Toxicological Sciences最新文献_第2页

Mixtures of phthalates disrupt expression of genes related to lipid metabolism and peroxisome proliferator-activated receptor signaling in mouse granulosa cells. 邻苯二甲酸盐混合物会干扰小鼠颗粒细胞中与脂质代谢和过氧化物酶体增殖激活受体信号转导有关的基因的表达。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-11-01 DOI: 10.1093/toxsci/kfae105

Hanin Alahmadi, Stephanie Martinez, Rivka Farrell, Rafiatou Bikienga, Nneka Arinzeh, Courtney Potts, Zhong Li, Genoa R Warner

{"title":"Mixtures of phthalates disrupt expression of genes related to lipid metabolism and peroxisome proliferator-activated receptor signaling in mouse granulosa cells.","authors":"Hanin Alahmadi, Stephanie Martinez, Rivka Farrell, Rafiatou Bikienga, Nneka Arinzeh, Courtney Potts, Zhong Li, Genoa R Warner","doi":"10.1093/toxsci/kfae105","DOIUrl":"10.1093/toxsci/kfae105","url":null,"abstract":"Phthalates are a class of known endocrine-disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian function, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 h in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1 to 100 μg/ml). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways was confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary, but both interfere with PPAR signaling in granulosa cells.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"69-84"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992405","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

Defining VOC signatures of Airway Epithelial Cells with PM2.5 Exposure. 通过 PM2.5 暴露确定气道上皮细胞的挥发性有机化合物特征。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-30 DOI: 10.1093/toxsci/kfae141

Angela L Linderholm, Eva Borras, Katyayini Aribindi, Leilani L Jones, Dante E Rojas, Keith Bein, Mitchell M McCartney, Cristina E Davis, Richart W Harper, Nicholas J Kenyon

{"title":"Defining VOC signatures of Airway Epithelial Cells with PM2.5 Exposure.","authors":"Angela L Linderholm, Eva Borras, Katyayini Aribindi, Leilani L Jones, Dante E Rojas, Keith Bein, Mitchell M McCartney, Cristina E Davis, Richart W Harper, Nicholas J Kenyon","doi":"10.1093/toxsci/kfae141","DOIUrl":"https://doi.org/10.1093/toxsci/kfae141","url":null,"abstract":"Volatile organic compounds (VOCs) produced by the lung in response to exposure to environmental pollutants can be utilized to study their impact on lung health and function. Previously, we developed a method to measure VOCs emitted from well-differentiated tracheobronchial epithelial cells in vitro. Using this method, we exposed well-differentiated proximal (PECs) and distal airway epithelial cells (DECs) to varying doses of traffic-related air pollutants (TRAP) and wildfire particulates to determine specific VOC signatures after exposure. We utilized PM2.5 TRAP collected from the Caldecott tunnel in Oakland, CA and the 2018 Camp Fire to model \"real-life\" exposures. The VOCs were collected and extracted from Twisters and analyzed using gas chromatography-mass spectrometry (GC-MS). Exposure to both types of particulate matter (PM) resulted in specific VOC responses grouped by individual subjects with little overlap. Interestingly the VOCs produced by the PECs and DECs were also differentiated from each other. Our studies suggest that PM exposure induces a specific compartmentalized cellular response that can be exploited for future studies. This response is cell-type specific and potentially related to a phenotype we have yet to uncover.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547643","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

Development of a Physiologically Based Pharmacokinetic Model for Flunixin in Cattle and Swine Following Dermal Exposure. 针对牛和猪皮肤接触氟尼辛的生理药代动力学模型的开发。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-30 DOI: 10.1093/toxsci/kfae139

Xue Wu, Qiran Chen, Wei-Chun Chou, Fiona P Maunsell, Lisa A Tell, Ronald E Baynes, Jennifer L Davis, Majid Jaberi-Douraki, Jim E Riviere, Zhoumeng Lin

