Toxicological Sciences最新文献_第3页

An FDA/CDER nonclinical perspective on the use of hiPSC-CM data for cardiovascular safety assessment and regulatory decisions. FDA/CDER对使用hiPSC-CM数据进行心血管安全性评估和监管决策的非临床观点

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-08 DOI: 10.1093/toxsci/kfaf064

Natalie E Simpson, Todd Bourcier, Nakissa Sadrieh

{"title":"An FDA/CDER nonclinical perspective on the use of hiPSC-CM data for cardiovascular safety assessment and regulatory decisions.","authors":"Natalie E Simpson, Todd Bourcier, Nakissa Sadrieh","doi":"10.1093/toxsci/kfaf064","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf064","url":null,"abstract":"Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a New Approach Methodology (NAM) used in regulatory submissions to the U.S Food and Drug Administration (FDA). This article builds on the previous FDA analysis using a new search strategy to provide an updated landscape of hiPSC-CM studies submitted to the FDA for review. The current search method is more comprehensive than the previous ones, emphasizing the importance of standardized keywords in study titles for easier identification of NAMs submitted to FDA. Here the authors report an increase in hiPSC-CM studies submitted to FDA, with most using the multielectrode array (MEA) platform. In this new analysis, the authors observed that the study methodology, context of use (COU), and reasons for submission are often unclear, despite their importance for regulatory acceptance and review. hiPSC-CM study results are not discussed in many archived reviews, suggesting limited impact on regulatory decisions. Detailed reporting to characterize the clinical relevance of findings and systematic submission of hiPSC-CM studies to better understand their predictivity compared to familiar nonclinical assessment methods are key components from a Pharmacology/Toxicology perspective to increase regulatory use of this subset of NAMs.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027977","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}

引用次数: 0

4-Methylpyrazole-mediated inhibition of Cytochrome P450 2E1 protects renal epithelial cells, but not bladder cancer cells, from cisplatin toxicity. 4-甲基吡唑介导的细胞色素P450 2E1抑制可保护肾上皮细胞，但不能保护膀胱癌细胞免受顺铂毒性的影响。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-05 DOI: 10.1093/toxsci/kfaf053

Jephte Y Akakpo, Erika Abbott, Benjamin L Woolbright, Anup Ramachandran, Rick G Schnellmann, Darren P Wallace, John A Taylor

{"title":"4-Methylpyrazole-mediated inhibition of Cytochrome P450 2E1 protects renal epithelial cells, but not bladder cancer cells, from cisplatin toxicity.","authors":"Jephte Y Akakpo, Erika Abbott, Benjamin L Woolbright, Anup Ramachandran, Rick G Schnellmann, Darren P Wallace, John A Taylor","doi":"10.1093/toxsci/kfaf053","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf053","url":null,"abstract":"Cisplatin is an effective chemotherapeutic drug for the treatment of bladder cancer, though cisplatin-induced nephrotoxicity (CIN) occurs in approximately 20-30% of patients, limiting its clinical use. Evidence has shown that cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme expressed in proximal tubules, mediates the production of reactive oxygen species (ROS) during cisplatin-induced injury. Previously, we showed that the repurposed drug 4-methylpyrazole (4MP) blocks CYP2E1 activity. Here, we investigated the potential protective effects of 4MP against CIN. Male and female C57BL/6J mice were treated intraperitoneally (ip.) with a single 20 mg/kg dose of cisplatin for 3 days or 9 mg/kg/week for 4 weeks with or without 50 mg/kg 4MP as a co-treatment. Our findings revealed that acute treatment with cisplatin induced severe histological tubular damage and elevated plasma BUN and creatinine levels in male but not female mice. This difference correlated with higher basal CYP2E1 expression in the kidneys of male mice compared to female mice. We also found that cisplatin increased renal CYP2E1 activity and that inhibition of CYP2E1 with 4MP significantly reduced cisplatin induced cell death in male mice and primary normal human kidney cells. By contrast, human bladder cancer cells do not express CYP2E1, and treatment with 4MP did not interfere with cisplatin's anti-cancer effects in human bladder cancer HTB9 cells. This study highlights the critical role of CYP2E1 in CIN and suggests that its inhibition with 4MP in the kidney is a potential prophylactic therapeutic option to prevent CIN in bladder cancer patients without affecting its anti-neoplastic effect.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988126","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}

