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Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic ReticulumMitochondria Interaction

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Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic ReticulumMitochondria Interaction
邻苯二甲酸盐通过破坏Mfn2 - PERK-介导的内质网-线粒体相互作用诱导神经毒性
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  • Yi Zhao
    Yi Zhao
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P. R. China
    Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    More by Yi Zhao
  • Yuan-Hang Chang
    Yuan-Hang Chang
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
  • Hao-Ran Ren
    Hao-Ran Ren
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    More by Hao-Ran Ren
  • Ming Lou
    Ming Lou
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    More by Ming Lou
  • Fu-Wei Jiang
    Fu-Wei Jiang
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    More by Fu-Wei Jiang
  • Jia-Xin Wang
    Jia-Xin Wang
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
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  • Ming-Shan Chen
    Ming-Shan Chen
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
  • Shuo Liu
    Shuo Liu
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
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  • Yu-Sheng Shi
    Yu-Sheng Shi
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    More by Yu-Sheng Shi
  • Hong-Mei Zhu
    Hong-Mei Zhu
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
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  • Jin-Long Li*
    Jin-Long Li
    College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P. R. China
    Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    *Email: Jinlongli@neau.edu.cn. Phone: +86 451 55190407. Fax: +86 451 55190407.
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Open PDFSupporting Information (1)

Journal of Agricultural and Food Chemistry

Cite this: J. Agric. Food Chem. 2024, 72, 13, 7411–7422
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https://doi.org/10.1021/acs.jafc.3c07752 IF: 5.7 Q1
Published February 23, 2024
Copyright © 2024 American Chemical Society

Abstract 抽象的

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Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER–mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood–brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER–mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.
邻苯二甲酸二(2-乙基己基)酯(DEHP)作为最常见的邻苯二甲酸酯,被广泛用作增塑剂以提高农产品的可塑性,对人体健康造成严重危害。线粒体动力学和内质网 (ER) 稳态对于维持线粒体相关 ER 膜 (MAM) 的完整性至关重要。在本研究中,我们旨在探讨 DEHP 对神经系统的影响及其与 ER-线粒体相互作用的关系。在这里,我们发现 DEHP 会导致大脑形态变化、运动缺陷、认知障碍和血脑屏障破坏。 DEHP 引发内质网应激,该应激主要由蛋白激酶 R 样内质网激酶 (PERK) 信号传导介导。此外,DEHP诱导的mitofusin-2 (Mfn2) 下调会导致线粒体动力学失衡。有趣的是,DEHP 暴露通过抑制Mfn2 - PERK相互作用来损害 MAM。最重要的是,这项研究阐明了Mfn2 - PERK介导的ER-线粒体相互作用的破坏是邻苯二甲酸盐诱导的神经毒性,有可能开发为神经系统疾病的新型疗法。

