Comparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA

IF 4.8 3区 医学 Q1 PHARMACOLOGY & PHARMACY Toxicology Pub Date : 2025-02-01 DOI:10.1016/j.tox.2025.154048
Wataru Murase , Atsuhito Kubota , Ryo Hakota , Ayaka Yasuda , Atsuko Ikeda , Koji Nakagawa , Ryota Shizu , Kouichi Yoshinari , Hiroyuki Kojima
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Abstract

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.
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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。
六氟环氧丙烷二聚酸(HFPO-DA)属于全氟烷基醚羧酸(pfea)类,是全氟辛酸(PFOA)的新替代品。然而,HFPO-DA在新生儿中是否比PFOA更安全仍不清楚。在这项研究中,我们通过从妊娠第15至17天口服0.3或3.0mg/kg/天(低剂量或高剂量)的HFPO-DA或PFOA,评估了出生后9-10天的新生儿肝毒性。结果表明,妊娠小鼠暴露于HFPO-DA和PFOA诱导了相似的表型效应,在高剂量下,新生儿体重(BW)显著降低,肝脏重量相对于BW显著增加。值得注意的是,低剂量组HFPO-DA暴露显著降低了新生儿体重,而PFOA则没有。综合基因表达分析显示,HFPO-DA低剂量组和高剂量组新生儿肝脏中差异表达基因(DEGs)分别有408和1402个显著改变,PFOA组差异表达基因(DEGs)分别有0和292个显著改变。基因集富集分析表明,HFPO-DA和PFOA诱导的deg富集于“PPAR信号通路”、“脂肪酸代谢”和“生物氧化”相关通路。此外,转激活实验显示HFPO-DA的小鼠(m)PPARα和mPPARγ活性超过PFOA,分子对接模拟分析预测PFOA和HFPO-DA的结合构象不同。总体而言,我们的研究结果表明,HFPO-DA在较低浓度下持续影响新生儿表型、肝脏基因表达和涉及PPARα/γ的分子启动事件。
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来源期刊
Toxicology
Toxicology 医学-毒理学
CiteScore
7.80
自引率
4.40%
发文量
222
审稿时长
23 days
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.
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