Toxicological Sciences最新文献_第10页

Quantitation and identification of microplastics accumulation in human placental specimens using pyrolysis gas chromatography mass spectrometry. 利用热解气相色谱质谱法对人体胎盘标本中的微塑料积聚进行定量和鉴定。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-04-29 DOI: 10.1093/toxsci/kfae021

Marcus A Garcia, Rui Liu, Alex Nihart, Eliane El Hayek, Eliseo Castillo, Enrico R Barrozo, Melissa A Suter, Barry Bleske, Justin Scott, Kyle Forsythe, Jorge Gonzalez-Estrella, Kjersti M Aagaard, Matthew J Campen

{"title":"Quantitation and identification of microplastics accumulation in human placental specimens using pyrolysis gas chromatography mass spectrometry.","authors":"Marcus A Garcia, Rui Liu, Alex Nihart, Eliane El Hayek, Eliseo Castillo, Enrico R Barrozo, Melissa A Suter, Barry Bleske, Justin Scott, Kyle Forsythe, Jorge Gonzalez-Estrella, Kjersti M Aagaard, Matthew J Campen","doi":"10.1093/toxsci/kfae021","DOIUrl":"10.1093/toxsci/kfae021","url":null,"abstract":"The exponential increase in global plastic usage has led to the emergence of nano- and microplastic (NMP) pollution as a pressing environmental issue due to its implications for human and other mammalian health. We have developed methodologies to extract solid materials from human tissue samples by saponification and ultracentrifugation, allowing for highly specific and quantitative analysis of plastics by pyrolysis-gas chromatography and mass spectrometry (Py-GC-MS). As a benchmark, placenta tissue samples were analyzed using fluorescence microscopy and automated particle count, which demonstrated the presence of >1-micron particles and fibers, but not nano-sized plastic particles. Analyses of the samples (n = 10) using attenuated total reflectance-Fourier transform infrared spectroscopy indicated presence of rayon, polystyrene, polyethylene, and unclassified plastic particles. By contrast, among 62 placenta samples, Py-GC-MS revealed that microplastics were present in all participants' placentae, with concentrations ranging widely from 6.5 to 685 µg NMPs per gram of placental tissue, averaging 126.8 ± 147.5 µg/g (mean±SD). Polyethylene was the most prevalent polymer, accounting for 54% of total NMPs and consistently found in nearly all samples (mean 68.8 ± 93.2 µg/g placenta). Polyvinyl chloride and nylon each represented approximately 10% of the NMPs by weight, with the remaining 26% of the composition represented by 9 other polymers. Together, these data demonstrate advancements in the unbiased quantitative resolution of Py-GC-MS applied to the identification and quantification of NMP species at the maternal-fetal interface. This method, paired with clinical metadata, will be pivotal to evaluating potential impacts of NMPs on adverse pregnancy outcomes.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11057519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139898285","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

Exploring rabbit as a nonrodent species for general toxicology studies. 探索将兔子作为一般毒理学研究的非啮齿动物物种。

IF 3.8 3区医学

Toxicological Sciences Pub Date : 2024-04-29 DOI: 10.1093/toxsci/kfae022

Katie Sokolowski, Patricia V Turner, Elise Lewis, Ronald L Wange, Marie C Fortin

{"title":"Exploring rabbit as a nonrodent species for general toxicology studies.","authors":"Katie Sokolowski, Patricia V Turner, Elise Lewis, Ronald L Wange, Marie C Fortin","doi":"10.1093/toxsci/kfae022","DOIUrl":"10.1093/toxsci/kfae022","url":null,"abstract":"To avoid adverse events in humans, toxicity studies in nonclinical species have been the foundation of safety evaluation in the pharmaceutical industry. However, it is recognized that working with animals in research is a privilege, and conscientious use should always respect the 3Rs: replacement, reduction, and refinement. In the wake of the shortages in routine nonrodent species and considering that nonanimal methods are not yet sufficiently mature, the value of the rabbit as a nonrodent species is worth exploring. Historically used in vaccine, cosmetic, and medical device testing, the rabbit is seldom used today as a second species in pharmaceutical development, except for embryo-fetal development studies, ophthalmic therapeutics, some medical devices and implants, and vaccines. Although several factors affect the decision of species selection, including pharmacological relevance, pharmacokinetics, and ADME considerations, there are no perfect animal models. In this forum article, we bring together experts from veterinary medicine, industry, contract research organizations, and government to explore the pros and cons, residual concerns, and data gaps regarding the use of the rabbit for general toxicity testing.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139906473","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