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1. Introduction 一、简介

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Phthalates are widely used as plasticizers in agricultural plastic products to improve the flexibility, elasticity, and softness. (1) The annual use of phthalates is almost 8 million tons worldwide, and this number is expected to grow continuously in the following years. (2) Di-(2-ethylhexyl) phthalate (DEHP) is one of the most commonly used phthalates in agricultural chemicals and products, such as greenhouses and agricultural mulch. (3) With a strong noncovalent bond with plastics and other materials, DEHP is easily released from agricultural products, leading to exposure in the environment including soil, air, and aquatic systems. (4) Agricultural soil is a major reservoir for DEHP. In some manufacturing areas, DEHP concentrations reached 153 mg/kg in soil, which is an alarming level of pollution. (5) Subsequently, DEHP could be taken up and accumulated by crops grown including wheat kernel, rice, and vegetables and then poses potential risks to human health via food consumption. Recently, DEHP has been reported in different greenhouse vegetables with a range of 10.14–36.16 mg/kg. (6) As a result, animals and humans can be exposed to DEHP through numerous routes such as inhalation, ingestion, and dermal exposure, which cause concerns regarding the potential risks to health. Several countries have established strict standards for allowable levels of DEHP in soil, water, and foods. (7) Therefore, DEHP has been listed as a probable human carcinogen and a priority pollutant by the USEPA and the European Union. (8) Over the past few decades, previous research has demonstrated that DEHP could elicit different types of toxicity such as reproductive toxicity, hepatotoxicity, cardiotoxicity, and nephrotoxicity. (9−11) Nevertheless, it is not known whether the nervous system could be affected by DEHP, and its connection with neurological disease is still unclear. Thus, it is essential to understand the toxic effect of DEHP on the nervous system as well as its underlying molecular mechanism of toxicity.
邻苯二甲酸盐广泛用作农用塑料制品中的增塑剂,以提高柔韧性、弹性和柔软度。 (1)全球邻苯二甲酸酯的年使用量接近800万吨,预计未来几年这一数字将持续增长。 (2)邻苯二甲酸二(2-乙基己基)酯 (DEHP) 是农用化学品和产品(例如温室和农业覆盖物)中最常用的邻苯二甲酸酯之一。 (3) DEHP与塑料等材料有很强的非共价键,很容易从农产品中释放出来,导致暴露在土壤、空气和水生系统等环境中。 (4)农田土壤是DEHP的主要库。在一些生产区域,土壤中DEHP浓度达到153毫克/千克,这是一个令人震惊的污染水平。 (5)随后,DEHP可被麦仁、水稻、蔬菜等农作物吸收积累,并通过食用对人体健康构成潜在风险。最近有报道称,不同温室蔬菜中的 DEHP 含量范围为 10.14–36.16 mg/kg。 (6)因此,动物和人类可以通过吸入、摄入和皮肤接触等多种途径接触 DEHP,这引起了人们对潜在健康风险的担忧。一些国家针对土壤、水和食品中 DEHP 的允许含量制定了严格的标准。 (7)因此,DEHP已被USEPA和欧盟列为可能的人类致癌物和优先污染物。 (8)过去几十年来,已有研究表明DEHP可引起不同类型的毒性,如生殖毒性、肝毒性、心脏毒性和肾毒性。 (9−11)然而,目前尚不清楚DEHP是否会影响神经系统,其与神经系统疾病的关系仍不清楚。因此,了解DEHP对神经系统的毒性作用及其潜在的毒性分子机制至关重要。
Communication among organelles is critical to maintain homeostasis in the cell, which can be mediated by signaling molecules between organelles. Recent studies have shown that in addition to their distinct functions in the cell, the mitochondria and endoplasmic reticulum (ER) interact both physically and functionally, which has attracted significant study interest in recent years. (12) Mitochondria-associated ER membranes (MAMs) are the contact sites between the ER membrane and the mitochondria membrane, which can mediate Ca2+ and metabolite transfer between mitochondria and ER. (13) MAMs regulate various cell processes through signaling events including Ca2+ homeostasis, inflammatory response, oxidative stress, or apoptosis. (14) Several recent studies highlight the connection of MAM dysfunctions in Alzheimer’s disease (AD) development and raise the possibility of targeting MAM molecular components to alleviate AD pathogenesis. (15) Several research studies have suggested that MAMs are damaged and disrupted in neurodegenerative diseases including Parkinson’s disease (PD) and frontotemporal dementia. (16) However, it remains unclear whether MAMs are involved in a critical step in DEHP-induced neurotoxicity.