{"title":"Development of a Physiologically Based Pharmacokinetic Model for Flunixin in Cattle and Swine Following Dermal Exposure.","authors":"Xue Wu, Qiran Chen, Wei-Chun Chou, Fiona P Maunsell, Lisa A Tell, Ronald E Baynes, Jennifer L Davis, Majid Jaberi-Douraki, Jim E Riviere, Zhoumeng Lin","doi":"10.1093/toxsci/kfae139","DOIUrl":"https://doi.org/10.1093/toxsci/kfae139","url":null,"abstract":"Flunixin meglumine is a nonsteroidal anti-inflammatory drug (NSAID). Banamine® Transdermal is a pour-on formulation of flunixin approved for pain control in beef and dairy cattle, but not for calves and some classes of dairy cattle or swine. Violative flunixin residues in edible tissues in cattle and swine have been reported and are usually attributed to non-compliant drug use or failure to observe an appropriate withdrawal time. This project aimed to develop a physiologically based pharmacokinetic (PBPK) model for flunixin in cattle and swine to predict withdrawal intervals (WDI) after exposures to different therapeutic regimens of Banamine® Transdermal. Due to the lack of comprehensive skin physiological data in cattle, the model was initially developed for swine and then adapted for cattle. Monte Carlo simulation was employed for population variability analysis. The model predicted WDIs were rounded to 1 and 2 days for liver and muscle in cattle, respectively, under FDA tolerance levels, while under EU maximum residue limits (MRLs), the WDIs were rounded to 1, 3, 2, and 2 days for liver, kidney, muscle, and fat, respectively, following a labeled single transdermal 3.3 mg/kg dose in cattle. The model was converted into a user-friendly interactive PBPK (iPBPK) interface. This study reports the first transdermal absorption model for drugs in cattle. This iPBPK model provides a scientifically based tool for the prediction of WDIs in cattle and swine administered with flunixin in an extra-label manner, especially by the transdermal route.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547644","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

Health risk assessment of toxic metals and DNA damage in somatic and germ cells by soil and groundwater of a major cement factory in Nigeria. 尼日利亚一家大型水泥厂的土壤和地下水对有毒金属以及体细胞和生殖细胞 DNA 损伤的健康风险评估。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-30 DOI: 10.1093/toxsci/kfae140

Okunola A Alabi, Funmilayo E Ayeni, Tomiwa A Afolabi

{"title":"Health risk assessment of toxic metals and DNA damage in somatic and germ cells by soil and groundwater of a major cement factory in Nigeria.","authors":"Okunola A Alabi, Funmilayo E Ayeni, Tomiwa A Afolabi","doi":"10.1093/toxsci/kfae140","DOIUrl":"https://doi.org/10.1093/toxsci/kfae140","url":null,"abstract":"The waste generated from cement manufacturing is an important source of heavy metal contamination of groundwater and soil. This study investigated the concentration of toxic metals in the soil of a major cement factory and nearby groundwater. Ecological and carcinogenic risks of the metals were calculated. Potential reproductive toxicity and genotoxic effects of the samples were assessed in sex and somatic cells of male mice using sperm abnormalities and bone marrow micronucleus (MN) assays, respectively. Also, the serum ALP, ALT, AST, Total Testosterone (TT), Luteinizing Hormone (LH), and Follicle Stimulating Hormone (FSH); and liver SOD and CAT activities were measured in the treated mice. Cr, Cu, Ni, Zn, Mn, Cd, and Pb levels in the soil and groundwater exceeded the allowable maximum standard. Ingestion and dermal contact were the most probable routes of human exposure with children having about three times higher probability of exposure to the metals than the adults. Ni, Pb, and Cr presented carcinogenic risks in children and adults. In the MN result, nuclear abnormalities in the studied mice especially micronucleated polychromatic erythrocytes increased significantly (p < 0.05). Compared to the negative control, the ratio of PCE/NCE showed the cytotoxicity of the two samples. Data further showed a significant increase in the serum ALP, AST, and ALT while the liver CAT and SOD activities concomitantly decreased in the exposed mice. Sperm morphology result showed that the samples contained constituents capable of inducing reproductive toxicity in exposed organisms, with alterations to the concentrations of TT, LH, and FSH. Toxic metal constituents of the samples were believed to induce these reported reproductive toxicity and genotoxic effect. These results showed the environmental pollution caused by cement factory and the potential effects the pollutants might have on exposed eukaryotic organisms.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547645","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

Comment on: "microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis". 评论："狗和人类睾丸中的微塑料及其与精子数量、睾丸和附睾重量的潜在联系"。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-30 DOI: 10.1093/toxsci/kfae136

Rao M Uppu, Ir Willie Peijnenburg, Sean M Hays

引用次数: 0

The Impact of Neonicotinoid Pesticides on Reproductive Health. 新烟碱类杀虫剂对生殖健康的影响。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-26 DOI: 10.1093/toxsci/kfae138

Jadesola I Oladosu, Jodi A Flaws

{"title":"The Impact of Neonicotinoid Pesticides on Reproductive Health.","authors":"Jadesola I Oladosu, Jodi A Flaws","doi":"10.1093/toxsci/kfae138","DOIUrl":"https://doi.org/10.1093/toxsci/kfae138","url":null,"abstract":"Neonicotinoids are some of the most widely used insecticides in the world because they broadly target chewing and sucking insects. Neonicotinoids are used in commercial agricultural systems, sold for use in home gardens, and found in veterinary pharmaceuticals in the form of flea and tick preventatives for companion animals. They are also used as crop seed treatments and spread throughout crops as they mature. As a result, humans, wildlife, livestock, and pets are routinely exposed to neonicotinoids through consumption of contaminated food and water as well as through use of some veterinary pharmaceuticals. Although several studies indicate that neonicotinoid exposure causes genotoxicity, neurotoxicity, hepatotoxicity, and immunotoxicity in some non-target species, the impact of neonicotinoid pesticides on the male and female reproductive systems in mammals is largely understudied. This review summarizes current insights on the impact of common neonicotinoid pesticides such as acetamiprid, clothianidin, imidacloprid, and thiacloprid on male and female reproductive health in mammals. The review also summarizes the impacts of exposure to mixtures of neonicotinoids on reproductive endpoints. In addition, this review highlights where gaps in research on neonicotinoid pesticides and reproductive health exist so that future studies can be designed to fill current gaps in knowledge.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508640","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

