Toxicological Sciences最新文献

{"title":"2023-2024 Toxicological Sciences Paper of the Year.","authors":"Deborah Cory-Slechta, Jeffrey M Peters","doi":"10.1093/toxsci/kfae153","DOIUrl":"https://doi.org/10.1093/toxsci/kfae153","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":"204 1","pages":"1"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558062","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":"Response to reader comment on: \"Comprehensive genotoxicity and carcinogenicity assessment of molnupiravir\".","authors":"Patricia A Escobar, Zhanna Sobol, Randy R Miller, Sandrine Ferry-Martin, Angela Stermer, Binod Jacob, Nagaraja Muniappa, Rosa I Sanchez, Kerry T Blanchard, Alema Galijatovic-Idrizbegovic, Rupesh P Amin, Sean P Troth","doi":"10.1093/toxsci/kfae157","DOIUrl":"10.1093/toxsci/kfae157","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"118-119"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847636","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":"Application of a quantitative uncertainty assessment to develop ranges of plausible toxicity values when using observational data in risk assessment: a case study examining associations between PFOA and PFOS exposures and vaccine response.","authors":"Daniele S Wikoff, Melissa J Vincent, Melissa M Heintz, Susan T Pastula, Heidi Reichert, William D Klaren, Laurie C Haws","doi":"10.1093/toxsci/kfae152","DOIUrl":"10.1093/toxsci/kfae152","url":null,"abstract":"<p><p>Traditional approaches for quantitatively characterizing uncertainty in risk assessment require adaptation to accommodate increased reliance on observational (vs experimental) studies in developing toxicity values. Herein, a case study with perfluorooctanoic acid (PFOA) and PFOS and vaccine response explores approaches for qualitative and-where possible-quantitative assessments of uncertainty at each step in the toxicity value development process when using observational data, including review and appraisal of individual studies, candidate study selection, dose-response modeling, and application of uncertainty factors. Each of the 15 studies identified had uncertainties due to risk of bias in confounding, outcome, and exposure ascertainment, likely contributing to the observed inconsistencies within and across studies, and resulting in lack of candidacy for dose-response assessment. Nonetheless, 2 representative studies were selected to demonstrate possible methods to quantify uncertainty in the remaining steps. Data simulations indicated lack of a clear dose-response relationship; dose-response models fit to representative simulations indicated high uncertainty in both the magnitude and direction of effect with simulated benchmark dose and its lower limit values varying at least 66- and 86-fold for PFOA and PFOS. Uncertainty factor application added minimal uncertainty. Combined, a high level of uncertainty was observed, precluding the ability to confidently assess causal dose-response relationships with the observational data, alone. This case study highlights the need for quantitative uncertainty analysis when developing toxicity values with observational data and, importantly, emphasizes the need for application of additional techniques to directly assess causality and the specificity of dose-response when relying on studies of association in quantitative risk assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"96-115"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955677","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":"Simulated burn pit smoke condensates cause sustained impact on human airway epithelial cells.","authors":"Arunava Ghosh, Keith L Rogers, Samuel C Gallant, Stephanie A Brocke, Adam M Speen, Yong Ho Kim, M Ian Gilmour, Scott H Randell, Ilona Jaspers","doi":"10.1093/toxsci/kfae161","DOIUrl":"10.1093/toxsci/kfae161","url":null,"abstract":"<p><p>Inhalation of smoke from burn pits during military deployment is associated with several adverse pulmonary outcomes. We exposed human airway epithelial cells to smoke condensates from burn pit waste materials. Single and repeated exposure to condensates triggered unique and common responses in terms of gene expression that were sustained through the recovery phase. Source material and combustion condition influenced the outcome. Intensified response in female donor cells indicated a determining role of biological sex. The observations indicate a lasting impact of burn pit smoke exposure on epithelial gene expression, potentially contributing to disease pathogenesis.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"2-8"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824503","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 effect of TiO2 nanoparticles on antral follicles is dependent on the nanoparticle internalization rate.","authors":"Ramsés Santacruz-Márquez, Luz Del Carmen Sánchez Peña, Jodi A Flaws, Isabel Hernández-Ochoa","doi":"10.1093/toxsci/kfae155","DOIUrl":"10.1093/toxsci/kfae155","url":null,"abstract":"<p><p>Titanium dioxide nanoparticles (TiO2 NPs) are among the most widely produced metallic NPs due to commercial and industrial applications in products including food, cosmetics, paints, and plastics. TiO2 NPs are released into the environment posing health risks for humans and wildlife. Widespread uses have raised concerns about the potential toxicity of TiO2 NPs in reproduction. The ovary is an important endocrine organ responsible for sex steroid hormone production and folliculogenesis. NPs can reach the ovary, but limited information is available regarding NP toxicity and its effects on ovarian antral follicles. Thus, we tested the hypothesis that exposure to TiO2 NP affects sex hormone synthesis, oxidative