引用次数: 0

Exposure to phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial hyperplasia in mice. 暴露于邻苯二甲酸酯增强雌激素和β -连环蛋白信号通路，导致小鼠子宫内膜增生。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-05 DOI: 10.1093/toxsci/kfaf062

Ritwik Shukla, Athilakshmi Kannan, Mary J Laws, Amy Wagoner Johnson, Jodi A Flaws, Milan K Bagchi, Indrani C Bagchi

{"title":"Exposure to phthalates enhances estrogen and beta-catenin signaling pathways, leading to endometrial hyperplasia in mice.","authors":"Ritwik Shukla, Athilakshmi Kannan, Mary J Laws, Amy Wagoner Johnson, Jodi A Flaws, Milan K Bagchi, Indrani C Bagchi","doi":"10.1093/toxsci/kfaf062","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf062","url":null,"abstract":"Phthalates, synthetic chemicals widely utilized as plasticizers and stabilizers in various consumer products, present a significant concern due to their persistent presence in daily human life. While past research predominantly focused on individual phthalates, real-life human exposure typically encompasses complex mixtures of these compounds. The cumulative effects of prolonged exposure to phthalate mixtures on uterine health remain poorly understood. To address this knowledge gap, we conducted studies utilizing adult female mice exposed chronically to a mixture of phthalates for 12 months through ad libitum chow consumption. Our studies revealed that continuous exposure to this phthalate mixture led to uterine hyperplasia with a significant increase in gland-to-stroma ratio. Endometrial hyperplasia is commonly caused by heightened estrogenic action and inflammatory response in the uterus, leading to increased proliferation of endometrial epithelial cells. Indeed, we observed a marked upregulation of several known estrogen-regulated genes, pro-inflammatory chemokines, elevated homing of macrophages, and increased KI67 staining in the endometrial epithelial cells upon phthalate exposure. Several signaling pathways, including the MAPK/ERK and Wnt/β-Catenin pathways, promote cell proliferation, leading to the hyperproliferative state of the endometrial cells. Our studies revealed no alteration of the MAPK/ERK pathway but a marked enhancement of the Wnt/β-Catenin signaling pathway in phthalate-exposed uteri. Collectively, this study underscores the significance of understanding the exposure to environmental factors in the pathogenesis of endometrial disorders.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035684","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}

引用次数: 0

Developmental exposure to 1,4-dioxane, a volatile organic compound of emerging concern, induces immediate phenotypic, transcriptomic, and adult-onset neurodevelopmental effects. 发展暴露于1,4-二氧六环，一种新兴关注的挥发性有机化合物，诱导立即表型，转录组和成人发病的神经发育效应。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-05 DOI: 10.1093/toxsci/kfaf063

Mackenzie L Connell, Camille Akemann, Chia-Chen Wu, Emily Kintzele, Emma Cavaneau, Gabrielle F Gonzalez, Bridget B Baker, Tracie R Baker