Response to Comment on: "Microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis". 对有关评论的回应："狗和人类睾丸中的微塑料及其与精子数量、睾丸和附睾重量的潜在联系"。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-21 DOI: 10.1093/toxsci/kfae137

Chelin Jamie Hu, Marcus A Garcia, Alexander Nihart, Rui Liu, Lei Yin, Natalie Adolphi, Daniel F Gallego, Huining Kang, Matthew J Campen, Xiaozhong Yu

引用次数: 0

Limitations of acetaminophen as a reference hepatotoxin for the evaluation of in vitro liver models. 对乙酰氨基酚作为评估体外肝脏模型的参考肝毒素的局限性。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-14 DOI: 10.1093/toxsci/kfae133

Lucia A Livoti, Rowena Sison-Young, Dennis Reddyhoff, Ciarán P Fisher, Iain Gardner, Rafael Diaz-Nieto, Christopher E Goldring, Ian M Copple

引用次数: 0

Physiological liver microtissue 384-well microplate system for preclinical hepatotoxicity assessment of therapeutic small molecule drugs. 用于小分子治疗药物临床前肝脏毒性评估的生理性肝脏微组织 384 孔微孔板系统。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-14 DOI: 10.1093/toxsci/kfae123

Lola Fäs, Minjun Chen, Weida Tong, Friederike Wenz, Nicola J Hewitt, Monika Tu, Katarzyna Sanchez, Natalia Zapiórkowska-Blumer, Hajnalka Varga, Karolina Kaczmarska, Maria Vittoria Colombo, Bruno G H Filippi

{"title":"Physiological liver microtissue 384-well microplate system for preclinical hepatotoxicity assessment of therapeutic small molecule drugs.","authors":"Lola Fäs, Minjun Chen, Weida Tong, Friederike Wenz, Nicola J Hewitt, Monika Tu, Katarzyna Sanchez, Natalia Zapiórkowska-Blumer, Hajnalka Varga, Karolina Kaczmarska, Maria Vittoria Colombo, Bruno G H Filippi","doi":"10.1093/toxsci/kfae123","DOIUrl":"https://doi.org/10.1093/toxsci/kfae123","url":null,"abstract":"Hepatotoxicity can lead to the discontinuation of approved or investigational drugs. The evaluation of the potential hepatoxicity of drugs in development is challenging because current models assessing this adverse effect are not always predictive of the outcome in human beings. Cell lines are routinely used for early hepatotoxicity screening, but to improve the detection of potential hepatotoxicity, in vitro models that better reflect liver morphology and function are needed. One such promising model is human liver microtissues. These are spheroids made of primary human parenchymal and nonparenchymal liver cells, which are amenable to high throughput screening. To test the predictivity of this model, the cytotoxicity of 152 FDA (US Food & Drug Administration)-approved small molecule drugs was measured as per changes in ATP content in human liver microtissues incubated in 384-well microplates. The results were analyzed with respect to drug label information, drug-induced liver injury (DILI) concern class, and drug class. The threshold IC50ATP-to-Cmax ratio of 176 was used to discriminate between safe and hepatotoxic drugs. \"vMost-DILI-concern\" drugs were detected with a sensitivity of 72% and a specificity of 89%, and \"vMost-DILI-concern\" drugs affecting the nervous system were detected with a sensitivity of 92% and a specificity of 91%. The robustness and relevance of this evaluation were assessed using a 5-fold cross-validation. The good predictivity, together with the in vivo-like morphology of the liver microtissues and scalability to a 384-well microplate, makes this method a promising and practical in vitro alternative to 2D cell line cultures for the early hepatotoxicity screening of drug candidates.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475445","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

Multi-defense Pathways against Electrophiles through Adduct Formation by Low Molecular Weight Substances with Sulfur Atoms. 通过含硫原子的低分子量物质形成的加合物来抵御电介质的多重防御途径。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-07 DOI: 10.1093/toxsci/kfae132

Yoshito Kumagai, Yumi Abiko, Masahiro Akiyama, Takamitsu Unoki, Yasuhiro Shinkai

引用次数: 0