Carbamazepine transmits immune effect by activation of gut-liver axis and TLR signaling pathway from parental zebrafish to offspring. 卡马西平通过激活亲代斑马鱼的肠肝轴和 TLR 信号通路向子代斑马鱼传递免疫效应。

IF 3.8 3区医学

Toxicological Sciences Pub Date : 2024-04-29 DOI: 10.1093/toxsci/kfae026

Xuan Liu, Fan Liu, Li Liu, You Song, Hongling Liu

{"title":"Carbamazepine transmits immune effect by activation of gut-liver axis and TLR signaling pathway from parental zebrafish to offspring.","authors":"Xuan Liu, Fan Liu, Li Liu, You Song, Hongling Liu","doi":"10.1093/toxsci/kfae026","DOIUrl":"10.1093/toxsci/kfae026","url":null,"abstract":"Carbamazepine (CBZ) has been identified in the aquatic environment as an emerging contaminant. Its immune effect across generations at environmentally relevant concentrations is little known. We aim to elucidate the effects of CBZ on the immune system in zebrafish (Danio rerio), hypothesizing the effects caused by CBZ exposure in the parental generation can be passed on to its offspring, leading to impairment of innate immune function and defense against pathogen weakened. A suite of bioassays (including a test with added lipopolysaccharide) was used to measure the effects of environmentally relevant levels of CBZ (1, 10, and 100 μg/l) on zebrafish at multiple biological levels, and across 2 successive generations (21 days exposure for F0; 5 and 21 days exposure or nonexposure for F1). The results showed that CBZ affected homeostasis in the immune system, caused liver vacuolization, increased the inflammation-related microbiota proportion in gut, and decreased reproduction, by induction of oxidative stress and modulation of Toll-like receptors (TLR) signaling pathway on gut-liver axis. The effects of exposure to CBZ over 21 days in F0 could be passed to the next generation. Intergenerational effects on TLR and antioxidant defense system were also observed in nonexposed F1 at 5 days post-fertilization (5 dpf), but diminished at 21 dpf. The finding provided evidence to unravel immune response by gut-liver axis mediated and oxidative stress under 4 test conditions. The study has raised a potential concern about the multigenerational immune effects of environmental pollutants and calls for a focus on the risk of synergetic pathogen infection.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140040393","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

Technical evaluation and standardization of the human thyroid microtissue assay. 人类甲状腺微组织测定的技术评估和标准化。

IF 3.8 3区医学

Toxicological Sciences Pub Date : 2024-04-29 DOI: 10.1093/toxsci/kfae014

Briana Foley, Kristen Hopperstad, John Gamble, Scott G Lynn, Russell S Thomas, Chad Deisenroth