{"title":"Developmental exposure to 1,4-dioxane, a volatile organic compound of emerging concern, induces immediate phenotypic, transcriptomic, and adult-onset neurodevelopmental effects.","authors":"Mackenzie L Connell, Camille Akemann, Chia-Chen Wu, Emily Kintzele, Emma Cavaneau, Gabrielle F Gonzalez, Bridget B Baker, Tracie R Baker","doi":"10.1093/toxsci/kfaf063","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf063","url":null,"abstract":"1,4-dioxane, a synthetic volatile organic compound (VOC), has been found in products including paints, cosmetics, and pesticides as well as food products and drinking water. Contamination in groundwater poses significant environmental and public health risks due to its high mobility and widespread human exposure through vapor intrusion and multi-route exposure pathways. Adverse health effects have been observed as a result of exposure to this compound; however, there is little research on the developmental and reproductive effects. Controlled VOC exposures (0.004, 0.40, and 40 parts per million (ppm)) of zebrafish embryos were conducted in sealed glass vials over a developmental period (120 hours). Endpoints evaluated were mortality, abnormalities, larval behavior, transcriptomics, and adult-onset effects. The behavior of zebrafish larvae was significantly altered for the 40 ppm group. Expression of key genes (insig1, tbc1d10aa) were observed immediately following exposure and some persisted into adulthood. The top dysregulated diseases and disorders pathways in every concentration were cancer, organismal injury and abnormality, endocrine system disorders, gastrointestinal disease, and neurological disorders. Pathways of note enriched in larval and adult tissues include endocrine gland tumorigenesis, insulin resistance, movement disorders, cell survival, and cellular homeostasis. Specific reproductive pathways included pelvic, genital, uterine, and mammary tumors and carcinomas, however, there was no significant effect on adult zebrafish fertility. This study moves the field forward by integrating a novel zebrafish model and lifespan approach shedding new light on understudied implications of low-level VOC exposure, ultimately informing public health policies to mitigate the risks associated with this ubiquitous environmental contaminant.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049192","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}

引用次数: 0

Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies. 在小鼠和食蟹猴毒理学研究中，tgf - β2,3的双重抑制是严重毒性的，而tgf - β1,2或3的选择性抑制和tgf - β1,2的双重抑制通常是耐受的。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-02 DOI: 10.1093/toxsci/kfaf060

Mayur S Mitra, Wendy Halpern, Michelle Lepherd, Janice Corpuz, Adeyemi O Adedeji, Rajbharan Yadav, Isabel Duarte, Tianhe Sun, Joseph R Arron, Shannon J Turley, Wei-Ching Liang, Yan Wu

{"title":"Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies.","authors":"Mayur S Mitra, Wendy Halpern, Michelle Lepherd, Janice Corpuz, Adeyemi O Adedeji, Rajbharan Yadav, Isabel Duarte, Tianhe Sun, Joseph R Arron, Shannon J Turley, Wei-Ching Liang, Yan Wu","doi":"10.1093/toxsci/kfaf060","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf060","url":null,"abstract":"The transforming growth factor-β (TGFβ) cytokine family, which comprises three pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer and fibrosis. The role of TGFβ in disease is well established and efforts to develop therapies via inhibition of the three isoforms and their receptors have been pursued for decades. Unfortunately, progress in this pursuit has been limited as complete inhibition of the TGFβ signaling pathway using small molecule inhibitors of TGFβ receptor or following administration of potent pan-TGFβ (inhibiting TGFβ1, TGFβ2, and TGFβ3) neutralizing monoclonal antibodies (mAb) has been associated with adverse toxicities including cardiac valvulopathies, hemorrhage, and anemia in nonclinical toxicology species. Here we have evaluated the toxicities associated with selective inhibition of individual (TGFβ1 alone, TGFβ2 alone, or TGFβ3 alone) or dual (TGFβ1,2 or TGFβ2,3) TGFβ isoforms in mice and/or cynomolgus monkeys using mAbs targeted against these isoforms. Our data show that dual inhibition of TGFβ2,3 resulted in adverse toxicities in several organs, including cardiovascular toxicity. However, selective isoform-specific inhibition of TGFβ1, 2, or 3 is generally tolerated and devoid of adverse toxicities in nonclinical toxicology studies. Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb that is currently in Phase 1 clinical trials, was well tolerated in GLP mouse and cynomolgus monkey toxicology studies and the RO7303509-related effects were limited to non-adverse histopathologic findings in the teeth and injection-site reactions. In conclusion, inhibition of TGFβ in an isoform-specific manner is generally safe in nonclinical toxicology species and could be explored for therapeutic intervention.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982047","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}

引用次数: 0

Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies. 在小鼠和食蟹猴毒理学研究中，tgf - β2,3的双重抑制是严重毒性的，而tgf - β1,2或3的选择性抑制和tgf - β1,2的双重抑制通常是耐受的。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-02 DOI: 10.1093/toxsci/kfaf059

