Toxicological Sciences最新文献

{"title":"Diet-induced obesity alters the ovarian chemical biotransformation and oxidative stress response proteins both basally and in response to 7,12-dimethylbenz[a]anthracene exposure.","authors":"Kelsey Timme, Imaobong Inyang, Hunter E White, Aileen F Keating","doi":"10.1093/toxsci/kfae150","DOIUrl":"10.1093/toxsci/kfae150","url":null,"abstract":"<p><p>7,12-Dimethylbenz[a]anthracene (DMBA) is a polycyclic aromatic hydrocarbon that causes female infertility via DNA damage, and the ovary has the capacity to mitigate DMBA exposure via the action of proteins including the glutathione S-transferase (GST) family. Due to previous findings of DNA damage and a reduced ovarian chemical biotransformation response to DMBA exposure in hyperphagia-induced obese mice, this study investigated the hypothesis that diet-induced obesity would hamper the ovarian biotransformative response to DMBA exposure. Six-week-old C57BL6/J mice were fed either a normal rodent diet (L) or a high fat high sucrose diet (O) until the O group was ∼30% heavier than the L. Both L and O mice were exposed to either corn oil (C) or DMBA (1 mg/kg) for 7 d. Liver weight was increased (P < 0.05) in obese mice exposed to DMBA but no effect on spleen weight, uterine weight, ovary weight, estrous cyclicity, or circulating 17β-estradiol and progesterone were observed. Primordial and preantral follicle numbers were higher (P < 0.05) in the obese mice and there was a tendency (P = 0.055) for higher antral follicles in DMBA-exposed obese mice. The ovarian proteome was identified by LC-MS/MS analysis to be altered both by diet-induced obesity and by DMBA exposure with changes observed in levels of proteins involved in oocyte development and chemical biotransformation, including GST isoform pi. Fewer proteins were affected by the combined exposure of diet and DMBA than by a single treatment, indicating that physiological status impacts the response to DMBA exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"9-19"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256822","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":"Advancing systemic toxicity risk assessment: Evaluation of a NAM-based toolbox approach.","authors":"Sophie Cable, Maria Teresa Baltazar, Fazila Bunglawala, Paul L Carmichael, Leonardo Contreas, Matthew Philip Dent, Jade Houghton, Predrag Kukic, Sophie Malcomber, Beate Nicol, Katarzyna R Przybylak, Ans Punt, Georgia Reynolds, Joe Reynolds, Sharon Scott, Dawei Tang, Alistair M Middleton","doi":"10.1093/toxsci/kfae159","DOIUrl":"10.1093/toxsci/kfae159","url":null,"abstract":"<p><p>For many years, a method that allowed systemic toxicity safety assessments to be conducted without generating new animal test data, seemed out of reach. However, several different research groups and regulatory authorities are beginning to use a variety of in silico, in chemico, and in vitro techniques to inform safety decisions. To manage this transition to animal-free safety assessments responsibly, it is important to ensure that the level of protection offered by a safety assessment based on new approach methodologies (NAMs), is at least as high as that provided by a safety assessment based on traditional animal studies. To this end, we have developed an evaluation strategy to assess both the level of protection and the utility offered by a NAM-based systemic safety \"toolbox.\" The toolbox comprises physiologically based kinetic models to predict internal exposures, and bioactivity NAMs designed to give broad coverage across many different toxicity modes of action. The output of the toolbox is the calculation of a bioactivity:exposure ratio (analogous to a margin of internal exposure), which can be used to inform decision-making. In this work, we have expanded upon an initial pilot study of 10 chemicals with an additional 38 chemicals and 70 consumer exposure scenarios. We found that, for the majority of these (>90%), the NAM-based workflow is protective of human health, enabling us to make animal-free safety decisions for systemic toxicity and preventing unnecessary animal use. We have also identified critical areas for improvement to further increase our confidence in the robustness of the approach.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"79-95"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847994","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":"Reader comment on: \"Comprehensive genotoxicity and carcinogenicity assessment of molnupiravir\".","authors":"Clay B Frederick, Raymond F Schinazi, Ronald Swanstrom","doi":"10.1093/toxsci/kfae156","DOIUrl":"10.1093/toxsci/kfae156","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"116-117"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847601","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":"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":"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":"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":"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":"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}