{"title":"Technical evaluation and standardization of the human thyroid microtissue assay.","authors":"Briana Foley, Kristen Hopperstad, John Gamble, Scott G Lynn, Russell S Thomas, Chad Deisenroth","doi":"10.1093/toxsci/kfae014","DOIUrl":"10.1093/toxsci/kfae014","url":null,"abstract":"The success and sustainability of U.S. EPA efforts to reduce, refine, and replace in vivo animal testing depends on the ability to translate toxicokinetic and toxicodynamic data from in vitro and in silico new approach methods (NAMs) to human-relevant exposures and health outcomes. Organotypic culture models employing primary human cells enable consideration of human health effects and inter-individual variability but present significant challenges for test method standardization, transferability, and validation. Increasing confidence in the information provided by these in vitro NAMs requires setting appropriate performance standards and benchmarks, defined by the context of use, to consider human biology and mechanistic relevance without animal data. The human thyroid microtissue (hTMT) assay utilizes primary human thyrocytes to reproduce structural and functional features of the thyroid gland that enable testing for potential thyroid-disrupting chemicals. As a variable-donor assay platform, conventional principles for assay performance standardization need to be balanced with the ability to predict a range of human responses. The objectives of this study were to (1) define the technical parameters for optimal donor procurement, primary thyrocyte qualification, and performance in the hTMT assay, and (2) set benchmark ranges for reference chemical responses. Thyrocytes derived from a cohort of 32 demographically diverse euthyroid donors were characterized across a battery of endpoints to evaluate morphological and functional variability. Reference chemical responses were profiled to evaluate the range and chemical-specific variability of donor-dependent effects within the cohort. The data-informed minimum acceptance criteria for donor qualification and set benchmark parameters for method transfer proficiency testing and validation of assay performance.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139681592","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

Parenteral nutrition-associated liver injury: clinical relevance and mechanistic insights. 肠外营养相关肝损伤：临床意义和机理认识。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-04-29 DOI: 10.1093/toxsci/kfae020

Milos Mihajlovic, Zenzi Rosseel, Elisabeth De Waele, Mathieu Vinken

{"title":"Parenteral nutrition-associated liver injury: clinical relevance and mechanistic insights.","authors":"Milos Mihajlovic, Zenzi Rosseel, Elisabeth De Waele, Mathieu Vinken","doi":"10.1093/toxsci/kfae020","DOIUrl":"10.1093/toxsci/kfae020","url":null,"abstract":"Intestinal failure-associated liver disease (IFALD) is a relatively common complication in individuals receiving parenteral nutrition (PN). IFALD can be manifested as different types of liver injury, including steatosis, cholestasis, and fibrosis, and could result in liver failure in some cases. The onset and progression of IFALD are highly dependent on various patient and PN-related risk factors. Despite still being under investigation, several mechanisms have been proposed. Liver injury can originate due to caloric overload, nutrient deficiency, and toxicity, as well as phytosterol content, and omega-6 to omega-3 fatty acids ratio contained in lipid emulsions. Additional mechanisms include immature or defective bile acid metabolism, acute heart failure, infections, and sepsis exerting negative effects via Toll-like receptor 4 and nuclear factor κB inflammatory signaling. Furthermore, lack of enteral feeding, gut dysbiosis, and altered enterohepatic circulation that affect the farnesoid x receptor-fibroblast growth factor 19 axis can also contribute to IFALD. Various best practices can be adopted to minimize the risk of developing IFALD, such as prevention and management of central line infections and sepsis, preservation of intestine's length, a switch to oral and enteral feeding, cyclic PN, avoidance of overfeeding and soybean oil-based lipid formulations, and avoiding hepatotoxic substances. The present review thus provides a comprehensive overview of all relevant aspects inherent to IFALD. Further research focused on clinical observations, translational models, and advanced toxicological knowledge frameworks is needed to gain more insight into the molecular pathogenesis of hepatotoxicity, reduce IFALD incidence, and encourage the safe use of PN.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932974","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

Single pulmonary nanopolystyrene exposure in late-stage pregnancy dysregulates maternal and fetal cardiovascular function. 妊娠晚期单次肺部接触纳米聚苯乙烯会导致母体和胎儿心血管功能失调。