stress, and antioxidant response in ovarian antral follicles in vitro. In addition, we characterized the NP internalization in the antral follicles over time to determine any association between NP internalization and effects on the antral follicle. Antral follicles were exposed to vehicle control or TiO2 NPs (5, 25, and 50 µg/ml) for 96 h. The lowest NP concentration (5 µg/ml) showed no internalization and no effects in antral follicles. The 25-µg/ml concentration had the highest internalization rate, leading to increased mRNA ratio of Bax to Bcl2. Interestingly, the highest concentration (50 µg/ml) showed lower internalization compared with the 25 µg/ml, with altered levels of steroidogenic involved genes and increased levels of progesterone and testosterone compared with control. In conclusion, these data suggest that TiO2 NP is internalized in antral follicles as the first step process in impairing follicle functions.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"31-42"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814196","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":"An open source interactive physiologically based pharmacokinetic (iPBPK) model of tylosin in broiler chickens and laying hens.","authors":"Zhicheng Zhang, Melissa A Mercer, Lisa A Tell, Zhoumeng Lin","doi":"10.1093/toxsci/kfaf030","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf030","url":null,"abstract":"<p><p>Tylosin, a broad-spectrum macrolide antibiotic, is used to treat chronic respiratory infectious diseases in both urban and commercial broiler chickens and laying hens in an extra-label manner. To ensure food safety and facilitate extra-label withdrawal interval (WDI) estimations, a physiologically based pharmacokinetic (PBPK) model for tylosin in broiler chickens and laying hens was developed. The model structure encompassed plasma, crop, gizzard, small intestine, colon, muscle, liver, kidney, fat, rest of body, and an integrated reproductive system consisting of the ovary and oviduct (for hens). This model adequately predicted the pharmacokinetics of tylosin in plasma, tissues, egg yolk and white under different scenarios in both broilers and layers with determination coefficients of 0.87 and 0.78, respectively. The model was converted to a user-friendly web-based interface. The estimated WDIs were 2.0, 3.0, 4.0, 2.0, and 2.0 days for eggs, kidney, liver, muscle, and fat, respectively, based on FDA tolerance after daily oral administration at 110 mg/kg tylosin via medicated water for five consecutive days in laying hens. This model provides a useful and flexible tool for food safety assessment of tylosin in chickens and lays the groundwork for extrapolating to other drugs in other poultry species.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558139","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":"Impact of exposure to a mixture of organophosphate esters on the adrenal glands of Sprague Dawley rats.","authors":"Zixuan Li, Barbara F Hales, Bernard Robaire","doi":"10.1093/toxsci/kfae154","DOIUrl":"10.1093/toxsci/kfae154","url":null,"abstract":"<p><p>There is growing evidence that organophosphate esters (OPEs) can act as endocrine-disrupting chemicals. However, only a few studies have assessed the effects of OPE exposure on one of the most important endocrine glands in the body, the adrenal gland. Our aim was to test the effects of a mixture of OPEs detected in Canadian house dust on adrenal function in Sprague Dawley rats. Adult male and female rats (n = 15 per treatment group) were administered either a vehicle or an OPE mixture (0.048, 1.6, or 48 mg/kg bw/d) for 70 to 72 d via their diet. With OPE exposure, adrenal glands from male adult rats were reduced in weight, whereas those of female rats showed an increase in weight. This led us to investigate whether OPEs induce sex-specific effects on adrenal gland function and the mechanisms involved. Serum levels of two adrenal hormones, aldosterone and corticosterone, were decreased only in male serum samples. Serum levels of renin and adrenocorticotropic hormone, which regulate aldosterone and corticosterone synthesis, respectively, were assessed. Exposure to the OPE mixture decreased renin levels only in males. Serum biochemistry analysis revealed that triglycerides and LDL cholesterol levels were increased in males. Transcriptomic analysis revealed that the top affected pathways in male adrenal glands from all three treatment groups were related to potassium channels, which play a role in regulating aldosterone and corticosterone levels. The most affected pathways in female adrenal glands were related to cholesterol biosynthesis and immune functions. These results show that an environmentally relevant mixture of OPEs affects adrenal function and that these effects are sex specific.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"43-56"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807625","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":"Inhaled ozone induces distinct alterations in pulmonary function in models of acute and episodic exposure in female mice.","authors":"Jordan M Lee, Jaclynn A Meshanni, Kinal N Vayas, Vasanthi R Sunil, Jared Radbel, Jeffrey D Laskin, Debra L Laskin, Andrew J Gow","doi":"10.1093/toxsci/kfae162","DOIUrl":"10.1093/toxsci/kfae162","url":null,"abstract":"<p><p>Ozone is an urban air pollutant known to cause lung injury and altered function. Using established models of acute (0.8 ppm, 3 h) and episodic (1.5 ppm, 2 h, 2 times/wk, 6 wk) inhalation exposure, we observed distinct structural changes in the lung; whereas acutely, ozone primarily disrupts the bronchiolar epithelial barrier, episodic exposure causes airway remodeling. Herein