Journal of Applied Toxicology最新文献

Safety Evaluation of Serendipity Berry Sweet Protein From Komagataella phaffii.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-31 DOI: 10.1002/jat.4781

Yael Lifshitz, Shira Paz, Rotem Saban, Inbar Zuker, Hagay Shmuely, Katy Gorshkov, Jwar Meetro, Shahrzad Tafazoli, Trung Vo, Gabriela Amiram, Carmit Shani Levi, Uri Lesmes, Ilan Samish

{"title":"Safety Evaluation of Serendipity Berry Sweet Protein From Komagataella phaffii.","authors":"Yael Lifshitz, Shira Paz, Rotem Saban, Inbar Zuker, Hagay Shmuely, Katy Gorshkov, Jwar Meetro, Shahrzad Tafazoli, Trung Vo, Gabriela Amiram, Carmit Shani Levi, Uri Lesmes, Ilan Samish","doi":"10.1002/jat.4781","DOIUrl":"https://doi.org/10.1002/jat.4781","url":null,"abstract":"Serendipity Berry Sweet Protein (sweelin) is a novel hyper-sweet thermophilic protein designed using Artificial Intelligence Computational Protein Design (AI-CPD) to improve the stability and sensory profile of the protein found in serendipity berry (Dioscoreophyllum cumminsii). sweelin is produced through precision fermentation by expression in Komagataella phaffii. The safety of sweelin was investigated through an evaluation of its genotoxicity, mutagenicity, systemic toxicity and digestibility potential in in vitro and in vivo models. sweelin was not genotoxic in in vitro reverse mutation and mammalian micronucleus assays and was not associated with systemic toxicity in a 90-day dietary toxicity study in rats. The no-observed-adverse-effect level for sweelin in Sprague Dawley rats was established as 14,300 ppm, the highest dose tested. This dose level corresponds to dietary intakes of 838.3 and 946.0 mg/kg body weight/day in male and female rats, respectively. sweelin was demonstrated to be readily digestible in an in vitro semi-dynamic model of the gastrointestinal tract. The results support the safety of sweelin as a food ingredient for sweetening purposes.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 Di(2-Ethylhexyl) Phthalate Increases the Internalization of Polystyrene Microplastics by Human Hepatocellular Carcinoma Cells and Leads to Cell Damage.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-26 DOI: 10.1002/jat.4771

Haobin Zhang, Huaying Hao, Wenyu Fan, Wenhua Gao, Jun Liang

{"title":"Exposure to Di(2-Ethylhexyl) Phthalate Increases the Internalization of Polystyrene Microplastics by Human Hepatocellular Carcinoma Cells and Leads to Cell Damage.","authors":"Haobin Zhang, Huaying Hao, Wenyu Fan, Wenhua Gao, Jun Liang","doi":"10.1002/jat.4771","DOIUrl":"https://doi.org/10.1002/jat.4771","url":null,"abstract":"Microplastics (MPs) and the plasticizer di(2-ethylhexyl) phthalate (DEHP) frequently co-occur, presenting substantial health risks to both humans and animals. While animal studies indicate adverse effects from exposure to MPs and DEHP, their potential toxicity in humans remains uncertain. This study examines the response of human hepatocellular carcinoma (HepG2) cells to concurrent exposure to synthetic spherical polystyrene (PS) particles and DEHP. We analyzed the effect of particle size on the internalization of PS-MPs using HepG2 spheres as a 3D model. The results showed that MPs at 100 nm had the highest internalization efficiency, which gradually decreased as the particle size increased to 1 and 5 μm. In addition, DEHP significantly improved the internalization of MPs, especially for 5 μm particles, which showed a 26% increase in internalization efficiency. We also evaluated changes in physiological activity. Co-exposure to MPs and DEHP resulted in significantly higher cytotoxicity than exposure to MPs alone, with a 20% reduction in cell viability. Larger particle sizes led to greater cellular damage, indicated by a 20% increase in reactive oxygen species (ROS) and a 40% rise in lactate dehydrogenase (LDH) release, suggesting membrane rupture. This study offers new insights into the potential toxicity of short-term exposure to MPs and DEHP, using HepG2 spheres to closely replicate in vivo conditions.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Cytogenotoxicity Induced by Dental Adhesives: A Systematic Review.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-20 DOI: 10.1002/jat.4780

Thiago Guedes Pinto, Meliça Alvarenga da Paschoa Martins, Ana Claudia Muniz Renno, Jean Nunes Dos Santos, Patricia Ramos Cury, Daniel Araki Ribeiro