Mayur S Mitra, Wendy Halpern, Michelle Lepherd, Janice Corpuz, Adeyemi O Adedeji, Rajbharan Yadav, Isabel Duarte, Tianhe Sun, Joseph R Arron, Shannon J Turley, Wei-Ching Liang, Yan Wu

{"title":"Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies.","authors":"Mayur S Mitra, Wendy Halpern, Michelle Lepherd, Janice Corpuz, Adeyemi O Adedeji, Rajbharan Yadav, Isabel Duarte, Tianhe Sun, Joseph R Arron, Shannon J Turley, Wei-Ching Liang, Yan Wu","doi":"10.1093/toxsci/kfaf059","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf059","url":null,"abstract":"The transforming growth factor-β (TGFβ) cytokine family, which comprises three pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer and fibrosis. The role of TGFβ in disease is well established and efforts to develop therapies via inhibition of the three isoforms and their receptors have been pursued for decades. Unfortunately, progress in this pursuit has been limited as complete inhibition of the TGFβ signaling pathway using small molecule inhibitors of TGFβ receptor or following administration of potent pan-TGFβ (inhibiting TGFβ1, TGFβ2, and TGFβ3) neutralizing monoclonal antibodies (mAb) has been associated with adverse toxicities including cardiac valvulopathies, hemorrhage, and anemia in nonclinical toxicology species. Here we have evaluated the toxicities associated with selective inhibition of individual (TGFβ1 alone, TGFβ2 alone, or TGFβ3 alone) or dual (TGFβ1,2 or TGFβ2,3) TGFβ isoforms in mice and/or cynomolgus monkeys using mAbs targeted against these isoforms. Our data show that dual inhibition of TGFβ2,3 resulted in adverse toxicities in several organs, including cardiovascular toxicity. However, selective isoform-specific inhibition of TGFβ1, 2, or 3 is generally tolerated and devoid of adverse toxicities in nonclinical toxicology studies. Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb that is currently in Phase 1 clinical trials, was well tolerated in GLP mouse and cynomolgus monkey toxicology studies and the RO7303509-related effects were limited to non-adverse histopathologic findings in the teeth and injection-site reactions. In conclusion, inhibition of TGFβ in an isoform-specific manner is generally safe in nonclinical toxicology species and could be explored for therapeutic intervention.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050164","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}

引用次数: 0

Incorporating Metabolic Competence into High-Throughput Profiling Assays. 将代谢能力纳入高通量分析分析。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-02 DOI: 10.1093/toxsci/kfaf061

Amanda Jurgelewicz, Kristen Breaux, Clinton M Willis, Felix R Harris, Gabrielle Byrd, Joshua Witten, Derik E Haggard, Joseph L Bundy, Logan J Everett, Chad Deisenroth, Joshua A Harrill

{"title":"Incorporating Metabolic Competence into High-Throughput Profiling Assays.","authors":"Amanda Jurgelewicz, Kristen Breaux, Clinton M Willis, Felix R Harris, Gabrielle Byrd, Joshua Witten, Derik E Haggard, Joseph L Bundy, Logan J Everett, Chad Deisenroth, Joshua A Harrill","doi":"10.1093/toxsci/kfaf061","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf061","url":null,"abstract":"High-throughput profiling assays such as high-throughput phenotypic profiling (HTPP) with Cell Painting and high-throughput transcriptomics (HTTr) with TempO-SeqTM have been used to characterize the bioactivity and potential hazards associated with large inventories of chemicals. Although both methods offer broad coverage of molecular targets, a limitation is that the cell types used in these in vitro assays typically lack the xenobiotic metabolism capabilities of humans or laboratory animals used for in vivo testing. To address this limitation, this proof-of-concept study coupled the Alginate Immobilization of Metabolic Enzymes (AIME) platform to both assays and evaluated the impact of metabolism on chemical bioactivity in a breast cancer cell line, VM7Luc4E2. HTPP detected concentration-dependent increases in chemical bioactivity corresponding to increased estrogen receptor (ER) activation measured using an ER transactivation assay (ERTA) that had been previously coupled to the AIME platform in VM7Luc4E2 cells. Additionally, HTTr detected a greater number of active genes in the metabolic condition associated with increased ER activation. This corresponded to a greater number of active ER high-confidence (ERHC) gene signatures and/or metabolism-induced shifts in ERHC signature enrichment as a transcriptomic readout of ER activity. This study demonstrates that the high-throughput profiling assays can detect changes in chemical bioactivity between parent compounds and metabolites generated using the AIME platform in a reproducible way. Incorporating metabolic competence into high-throughput profiling assays will better inform next generation risk assessment by capturing potential metabolite-based changes in bioactivity of test chemicals that may be missed by current screening approaches.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027642","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}

