doi":"10.1093/toxsci/kfag131","DOIUrl":"10.1093/toxsci/kfag131","url":null,"abstract":"<p><p>Di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are plasticizers used in many consumer products. Both phthalates alter estrous cyclicity, fertility indices, and folliculogenesis throughout the reproductive lifespan. Our companion paper showed that exposure to a phthalate mixture containing DEHP and DiNP altered the aryl hydrocarbon receptor (AHR) signaling pathway in the ovary. However, limited information was available on how DEHP and DiNP individually affect the AHR signaling pathway in the ovary throughout reproductive aging. Thus, we hypothesized that DEHP and DiNP individually affect the gene and protein expression and localization associated with the AHR pathway throughout the reproductive lifespan. We treated adult female CD-1 mice with corn oil control or doses (0.15 ppm, 1.5 ppm, or 1,500 ppm) of DEHP and DiNP in the diet for 1 to 12 mo. Sera were used to measure circulating estradiol (E2) concentrations. The AHR pathway was assessed using quantitative PCR (qPCR) for gene expression, RNAscope in situ hybridization for transcript localization, and immunohistochemistry for protein localization. Exposure to DEHP, but not DiNP, reduced serum E2 after 1 mo compared with control. DEHP exposure increased Cyp1a1 expression and CYP1B1 localization in the ovary after 6 mo compared with control. DiNP also increased Arnt expression and CYP1B1 localization in the ovary after 1 mo compared with control. DiNP exposure decreased Ahr and Cyp1a1 expression as well as CYP1A1 localization in the antral follicle after 12 mo compared with control. Overall, DEHP and DiNP both influence the ovarian AHR pathway, but at different time points and doses.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149064228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-exposure to high temperature and mono(2-ethylhexyl) phthalate inhibits mouse antral follicle growth and estradiol synthesis: phthalate-heat interactions in the ovary.","authors":"Sundus Ghuneim, Madison Wilson, Caroline Harper, Sophia Sherlock, Gretchen Ruschman, Patrick Hannon","doi":"10.1093/toxsci/kfag127","DOIUrl":"10.1093/toxsci/kfag127","url":null,"abstract":"<p><p>Humans are ubiquitously exposed to di(2-ethylhexyl) phthalate (DEHP), which is a phthalate plasticizer used in consumer goods that has been identified as a reproductive toxicant. DEHP toxicity is mediated by mono(2-ethylhexyl) phthalate (MEHP), its bioactive metabolite that has been shown to target ovarian processes, including folliculogenesis and steroidogenesis. Simultaneously, humans are ubiquitously exposed to nonchemical stressors like high temperatures, which have also been shown to impair ovarian function. Given the unavoidable exposure to both increasing heat and DEHP, this study tested the hypothesis that exposure to high temperature will exacerbate the negative effects of MEHP exposure on antral follicle function. Antral follicles from CD-1 mice were cultured for 24 to 96 h with vehicle control (DMSO) or MEHP (0.2 to 20 µg/ml) at a control temperature (CT; 37 °C) or high temperature (HT; 42 °C, 8 h per 24 h) to assess effects on follicle growth and steroidogenesis. Compared with control (CT+DMSO), HT+DMSO and HT+MEHP inhibited the cell cycle and steroidogenic pathway and upregulated follicle-stimulating hormone receptor expression. CT+MEHP, HT+DMSO, and HT+MEHP decreased estradiol levels over time, and HT+DMSO and HT+MEHP also inhibited antral follicle growth compared with CT+DMSO. Therefore, MEHP exposure decreased estradiol levels, whereas HT exposure and HT+MEHP co-exposure decreased estradiol levels and follicle growth by inhibiting the steroidogenic pathway and cell cycle. Further, several significant interactions were identified, providing the first evidence of a phthalate-heat interaction in a mammalian model. Thus, exposure to ubiquitous chemical and nonchemical stressors, like MEHP and HT, disrupt critical ovarian processes and may potentiate ovarian dysfunction when combined.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ToxCompl completion of the DrugMatrix toxicogenomics database: an integrated resource for hypothesis generation.","authors":"Laura J Word, Guojing Cong, Robert M Patton, Frank Chao, Daniel L Svoboda, Warren M Casey, Charles P Schmitt, Jeremy N Erickson, Parker Combs, Scott S Auerbach","doi":"10.1093/toxsci/kfag113","DOIUrl":"10.1093/toxsci/kfag113","url":null,"abstract":"<p><p>The DrugMatrix database contains systematically generated toxicogenomics data from short-term in vivo studies for over 600 chemicals. However, most potential endpoints are missing due to a lack of experimental measurements. Therefore, we leveraged matrix factorization and machine learning methods to predict the missing values, which includes gene expression across 8 tissues on 2 expression platforms along with paired clinical chemistry, hematology, and histopathology. We propose a method, ToxCompl, that applies systematic hybrid sampling guided by Bayesian optimization in conjunction with low-rank matrix factorization to predict the missing values. In-depth validation of the ToxCompl predicted data from machine learning, biological, and toxicological perspectives