细胞器之间的通讯对于维持细胞内的稳态至关重要,这可以通过细胞器之间的信号分子介导。最近的研究表明,线粒体和内质网(ER)除了在细胞中具有独特的功能外,还在物理和功能上相互作用,近年来引起了人们的广泛研究兴趣。 (12)线粒体相关内质网膜(MAM)是内质网膜与线粒体膜之间的接触位点,可介导线粒体与内质网之间的Ca 2+和代谢物转移。 (13) MAM 通过信号事件(包括 Ca 2+稳态、炎症反应、氧化应激或细胞凋亡)调节各种细胞过程。 (14)最近的几项研究强调了 MAM 功能障碍与阿尔茨海默病 (AD) 发展之间的联系,并提出了针对 MAM 分子成分来缓解 AD 发病机制的可能性。 (15)多项研究表明,MAM 在神经退行性疾病(包括帕金森病 (PD) 和额颞叶痴呆)中受到损害和破坏。 (16)然而,MAM 是否参与 DEHP诱导的神经毒性的关键步骤仍不清楚。
The ER is the essential organelle and more than one-third of the cellular proteins are synthesized, modified, and folded. ER stress refers to the accumulation of misfolded and unfolded proteins under stressful situations, triggering the unfolded protein response (UPR) to alleviate ER protein folding homeostasis and protect cells from stress. (17) UPR activation is involved in numerous inflammatory responses and neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. (18) Recently, some studies have showed that MAMs are necessary in modulating ER stress, which eventually initiates an apoptotic cascade. (19) Mitochondrial dynamics mean that mitochondria undergo morphologic changes to control energy production via maintaining a balance between mitochondrial fusion and mitochondrial fission. (20) Disorder of mitochondrial dynamics is related to mitochondrial dysfunction in nervous system diseases, including glaucoma and traumatic and neurodegenerative ones. (21) Recent studies showed that the MAMs are highlighted because they play a vital role in the mitochondrial fission process by marking the location of mitochondrial division. (22) However, the roles of UPR and mitochondrial dynamics in DEHP-induced neurotoxicity and its association with MAMs remain poorly characterized.
内质网是重要的细胞器,超过三分之一的细胞蛋白质被合成、修饰和折叠。内质网应激是指在应激情况下错误折叠和未折叠蛋白的积累,触发未折叠蛋白反应(UPR)以缓解内质网蛋白折叠稳态并保护细胞免受应激。 (17) UPR 激活涉及多种炎症反应和神经退行性疾病,例如帕金森病、阿尔茨海默病和亨廷顿病。 (18)最近,一些研究表明,MAM 对于调节 ER 应激是必要的,最终引发细胞凋亡级联反应。 (19)线粒体动力学是指线粒体发生形态变化,通过维持线粒体融合和线粒体裂变之间的平衡来控制能量产生。 (20)线粒体动力学紊乱与神经系统疾病中的线粒体功能障碍有关,包括青光眼、创伤性和神经退行性疾病。 (21)最近的研究表明,MAM 之所以受到关注,是因为它们通过标记线粒体分裂的位置,在线粒体裂变过程中发挥着至关重要的作用。 (22)然而,UPR 和线粒体动力学在 DEHP诱导的神经毒性中的作用及其与 MAM 的关联仍知之甚少。
Mitofusin-2 (Mfn2), as one of the vital mitochondrial fusion proteins, is physically associated with the MAM structure. (23) Protein kinase relative like endoplasmic reticulum kinase (PERK) as a MAM section can maintain the ER–mitochondria juxtapositions and facilitate mitochondrial apoptosis. (24) The blood–brain barrier (BBB) is an electively permeable cerebrovascular endothelial barrier that maintains the central nervous system homeostasis. (25) Here, we reported that DEHP could result in morphological changes, motor deficits, cognitive impairments, and BBB disruption in the brain. Moreover, DEHP could induce ER stress and mitochondrial dynamics disturbance, which inhibit the formation and function of MAMs. Interestingly, we found that the disruption of the Mfn2-PERK interaction played a pivotal role in DEHP-induced disorder of MAMs. Mechanistically, DEHP induced ER stress and mitochondrial dysfunction via inhibiting the Mfn2-PERK axis-mediated ER–mitochondria interaction in mouse brain. This study identifies the Mfn2-PERK axis as a critical regulator of nervous system development, which may be a novel way for treating neurological or systemic diseases.
Mitofusin-2 (Mfn2) 作为重要的线粒体融合蛋白之一,与 MAM 结构物理相关。 (23)内质网激酶 (PERK) 类似的蛋白激酶作为 MAM 部分可以维持 ER-线粒体并置并促进线粒体凋亡。 (24)血脑屏障(BBB)是一种选择性渗透性脑血管内皮屏障,可维持中枢神经系统的稳态。 (25)在此,我们报道 DEHP 可能导致大脑形态变化、运动缺陷、认知障碍和 BBB 破坏。此外,DEHP还可诱导内质网应激和线粒体动力学紊乱,从而抑制MAMs的形成和功能。有趣的是,我们发现Mfn2 - PERK相互作用的破坏在 DEHP诱导的 MAM 紊乱中发挥着关键作用。从机制上讲,DEHP 通过抑制小鼠大脑中Mfn2 - PERK介导的ER-线粒体相互作用诱导ER 应激和线粒体功能障碍。这项研究将Mfn2 - PERK轴确定为神经系统发育的关键调节因子,这可能是治疗神经系统或全身疾病的新方法。