IF 3.8 3区医学

Toxicological Sciences Pub Date : 2024-04-29 DOI: 10.1093/toxsci/kfae019

C M Cary, S B Fournier, S Adams, X Wang, E J Yurkow, P A Stapleton

{"title":"Single pulmonary nanopolystyrene exposure in late-stage pregnancy dysregulates maternal and fetal cardiovascular function.","authors":"C M Cary, S B Fournier, S Adams, X Wang, E J Yurkow, P A Stapleton","doi":"10.1093/toxsci/kfae019","DOIUrl":"10.1093/toxsci/kfae019","url":null,"abstract":"Large-scale production and waste of plastic materials have resulted in widespread environmental contamination by the breakdown product of bulk plastic materials to micro- and nanoplastics (MNPs). The small size of these particles enables their suspension in the air, making pulmonary exposure inevitable. Previous work has demonstrated that xenobiotic pulmonary exposure to nanoparticles during gestation leads to maternal vascular impairments, as well as cardiovascular dysfunction within the fetus. Few studies have assessed the toxicological consequences of maternal nanoplastic (NP) exposure; therefore, the objective of this study was to assess maternal and fetal health after a single maternal pulmonary exposure to polystyrene NP in late gestation. We hypothesized that this acute exposure would impair maternal and fetal cardiovascular function. Pregnant rats were exposed to nanopolystyrene on gestational day 19 via intratracheal instillation. 24 h later, maternal and fetal health outcomes were evaluated. Cardiovascular function was assessed in dams using vascular myography ex vivo and in fetuses in vivo function was measured via ultrasound. Both fetal and placental weight were reduced after maternal exposure to nanopolystyrene. Increased heart weight and vascular dysfunction in the aorta were evident in exposed dams. Maternal exposure led to vascular dysfunction in the radial artery of the uterus, a resistance vessel that controls blood flow to the fetoplacental compartment. Function of the fetal heart, fetal aorta, and umbilical artery after gestational exposure was dysregulated. Taken together, these data suggest that exposure to NPs negatively impacts maternal and fetal health, highlighting the concern of MNPs exposure on pregnancy and fetal development.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11057520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139898286","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

Quantitative cross-species comparison of serum albumin binding of per- and polyfluoroalkyl substances from five structural classes. 五种结构类别的全氟烷基和多氟烷基物质与血清白蛋白结合的跨物种定量比较。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-04-29 DOI: 10.1093/toxsci/kfae028

Hannah M Starnes, Thomas W Jackson, Kylie D Rock, Scott M Belcher

{"title":"Quantitative cross-species comparison of serum albumin binding of per- and polyfluoroalkyl substances from five structural classes.","authors":"Hannah M Starnes, Thomas W Jackson, Kylie D Rock, Scott M Belcher","doi":"10.1093/toxsci/kfae028","DOIUrl":"10.1093/toxsci/kfae028","url":null,"abstract":"Per- and polyfluoroalkyl substances (PFAS) are a class of over 8000 chemicals, many of which are persistent, bioaccumulative, and toxic to humans, livestock, and wildlife. Serum protein binding affinity is instrumental in understanding PFAS toxicity, yet experimental binding data is limited to only a few PFAS congeners. Previously, we demonstrated the usefulness of a high-throughput, in vitro differential scanning fluorimetry assay for determination of relative binding affinities of human serum albumin for 24 PFAS congeners from 6 chemical classes. In the current study, we used this assay to comparatively examine differences in human, bovine, porcine, and rat serum albumin binding of 8 structurally informative PFAS congeners from 5 chemical classes. With the exception of the fluorotelomer alcohol 1H, 1H, 2H, 2H-perfluorooctanol (6:2 FTOH), each PFAS congener bound by human serum albumin was also bound by bovine, porcine, and rat serum albumin. The critical role of the charged functional headgroup in albumin binding was supported by the inability of albumin of each species tested to bind 6:2 FTOH. Significant interspecies differences in serum albumin binding affinities were identified for each of the bound PFAS congeners. Relative to human albumin, perfluoroalkyl carboxylic and sulfonic acids were bound with greater affinity by porcine and rat serum albumin, and the perfluoroalkyl ether acid congener bound with lower affinity to porcine and bovine serum albumin. These comparative affinity data for PFAS binding by serum albumin from human, experimental model, and livestock species reduce critical interspecies uncertainty and improve accuracy of predictive bioaccumulation and toxicity assessments for PFAS.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11057469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190148","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