{"title":"Cytogenotoxicity Induced by Dental Adhesives: A Systematic Review.","authors":"Thiago Guedes Pinto, Meliça Alvarenga da Paschoa Martins, Ana Claudia Muniz Renno, Jean Nunes Dos Santos, Patricia Ramos Cury, Daniel Araki Ribeiro","doi":"10.1002/jat.4780","DOIUrl":"https://doi.org/10.1002/jat.4780","url":null,"abstract":"Dental adhesives are an essential tool for dental direct and indirect restoration and, therefore, have grown in popularity among clinicians and researchers. With the purpose of enhancing the contact between the walls of the dental prepared cavity and the restorative material, dental adhesives systems differ from one another according to the employed etching technique and to the area of the tooth to be etched. When dentin is etched, the adhesive may reach the dental pulp through the microtubules and induce changes in this vital tissue, including DNA damage and/or cellular death (cytogenotoxicity). The aim of this study was to evaluate cytogenotoxicity induced by dental adhesives by means of systematic review. Thus, a total of 17 selected studies were carefully analyzed by three reviewers (TGP, MAPM, and DAR), who attributed scores to each study according to the used analysis parameters. Our results revealed that dental adhesives may indeed induce cytogenotoxicity in vitro, because all included studies reported positive response at, at least, one administered dose. As for the quality assessment, 16 studies (out of 17) were categorized as either Strong or Moderate, which suggests our findings can be considered reliable. Positively, such findings suggest that dental adhesives and their cytogenotoxic effects are crucial data for elucidating the risk of genetic damage and/or cellular death associated with dental adhesives, as well as for guiding the development of new products with different compositions.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Environmental Concentrations of Polystyrene Nanoplastics Induce Low-Dose Tamoxifen Toxicity Through Oxidative Stress in Caenorhabditis elegans. 环境浓度的聚苯乙烯纳米塑料通过氧化应激诱导秀丽隐杆线虫产生低剂量他莫昔芬毒性

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-17 DOI: 10.1002/jat.4760

Chenchen Wang, Jun Yuan, Yingmao Tang, Chenyan Zhu, Ziheng Zhuang

{"title":"Environmental Concentrations of Polystyrene Nanoplastics Induce Low-Dose Tamoxifen Toxicity Through Oxidative Stress in Caenorhabditis elegans.","authors":"Chenchen Wang, Jun Yuan, Yingmao Tang, Chenyan Zhu, Ziheng Zhuang","doi":"10.1002/jat.4760","DOIUrl":"https://doi.org/10.1002/jat.4760","url":null,"abstract":"In recent years, significant focus has been placed on the negative impacts of nanoplastics on living organisms. However, nanoplastics at environmental concentrations may interact with drugs, leading to more severe side effects in organisms. This study used Caenorhabditis elegans (C. elegans) to investigate how environmental levels (μg/L) of polystyrene nanoparticles (PS-NPs) influence tamoxifen toxicity and its mechanisms. Combined exposure to tamoxifen and PS-NPs significantly impaired locomotion, pumping, brood size, growth, and induced oxidative stress in both parents and offspring compared to single exposures. DAF-2 mutations conferred resistance, while DAF-16 mutations increased susceptibility. The combined exposure promoted DAF-16::GFP nuclear translocation and decreased SOD-3::GFP and HSP-16.2::GFP fluorescence, indicating toxicity through the DAF-2/DAF-16 IIS pathway. Bacterial metabolism was also linked to the toxic effects, feeding C. elegans metabolically inactivated OP50 significantly reduced the toxicity associated with the combined exposure of PS-NPs and tamoxifen. Additionally, dietary N-acetyl-L-cysteine significantly improved resistance to combined PS-NP and tamoxifen exposure. In summary, this study highlights how long-term exposure to environmental nanoplastic levels can enhance drug side effects, providing new insights into nanoplastics' role in drug interactions.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Human Relevance of Pharmaceutical Drug-Induced Thyroid Tumors in Rats, Labeling Implications, and Carcinogenicity Study Requirements.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-13 DOI: 10.1002/jat.4779