引用次数: 0

Mixed lineage kinase domain-like protein deficiency exacerbates early injury in a mouse model of acetaminophen hepatotoxicity. MLKL缺乏加剧了对乙酰氨基酚肝毒性小鼠模型的早期损伤。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-01 DOI: 10.1093/toxsci/kfaf022

Giselle Sanchez-Guerrero, David S Umbaugh, Sawyer H Smith, Jephte Y Akakpo, Hartmut Jaeschke, Anup Ramachandran

{"title":"Mixed lineage kinase domain-like protein deficiency exacerbates early injury in a mouse model of acetaminophen hepatotoxicity.","authors":"Giselle Sanchez-Guerrero, David S Umbaugh, Sawyer H Smith, Jephte Y Akakpo, Hartmut Jaeschke, Anup Ramachandran","doi":"10.1093/toxsci/kfaf022","DOIUrl":"10.1093/toxsci/kfaf022","url":null,"abstract":"An overdose of acetaminophen (APAP) is the leading cause of drug-induced hepatotoxicity and acute liver failure in the United States. It is established that the predominant mode of hepatocyte cell death after an APAP overdose is through necrosis, and it is now recognized that this occurs through regulated pathways involving RIP kinases. These kinases, along with the pseudo-kinase MLKL, are central players in classical necroptotic cell death. Despite the skepticism regarding the role of necroptosis in APAP-induced liver injury, recent research demonstrating necroptosis-independent roles for MLKL led us to re-examine the role of this pseudo-kinase in APAP pathophysiology. Treatment of Mlkl-/- mice with a moderate (300 mg/kg) overdose of APAP resulted in an exacerbation of liver injury at 6- and 12-h post-APAP as evidenced by elevated plasma alanine aminotransferase activities, and extensive necrosis accompanied by diminished glutathione levels. Interestingly, these differences between Mlkl-/- and wild-type mice were negated at the 24-h mark, previously scrutinized by others. At 6 and 12 h post-APAP, Mlkl-/- mice exhibited augmented translocation of AIF and Endonuclease G without affecting JNK activation, suggesting enhanced mitochondrial permeability transition in the absence of MLKL. Lack of MLKL also impacted autophagy, the unfolded protein response and endoplasmic reticulum stress, with decreased levels of p62 and LC3B and increased expression of CHOP and GRP78 at 6 h post-APAP. In essence, our findings illuminate a noncanonical role for MLKL in the early phases of APAP-induced liver injury, warranting further exploration of its influence on APAP pathophysiology.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"220-232"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477040","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}

引用次数: 0

Distribution of perfluorooctanoic acid in exposed female postpubertal pigs in thermal neutral or heat-stressed conditions. 全氟辛酸在热中性或热应激条件下暴露的雌性青春期后猪体内的分布。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-01 DOI: 10.1093/toxsci/kfaf013

Samantha L Good, Collins Antwi-Boasiako, M Estefanía González-Alvarez, Bridget M Buol, Lance H Baumgard, Aileen F Keating, Joseph A Charbonnet

