Arachidonic acid metabolite prostaglandin E2 attenuates diethylhexyl phthalate-induced hepatotoxicity through promoting macrophage M2 polarization

IF 3.9 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology Pub Date : 2025-05-01 DOI:10.1016/j.fct.2025.115501

Miao Xu , Lijuan You , Yaru Tian , Jiuming Yan , Lei Shi , Yi Wan , Xudong Jia , Hui Yang , Wen Hu

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Abstract

The prevalence of nonalcoholic fatty liver disease (NAFLD), exacerbated by endocrine disruptors like phthalate-plasticizers, underscores the need to understand their impact on hepatic lipid metabolism. Although the suppression of hepatic macrophage M2 polarization is known to contribute to diethylhexyl phthalate (DEHP)-induced hepatic lipid accumulation, the role of intracellular metabolism in macrophages remains unclear. Here, we investigated the role of arachidonic acid metabolism—a key regulator of M2 macrophage polarization—and its metabolite prostaglandin E2 (PGE2) in DEHP-induced hepatic lipid disorders. DEHP exposure disrupted lipid metabolism and reduced hepatic macrophages. Genomic and metabolomic analyses of mice revealed a strong correlation between decreased hepatic M2 macrophages and perturbed arachidonic acid metabolism. Elevating the PGE2 level attenuated the inhibition of M2 macrophages caused by DEHP or its metabolite mono- (2-ethylhexyl) phthalate (MEHP) both in vitro and in vivo. Additionally, PGE2-induced M2 macrophages alleviated DEHP/MEHP-induced lipid metabolism disorders. In summary, arachidonic acid metabolism and PGE2 are critical metabolic regulators in DEHP-induced lipid metabolism disorders. This study identifies a novel metabolic target related to macrophage polarization in phthalates toxicity and provides a foundation for therapeutic strategies against endocrine disruptor-associated NAFLD.

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花生四烯酸代谢物前列腺素E2通过促进巨噬细胞M2极化减轻邻苯二甲酸二乙基己基引起的肝毒性

邻苯二甲酸酯增塑剂等内分泌干扰物加剧了非酒精性脂肪性肝病（NAFLD）的流行，这凸显了了解其对肝脏脂质代谢影响的必要性。虽然已知抑制肝巨噬细胞M2极化有助于邻苯二甲酸二乙基己基（DEHP）诱导的肝脏脂质积累，但细胞内代谢在巨噬细胞中的作用尚不清楚。在这里，我们研究了花生四烯酸代谢（M2巨噬细胞极化的关键调节因子）及其代谢物前列腺素E2 （PGE2）在dehp诱导的肝脂质紊乱中的作用。DEHP暴露破坏脂质代谢并减少肝巨噬细胞。小鼠的基因组和代谢组学分析显示，肝脏M2巨噬细胞减少与花生四烯酸代谢紊乱之间存在很强的相关性。提高PGE2水平可减轻DEHP或其代谢物邻苯二甲酸单-（2-乙基己基）酯（MEHP）对M2巨噬细胞的抑制作用。此外，pge2诱导的M2巨噬细胞减轻了DEHP/ mehp诱导的脂质代谢紊乱。综上所述，花生四烯酸代谢和PGE2是dehp诱导的脂质代谢紊乱的关键代谢调节因子。本研究确定了邻苯二甲酸盐毒性中巨噬细胞极化相关的新代谢靶点，并为针对内分泌干扰物相关NAFLD的治疗策略提供了基础。

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.