shows that the predicted differential gene expression aligns well with what would be anticipated. This includes examining the connectivity pattern of predicted gene expression responses, characterizing molecular pathway-level responses from sets of differentially expressed genes, evaluating known transcriptional biomarkers of tissue toxicity, and characterizing predicted apical endpoints. For example, we identified kidney toxicants using the transcriptional biomarker Havcr1. All measured and predicted DrugMatrix data (i.e., gene expression, clinical chemistry, hematology, and histopathology) are available to the public (https://rstudio.niehs.nih.gov/toxcompl/). Notably, predicted clinical chemistry of subtle effects and histopathological prediction are 2 areas we will continue to improve. The main advantage of the ToxCompl approach is that it drastically extends the toxicogenomic landscape into many data-poor tissues in the absence of acquiring additional experimental data, thereby allowing researchers to formulate mechanistic hypotheses about effects in tissues that have been underrepresented in the literature.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Review of in vitro approaches for assessing the toxicity of chemical stressors across diverse physiological systems.","authors":"Ranjini Mukherjee, Chathuri Mudalige, Ayesha Hammad Khan, Maria Fernanda Gonzalez-Acosta, Min Seo Hong, Jean-Pierre Desforges","doi":"10.1093/toxsci/kfag097","DOIUrl":"10.1093/toxsci/kfag097","url":null,"abstract":"<p><p>The widespread presence of chemicals in the environment poses significant health risks to humans and wildlife. Existing traditional in vivo approaches, while informative, are limited by considerable ethical, economic, and logistical challenges that prevent timely and effective chemical testing and management strategies. To overcome these challenges, new approach methodologies (NAMs) offer promising alternatives for high-throughput, mechanistic, and ethically conscious chemical toxicity testing. The key to testing chemicals for potential adverse effects is the selection of appropriate bioassays that cover the range of biological or physiological pathways likely targeted by the contaminant of interest. In other words, chemical testing strategies need to cover a broad range of physiological systems to account for the mechanistic specificity of contaminants. Researchers and regulators thus face the challenge of navigating this interdisciplinary and rapidly growing space. This in-depth review attempts to address this important challenge by identifying and describing existing in vitro bioassays that can be used to assess functional impacts of chemical contaminants across vital physiological systems: endocrine, immune, cardiovascular, neurological, and hepatic. By summarizing the current tools and methodologies, this article provides a comprehensive guide for researchers and regulators to help identify relevant NAMs for use in modern chemical toxicity testing strategies.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The aryl hydrocarbon signaling pathway in the ovary changes throughout reproductive aging and in response to a mixture of phthalates over time in mice.","authors":"Angela E Dean, Ramsés Santacruz-Márquez, Adira M Safar, Mary J Laws, Taylor A Seaton, Estella Miller, Justin Huff, Lydia M Hall, Jodi A Flaws","doi":"10.1093/toxsci/kfag130","DOIUrl":"10.1093/toxsci/kfag130","url":null,"abstract":"<p><p>Phthalates are plasticizers and solvents used in numerous consumer products. Exposure to a phthalate mixture (Mix) alters estrous cyclicity, fertility indices, ovarian follicle dynamics, and steroidogenesis. In cultured antral follicles, phthalates alter the aryl hydrocarbon receptor (AHR) pathway, which is known for estradiol (E2) and xenobiotic metabolism. However, how phthalates affect the AHR pathway in the ovary in vivo and how this pathway changes throughout the reproductive lifespan are unknown. Thus, we hypothesized that expression and localization of genes and proteins in the AHR pathway change throughout the reproductive lifespan and in response to Mix exposure. We exposed adult female CD-1 mice to corn oil control or varying doses (0.15, 1.5, or 1,500 ppm) of Mix for 1 to 12 months. Sera and ovaries were collected at each time point. Sera were used to determine circulating E2 concentrations. The AHR pathway in the ovaries was examined using quantitative polymerase chain reaction for gene expression, RNAscope in situ hybridization for transcript localization, and immunohistochemistry for protein localization. The AHR pathway was altered throughout the reproductive lifespan, with increased Cyp1a1 expression and decreased CYP1B1 protein localization in the ovary at 13 months of age. Circulating E2 decreased throughout aging. Mix exposure altered Arnt and Ahr expression after 1 and 12 months, respectively. Additionally, Mix exposure increased CYP1A1 protein localization after 6 months, with areas of increased staining intensity in the ovary. Overall, the AHR pathway was altered with reproductive aging, and Mix exposure affected the pathway over time.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149064245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}