{"title":"Distribution of perfluorooctanoic acid in exposed female postpubertal pigs in thermal neutral or heat-stressed conditions.","authors":"Samantha L Good, Collins Antwi-Boasiako, M Estefanía González-Alvarez, Bridget M Buol, Lance H Baumgard, Aileen F Keating, Joseph A Charbonnet","doi":"10.1093/toxsci/kfaf013","DOIUrl":"10.1093/toxsci/kfaf013","url":null,"abstract":"Perfluorooctanoic acid (PFOA), a legacy perfluoroalkyl substance with immuno- and repro-toxicant effects, has poorly characterized bioaccumulation and distribution patterns in postpubertal female pigs. The potential for heat stress (HS) to influence PFOA partitioning, potentially through intestinal hyperpermeability and alterations in systemic blood flow, also warrants investigation. This study investigated PFOA uptake, accumulation, and distribution in thermal neutral (TN) and heat-stressed gilts. Pigs (n = 48) were estrus synchronized and experienced TN (20 °C) or HS (26.6 to 32.2 °C) conditions during which they consumed 70 ng/kg bodyweight PFOA via cookie dough as vehicle control daily. Plasma was collected on d 1, 15, and 20. Liver, ovary, and follicular fluid were collected at euthanasia (d 20). Post-exposure, PFOA was detected in serum, liver, ovary, and follicular fluid. HS increased (P < 0.05) plasma PFOA compared with TN pigs on d 15, but on d 20, plasma PFOA levels in TN and HS pigs were similar. Liver PFOA concentrations were similar between TN and HS pigs. Ovarian PFOA levels tended (P = 0.06) to be higher in TN relative to HS pigs, with an opposing pattern in follicular fluid, in which PFOA concentrations were greater (P < 0.05) in HS pigs. These findings suggest that PFOA apportions to plasma, liver, ovary, and follicular fluid of exposed pigs and that HS alters PFOA distribution, which could negatively impact reproductive health. This study underscores the need to consider the interaction of HS and toxicant exposure in environmental health risk assessments.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"143-153"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122679","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}

引用次数: 0

Effects of dopamine agonists on the estradiol-induced prolactin surge in ovariectomized female Wistar Han rats. 多巴胺激动剂对去卵巢雌性Wistar Han大鼠雌二醇诱导的催乳素激增的影响。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-01 DOI: 10.1093/toxsci/kfaf027

Atish Patel, Travis L Calkins, Justin D Vidal, Pragati S Coder, Scott Carrier, Giri Gokulrangan, Ananth Srinivas R Chakilam, Sandeep Akare, Richard J Briscoe, Madhu S Mondal

{"title":"Effects of dopamine agonists on the estradiol-induced prolactin surge in ovariectomized female Wistar Han rats.","authors":"Atish Patel, Travis L Calkins, Justin D Vidal, Pragati S Coder, Scott Carrier, Giri Gokulrangan, Ananth Srinivas R Chakilam, Sandeep Akare, Richard J Briscoe, Madhu S Mondal","doi":"10.1093/toxsci/kfaf027","DOIUrl":"10.1093/toxsci/kfaf027","url":null,"abstract":"Dopamine agonists (DAs) are approved for the treatment of hypodopaminergic pathologies, including Parkinson's disease, restless legs syndrome, and periodic limb movement disorder. During drug development, drugs acting on dopaminergic receptors are often associated with a rat-specific endocrine tumor response, including changes in fertility, which are ascribed to DA-induced suppression of pituitary prolactin release. Although these effects are not observed in or relevant to humans, given species differences in the effects of prolactin on reproductive organs, modeling DA-mediated changes in prolactin and the reproductive system remains important for preclinical drug development. We investigated the effects of 2 D2/D3 DAs, pergolide and rotigotine, on the estradiol (E2)-induced prolactin surge in ovariectomized (OVX) female Wistar Han rats. Daily treatment with DAs over 7 days led to a reduction in the prolactin surge in E2-implanted OVX rats. Specifically, pergolide induced a significant decrease in prolactin levels at all time points compared with the OVX-E2 control group. Similarly, rotigotine dose-dependently suppressed plasma prolactin levels compared with the OVX-E2 control group. This study demonstrates the utility of the OVX rat model in evaluating the effects of DAs on the E2-induced prolactin surge. These results support the use of rotigotine, a DA with a long history of safe human use without significant endocrine-related adverse events, as a positive control at a dose level of 5.0 mg/kg/day for future nonclinical toxicity studies investigating the effects of novel DAs on reproductive hormones in rats.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"65-73"},"PeriodicalIF":3.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606431","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}

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