Drug-induced impairment of mitochondrial fatty acid oxidation and steatosis: assessment of causal relationship with 45 pharmaceuticals 药物诱导的线粒体脂肪酸氧化和脂肪变性损伤：评估与 45 种药物的因果关系

IF 3.8 3区医学

Toxicological Sciences Pub Date : 2024-04-27 DOI: 10.1093/toxsci/kfae055

Nelly Buron, Mathieu Porceddu, Roxane Loyant, Cécile Martel, Julien A Allard, Bernard Fromenty, Annie Borgne-Sanchez

{"title":"Drug-induced impairment of mitochondrial fatty acid oxidation and steatosis: assessment of causal relationship with 45 pharmaceuticals","authors":"Nelly Buron, Mathieu Porceddu, Roxane Loyant, Cécile Martel, Julien A Allard, Bernard Fromenty, Annie Borgne-Sanchez","doi":"10.1093/toxsci/kfae055","DOIUrl":"https://doi.org/10.1093/toxsci/kfae055","url":null,"abstract":"Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 non-steatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl-L-carnitine, palmitoyl-CoA + L-carnitine, or octanoyl-L-carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, while dexamethasone, olanzapine and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140808727","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

The association between histopathologic effects and liver weight changes induced in mice and rats by chemical exposures: An analysis of the data from Toxicity Reference Database (ToxRefDB) 化学品暴露对小鼠和大鼠造成的组织病理学影响与肝脏重量变化之间的关联：毒性参考数据库（ToxRefDB）数据分析

IF 3.8 3区医学

Toxicological Sciences Pub Date : 2024-04-23 DOI: 10.1093/toxsci/kfae056

R Mezencev, M Feshuk, L Kolaczkowski, G C Peterson, Q J Zhao, S Watford, J A Weaver

引用次数: 0

Single cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a pro-inflammatory metabolic signature in male mice at late adulthood 单细胞转录组学揭示了早期 BDE-99 暴露对肠道-肝脏轴的重编程作用，从而促进雄性小鼠成年晚期的促炎症代谢特征

IF 3.8 3区医学

Toxicological Sciences Pub Date : 2024-04-18 DOI: 10.1093/toxsci/kfae047

Joe Jongpyo Lim, Michael Goedken, Yan Jin, Haiwei Gu, Julia Yue Cui

{"title":"Single cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a pro-inflammatory metabolic signature in male mice at late adulthood","authors":"Joe Jongpyo Lim, Michael Goedken, Yan Jin, Haiwei Gu, Julia Yue Cui","doi":"10.1093/toxsci/kfae047","DOIUrl":"https://doi.org/10.1093/toxsci/kfae047","url":null,"abstract":"Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants that bioaccumulate in the environment. The gut microbiome is an important regulator of liver functions including xenobiotic biotransformation and immune regulation. We recently showed that neonatal exposure to polybrominated diphenyl ether-99 (BDE-99), a human breast milk-enriched PBDE congener, up-regulated pro-inflammation- and down-regulated drug metabolism-related genes predominantly in males in young adulthood. However, the persistence of dysregulation into late adulthood, differential impact of hepatic cell types, and the involvement of the gut microbiome from neonatal BDE-99 exposure remains unknown. To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2-4. At 15 months of age, neonatal BDE-99 exposure down-regulated xenobiotic and lipid metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes. Neonatal BDE-99 exposure also increased the hepatic proportion of neutrophils and led to a predicted increase of macrophage migration inhibitory factor signaling. This was associated with decreased intestinal tight junction protein (Tjp) transcripts, altered gut environment, and dysregulation of inflammation-related metabolites. ScRNA-seq using germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immune tolerance. Microbiota transplant to GF mice using large intestinal microbiome from adults neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in the large intestine. In conclusion, neonatal BDE-99 exposure reprogrammed cell type-specific gene expression and communication in liver towards pro-inflammation, and BDE-99-mediated pro-inflammatory signatures may be partly due to the dysregulated gut environment.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140798646","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