B D Hollingshead, Z A Radi

{"title":"Human Relevance of Pharmaceutical Drug-Induced Thyroid Tumors in Rats, Labeling Implications, and Carcinogenicity Study Requirements.","authors":"B D Hollingshead, Z A Radi","doi":"10.1002/jat.4779","DOIUrl":"https://doi.org/10.1002/jat.4779","url":null,"abstract":"In rats, thyroid tumors are common age-related findings with reported incidence rates up to 8.1% and 11.86% for follicular and C-cell adenomas, respectively. Increases of thyroid follicular neoplasms in rodents via the induction of hepatic UDP-glucuronosyltransferase (UGT) enzymes, resulting in elevated thyroid hormone (TH) metabolism, excretion, and subsequent follicular cell proliferation are generally accepted to have little or no relevance to humans due to species differences in sensitivity to this pathophysiologic process. In this analysis, we reviewed approved drugs that resulted in thyroid tumors in 2-year rat carcinogenicity studies and summarized the positioning of these findings in product labeling language and human risk assessments in the United States and Europe. Overall, although thyroid follicular cell tumors are commonly observed, the labels reviewed listed no suspected human risk or directly state the absence of human relevance for these findings. Like follicular cell tumors, thyroid C-cell tumors are common background findings in rats but comparatively are not as commonly increased in frequency as drug-related findings in 2-year rodent carcinogenicity studies. These findings are most notably observed with GLP-1 agonists and their human relevance is a topic of ongoing clinical safety surveillance analysis. Thyroid follicular cell hyperplasia, when specifically occurring through hepatic enzyme induction and/or enhanced TH clearance, should be evaluated for anticipated human translational relevance using nonclinical and clinical data. If no human relevance is anticipated, this rationale should be incorporated into a weight of evidence approach for carcinogenicity studies as outlined in the ICH S1B addendum.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Combined Effects of Lead and Chromium at Environmentally Relevant Concentrations in Zebrafish (Danio rerio) Liver: Role of Nrf2-Keap1-ARE Pathway.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-12 DOI: 10.1002/jat.4776

Olivia Sarkar, Shehnaz Islam, Sunanda Mukherjee, Ansuman Chattopadhyay

{"title":"Combined Effects of Lead and Chromium at Environmentally Relevant Concentrations in Zebrafish (Danio rerio) Liver: Role of Nrf2-Keap1-ARE Pathway.","authors":"Olivia Sarkar, Shehnaz Islam, Sunanda Mukherjee, Ansuman Chattopadhyay","doi":"10.1002/jat.4776","DOIUrl":"https://doi.org/10.1002/jat.4776","url":null,"abstract":"The extensive industrial use of lead (Pb) and chromium (Cr) has led to their persistent release into aquatic ecosystems, posing severe ecological and toxicological challenges. While the individual toxicities of these metals are well-documented, their combined effects, particularly on toxicity mechanisms and cellular stress responses, remain inadequately understood. This study investigated the hepatotoxic effects of Pb and Cr, both individually and in combination, in zebrafish (Danio rerio), focusing on oxidative stress and the Nrf2-Keap1-ARE signaling pathway. Zebrafish were exposed to environmentally relevant concentrations of Pb (2.5, 5, and 10 ppb), Cr (0.5, 1, and 2 ppm), and their combination for 15, 30, and 60 days. Combined exposure elicited heightened oxidative stress, marked by elevated reactive oxygen species, lipid peroxidation, catalase activity, and a significant reduction in glutathione levels. Histopathological analysis revealed severe alterations, including vacuolation, sinusoidal dilation, and necrosis, with the most pronounced effects observed in the combined exposure groups. Gene expression analysis demonstrated the upregulation of oxidative stress-related genes (nrf2, ho1, nqo1, gpx1, catalase, gst, cu/znsod, mnsod, and cyp1a) and heat shock protein (hsp70) and the downregulation of keap1, and ucp2, particularly in co-treated groups. Immunofluorescence observation confirmed enhanced nuclear translocation of Nrf2, while atomic absorption spectrophotometry studies revealed significant bioaccumulation of Pb and Cr in the liver, especially during combined exposures. These findings underscore that Pb and Cr co-exposure intensifies oxidative stress and hepatotoxicity via the Nrf2-Keap1-ARE pathway, emphasizing the environmental and health risks associated with heavy metal contamination in aquatic ecosystems.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Evaluation of Diagnostic Performance of Circulating microRNAs as Biomarkers of Retinal Toxicity in the Rat.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-11 DOI: 10.1002/jat.4775

Daichi Ishii, Yuki Nishikawa, Miharu Soeda, Yutaka Tonomura, Yuki Numakura, Yoko Kitsunai, Yuki Osawa, Keiichi Asakura, Yasuhiro Yamashita

