{"title":"产前暴露于PFOA及其替代品HFPO-DA的雄性新生小鼠肝脏基因表达谱的比较研究。","authors":"Wataru Murase , Atsuhito Kubota , Ryo Hakota , Ayaka Yasuda , Atsuko Ikeda , Koji Nakagawa , Ryota Shizu , Kouichi Yoshinari , Hiroyuki Kojima","doi":"10.1016/j.tox.2025.154048","DOIUrl":null,"url":null,"abstract":"<div><div>Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9–10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0 mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15–17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to “PPAR signaling”, “fatty acid metabolism”, and “biological oxidations”. In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"511 ","pages":"Article 154048"},"PeriodicalIF":4.8000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Comparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA\",\"authors\":\"Wataru Murase , Atsuhito Kubota , Ryo Hakota , Ayaka Yasuda , Atsuko Ikeda , Koji Nakagawa , Ryota Shizu , Kouichi Yoshinari , Hiroyuki Kojima\",\"doi\":\"10.1016/j.tox.2025.154048\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9–10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0 mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15–17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to “PPAR signaling”, “fatty acid metabolism”, and “biological oxidations”. In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.</div></div>\",\"PeriodicalId\":23159,\"journal\":{\"name\":\"Toxicology\",\"volume\":\"511 \",\"pages\":\"Article 154048\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0300483X25000046\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0300483X25000046","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Comparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA
Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9–10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0 mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15–17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to “PPAR signaling”, “fatty acid metabolism”, and “biological oxidations”. In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.
期刊介绍:
Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.