we examined how these responses altered pulmonary function. A SCIREQ small animal ventilator was used to assess lung function; impedance was used to conditionally model resistance and elastance. Episodic, but not acute ozone exposure reduced the inherent and frequency-dependent tissue recoil (elastance) of the lung. Episodic ozone also increased central and high-frequency resistance relative to air control after methacholine challenge, indicating airway hyperresponsiveness. Pressure-volume (PV)-loops showed that episodic ozone increased maximum lung volume, whereas acute ozone decreased lung volume. Episodic ozone-induced functional changes were accompanied by increases in alveolar circularization; conversely, minimal histopathology was observed after acute exposure. However, acute ozone exposure caused increases in total phospholipids, total surfactant protein D (SP-D), and low-molecular weight SP-D in bronchoalveolar lavage fluid. Episodic ozone exposure only increased total SP-D. These findings demonstrate that acute and episodic ozone exposure caused distinct alterations in surfactant composition and pulmonary function. Whereas loss in PV-loop area following acute ozone exposure is likely driven by increases in SP-D and inflammation, emphysematous pathology and airway hyperresponsiveness after episodic ozone appear to be the result of alterations in lung structure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"70-78"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972039","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":"Investigation of Urinary miRNA Profile Changes in Amphotericin B-Induced Nephrotoxicity in C57BL/6 Mouse, Sprague-Dawley Rats and Beagle Dogs.","authors":"Adeyemi O Adedeji, Michael R Tackett, Genesis Tejada, James E McDuffie","doi":"10.1093/toxsci/kfaf029","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf029","url":null,"abstract":"<p><p>MicroRNA (miRNAs) have been associated with drug-induced kidney injury (DIKI). However, there are few reports on the utility of miRNAs, when monitoring for nephrotoxicity across multiple species. The purpose of this study was to assess the value of urinary miRNA profile changes as renal safety biomarkers, when monitoring for kidney injury in investigative toxicology studies. To this end, we evaluated urine miRNA expression levels in response to amphotericin B (AmpB-induced nephrotoxicity in mice, rats and dogs. The results showed that 35 miRNAs were significantly differentially expressed across the three species in response to the induced renal injuries. Dogs showed the highest number of miRNAs with significant changes. miR-205-5p and miR-31-5p were the most consistently altered miRNA biomarkers across all three species. In rodents, these two miRNAs were the most sensitive markers and showed comparable or better sensitivities than the previously published urine protein biomarkers with the same nephrotoxicant. In dogs, none of the upregulated miRNAs were as sensitive as urine clusterin protein as observed in a previously published study with AmpB. Taken together, these miRNAs could complement the more established urinary protein biomarkers in monitoring DIKI in mice, rats and dogs. To our knowledge, this is the first report that demonstrates the comparative utility of urinary miRNAs for the early detection of DIKI across three nonclinical animal models.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558059","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":"Modeling the developing nervous system: a neuroscience perspective on the use of NAMs in DNT testing.","authors":"Andrew J Newell, Heather B Patisaul","doi":"10.1093/toxsci/kfaf028","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf028","url":null,"abstract":"<p><p>There is widespread concern that environmental exposures constitute an underappreciated but significant contribution to rising rates of neurodevelopmental disorders (NDDs). There is also international consensus that regulatory frameworks for developmental neurotoxicity (DNT) testing are woefully inadequate, prompting reappraisal of DNT testing methods. One approach aims to make testing more efficient, less animal-intensive, and higher throughput, through in vitro evaluation of DNT. These new approach methodologies (NAMs) promise to accelerate and standardize DNT testing through interrogation of fundamental mechanisms of neurodevelopment. While in the early stages of development, they have significant, well-publicized shortcomings, including little to no accounting for cellular or genetic diversity, cell extrinsic signaling molecules, sex as a biological variable, developmental stage, or relevance to NDDs. One of the most advanced NAM platforms is a collection of 17 in vitro assays termed the DNT in vitro battery (IVB). While it models some aspects of neurodevelopmental processes, it fails to capture others. Proper brain ontogeny, and consequently normal behavior and cognition, relies on the integrity of fundamental mechanisms, their temporal/spatial fidelity, and the magnitude of their expression. These fundamental mechanisms are regulated by factors not considered by the DNT IVB including diverse cell types and neurotransmitters. While the DNT IVB could prove to be an important tool in DNT hazard detection, we identify key areas, including cell-extrinsic neurotransmitter signaling, diversity of neural progenitors, interneurons, and biological sex, that should be prioritized for development and inclusion in future refinements to meaningfully enhance biological coverage and relevance to human cognition and behavior.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558060","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}