{"title":"Evaluation of Diagnostic Performance of Circulating microRNAs as Biomarkers of Retinal Toxicity in the Rat.","authors":"Daichi Ishii, Yuki Nishikawa, Miharu Soeda, Yutaka Tonomura, Yuki Numakura, Yoko Kitsunai, Yuki Osawa, Keiichi Asakura, Yasuhiro Yamashita","doi":"10.1002/jat.4775","DOIUrl":"https://doi.org/10.1002/jat.4775","url":null,"abstract":"Retinal toxicity is of great concern during drug development due to the irreversibility. Circulating microRNA (miRNA) is reported to be useful for detecting retinal toxicity in rats, although there has been no assessment of the diagnostic performance with statistical analysis. Therefore, we comparatively analyzed the diagnostic performance of circulating miRNAs enriched in the retina such as rno-miR-124-3p, -183-5p, -96-5p, -182, -9a-5p, -125b-5p, -204-5p and -211-5p. The toxicants used in this study resulted in three types of retinal injury in photoreceptor (PR) cells, neuroretinal (NR) cells and retinal pigment epithelium (RPE) cells in rats. The performance of these biomarkers of retinal toxicity were assessed by receiver operator characteristic (ROC) analysis, then cut-off values indicating the histopathological retinal lesions and performance indexes such as area under the ROC curve (ROC-AUC), sensitivity and specificity were calculated. The ROC-AUC for PR cell toxicity in relation to rno-miR-183-5p and -182 were 0.970 and 0.873, respectively, and for NR cell toxicity in relation to rno-miR-124-3p it was 0.896. Our results suggest that plasma rno-miR-124-3p and -183-5p/-182 would be suitable for detecting NR cell toxicity and PR cell toxicity, respectively. In conclusion, these plasma miRNAs may be an effective screening tool to detect drug-induced retinal toxicity in preclinical toxicology studies.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Embryotoxicity Evaluation of Novel Synthetic Cannabinoid 4F-MDMB-BUTICA Using Zebrafish Embryos.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-11 DOI: 10.1002/jat.4778

Berşan Kullebi, Ömercan Alat, Özkan Aksakal, Derya Yılmaztürk, Ayşe Lafzi, Turgay Şişman

{"title":"Embryotoxicity Evaluation of Novel Synthetic Cannabinoid 4F-MDMB-BUTICA Using Zebrafish Embryos.","authors":"Berşan Kullebi, Ömercan Alat, Özkan Aksakal, Derya Yılmaztürk, Ayşe Lafzi, Turgay Şişman","doi":"10.1002/jat.4778","DOIUrl":"https://doi.org/10.1002/jat.4778","url":null,"abstract":"Detailed studies on the embryotoxic and teratogenic effects of synthetic cannabinoids known to be abused are very limited. The present study aimed to evalutate the possible embryotoxic, teratogenic, behavioral, and molecular effects of 4F-MDMB-BUTICA, a new generation synthetic cannabinoid, using zebrafish embryos. The zebrafish embryos were exposed to the cannabinoid at 0.15, 0.30, 0.60, 1.20, 2.40, and 4.80 mg/L from 3 to 24 hpf (acute) and 3 to 120 hpf (subacute). No developmental abnormalities and mortality were observed in embryos after acute exposure. Subacute 4F-MDMB-BUTICA exposure induced mortality of the embryos with the 120 hpf LC50 and EC50 of 1.932 and 0.960 mg/L, respectively. 4F-MDMB-BUTICA also caused embryonic deformities, including spine formation, pericardial edema, impaired blood flow, yolk sac edema, and delayed development. Additionally, subacute cannabinoid exposure induced hypoactivity in response to the stimulus in 120-hpf larvae. qPCR analyses were performed on a subset of 19 genes associated with specific adverse outcomes. The cannabinoid exposure altered the transcriptional expression levels of apoptosis (casp3a, casp8, ifng1, and tp53) DNA repair (rad51), dopamine (dat, drd1, and drd3), serotonin (5ht1aa, 5ht1a, 5ht1b, and 5ht2c), γ-aminobutyric acid (gabra1, gat1, abat, and gad1b), and behavior (gnrh3, gnrhr3, and kiss2)-related genes. In conclusion, the subacute exposure to 4F-MDMB-BUTICA induces mortality, developmental toxicity, hypoactivity of larval behavior, and changes in some essential genes in zebrafish. These findings suggest that 4F-MDMB-BUTICA may have similar embryotoxic effects in humans.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Tissue Distribution of Methylmercury in Obese Pregnant Mice and Fetuses.

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-11 DOI: 10.1002/jat.4777

Megumi Yamamoto, Chisato Kataoka, Rie Yanagisawa, Tomoharu Yokooji, Eiji Shibata, Mayumi Tsuji, Toshihide Sakuragi, Masahisa Horiuchi, Masaaki Nakamura, Mineshi Sakamoto

{"title":"Tissue Distribution of Methylmercury in Obese Pregnant Mice and Fetuses.","authors":"Megumi Yamamoto, Chisato Kataoka, Rie Yanagisawa, Tomoharu Yokooji, Eiji Shibata, Mayumi Tsuji, Toshihide Sakuragi, Masahisa Horiuchi, Masaaki Nakamura, Mineshi Sakamoto","doi":"10.1002/jat.4777","DOIUrl":"https://doi.org/10.1002/jat.4777","url":null,"abstract":"Despite the high frequency of pregnancies complicated by abnormal glucose metabolism associated with obesity, methylmercury (MeHg) metabolism in pregnant women with abnormal glucose metabolism is unclear. We aimed to elucidate the MeHg tissue distribution in obese female mice with abnormal glucose metabolism and their fetuses. Female C57BL/6J mice were fed a high-fat diet (HFD) or a standard diet (Ctrl) for 12 weeks and mated. HFD mice showed mild glucose metabolism abnormalities as assessed by an oral glucose tolerance test. Maternal tissues (brain, liver, and kidney) and blood (plasma and blood cells) and fetal tissues (brain, liver, kidney, and placenta) were collected from these mice 24 h after oral administration of MeHg (a single dose of 1 or 5 mg Hg/kg) on Day 16 of mating. The total mercury level was determined in each sample, and its distribution to each tissue was estimated using Kp values (total mercury in each tissue/total mercury in maternal plasma). The Kp values for the maternal brain and liver were lower in HFD mice than in Ctrl mice, but no significant difference between groups was observed in the kidney or blood cells. The Kp values for all fetal tissues were lower in HFD mice than in Ctrl mice. Pregnant mice showed higher Kp values for the brain and lower Kp values for the kidney than those in nonpregnant mice, regardless of diet. These results will provide useful information to assess the risk of MeHg in obese mothers with glucose metabolism abnormalities and their fetuses.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Formaldehyde Promoted Tumor Cell Growth Through Reinforced Lactylation of Poly (ADP-Ribose) Polymerase 1. 甲醛通过加强聚（ADP-核糖）聚合酶 1 的乳化作用促进肿瘤细胞生长

IF 2.7 4区医学

Journal of Applied Toxicology Pub Date : 2025-03-11 DOI: 10.1002/jat.4773

Junfeng Wang, Huan Xu

{"title":"Formaldehyde Promoted Tumor Cell Growth Through Reinforced Lactylation of Poly (ADP-Ribose) Polymerase 1.","authors":"Junfeng Wang, Huan Xu","doi":"10.1002/jat.4773","DOIUrl":"https://doi.org/10.1002/jat.4773","url":null,"abstract":"As a group I carcinogen, environmental exposures to formaldehyde (FA) have been associated with various types of malignancies. However, exact mechanisms of FA-triggered carcinogenesis are still not clear. Lactylation is recently identified as a post-translational modification driven by overproduced lactic acid (LA) that regulates protein activities in different cellular processes. Our previous studies clearly demonstrated that environmentally relevant levels of FA could elevate LA in tumor cells. Poly (ADP-ribose) polymerase 1 (PARP1) is a major player in DNA repair and tumor cell survival, which has been shown to be activated by lactylation. In order to examine if PARP1 lactylation is promoted by FA environmental exposure, subcutaneous tumor models were established using BALB/c nude mice, which were exposed to 2.0 mg/m3 FA for 14 days. FA significantly elevated LA concentrations (p = 0.011) in the tumor tissues, which was confirmed in A549 cells treated with 100 μM FA in vitro. Both activity and lactylation of PARP1 were found to be induced by FA, which also enhanced DNA repair and tumor-promotive functions in vitro. Inhibition of LA production through lactate dehydrogenase A (LDHA) knockout reduced FA-potentiated PARP1 lactylation and activity. Collectively, these results revealed for the first time that FA promoted tumor cell growth through enhanced PARP1 lactylation, which could be the underlying mechanism of FA-related carcinogenesis.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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