2. Materials and Methods 2. 材料与方法

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2.1. Animals and Reagents
2.1.动物和试剂

All animal experiment processes and care of animals in this study were performed according to the Guidelines for Care and Use of Laboratory Animals of Northeast Agricultural University. Experiments were approved by the Animal Ethics Committee (NEAUEC20220341). All animal experiments comply with the ARRIVE guidelines. Institute of Cancer Research 3-week-old male mice were obtained from Liaoning Changsheng Biotech Co., Ltd. (Benxi, Liaoning, China) and housed in a 12:12 h light/dark cycle at 21–23 °C and with 35–65% humidity and fed with normal diet ad libitum. All mice were categorized as the control group (Con) and DEHP (200 mg/kg BW/day) exposure group (DEHP). Euthanasia of mice was performed by CO2 inhalation followed by cervical dislocation, and all samples were stored at −80 °C. DEHP was obtained from Aladdin Biochemical Technology Co., LTD., (Shanghai, China). The lowest observed adverse effect level of DEHP was established at 140 mg/kg. (26) For oral administration, the lethal dose 50 in rodent is 30 g/kg, and thus we used the doses of 200 mg/kg (1/150 LD50). (27) Therefore, it is difficult for DEHP to degrade in soil (1–264 mg/kg DEHP) or sewage sludge (12–1250 mg/kg DEHP), which persistently exists in the environment. (28)
本研究所有动物实验过程及动物护理均按照《东北农业大学实验动物护理与使用指南》进行。实验经动物伦理委员会批准(NEAUEC20220341)。所有动物实验均符合 ARRIVE 指南。 3周龄雄性小鼠获自辽宁长生生物科技有限公司(辽宁本溪),在21-23℃、35℃、12:12小时光/暗循环中饲养。 –65% 湿度,正常饮食随意喂养。所有小鼠均分为对照组 (Con) 和 DEHP (200 mg/kg BW/天) 暴露组 (DEHP)。通过CO 2吸入随后颈椎脱位对小鼠进行安乐死,所有样品均保存在-80℃。 DEHP 购自阿拉丁生化科技有限公司(中国上海)。 DEHP 观察到的最低不良反应水平为 140 毫克/千克。 (26)对于口服给药,啮齿动物的致死剂量 50 为30 g/kg,因此我们使用的剂量为200 mg/kg (1/150 LD 50 )。 (27)因此,DEHP在环境中持续存在的土壤(1-264 mg/kg DEHP)或污水污泥(12-1250 mg/kg DEHP)中很难降解。 (28)

2.2. Behavioral Experiments
2.2.行为实验

The forced swim and balance beam tests were conducted basically and essentially as previously described, (29,30) and their detailed methods are described in Supporting Information Methods 1.1.
强迫游泳和平衡木测试基本上如前所述进行(29,30) ,其详细方法在支持信息方法 1.1 中描述。

2.3. Evans Blue Staining 2.3.伊文思蓝染色

Evans blue staining was used to analyze BBB permeability as in a previous study. (31) Briefly, the mice were intravenously injected with 2% Evans blue dye (Sigma-Aldrich, USA), which was circulated for 2 h. The leakage of Evans blue into the brain tissue was analyzed. Then, the whole brain was harvested and photographed.
如之前的研究一样,使用伊文思蓝染色来分析 BBB 通透性。 (31)简而言之,给小鼠静脉注射2%伊文思蓝染料(Sigma-Aldrich,美国),循环2小时。分析了伊文思蓝渗入脑组织的情况。然后,收获整个大脑并拍照。

2.4. Histopathological Analysis
2.4.组织病理学分析

On the basis of a previous method, the brain tissues were embedded in paraffin and used for HE staining, Nissl staining, and Bielschowsky silver staining. (32−34) The slides were scanned using a microscope Panoramic MIDI (3DHISTECH Ltd., Budapest, Hungary). The numbers of total cells, neurons, and nerve fibers were quantified using ImageJ software according to a recent method. (35)
在原方法的基础上,将脑组织石蜡包埋,进行HE染色、尼氏染色、Bielschowsky银染。 (32−34)使用显微镜 Panoramic MIDI(3DHISTECH Ltd.,布达佩斯,匈牙利)扫描载玻片。根据最近的方法,使用 ImageJ 软件对总细胞、神经元和神经纤维的数量进行量化。 (35)

2.5. Ultrastructural Analysis
2.5.超微结构分析

Brain tissues were prepared for ultrastructural analysis according to previous methods. (36) In brief, the brain tissues were fixed in glutaraldehyde, postfixed in osmium tetroxide, and finally embedded in ethoxy resin. The sections were subsequently observed under a transmission electron microscope (Hitachi H7650 instrument, Tokyo, Japan).
根据之前的方法制备脑组织用于超微结构分析。 (36)简而言之,将脑组织固定在戊二醛中,后固定在四氧化锇中,最后包埋在乙氧基树脂中。随后在透射电子显微镜(日立 H7650 仪器,日本东京)下观察切片。

2.6. Quantitative Real-Time Polymerase Chain Reaction
2.6。定量实时聚合酶链式反应

Total RNA of brain tissues was isolated with the TRIZOL reagent, and reverse transcription was carried out with a reverse transcriptase kit (TransGen Biotech, Beijing, China) according to previous methods. (37) The gene expression was quantified by a QuantStudio 5 Real-Time PCR System (Thermo Fisher Scientific, USA). The 2–ΔΔCt method was chosen to calculate the mRNA relative level based on normalization to GAPDH. Primer sequences are listed in Supporting Information Table S1.
用TRIZOL试剂分离脑组织总RNA,并用逆转录酶试剂盒(全金生物科技,北京,中国)按照先前方法进行逆转录。 (37)通过QuantStudio 5实时PCR系统(Thermo Fisher Scientific,美国)对基因表达进行定量。选择 2 –ΔΔCt方法来计算基于 GAPDH 标准化的 mRNA 相对水平。引物序列列于支持信息表 S1 中。

2.7. Western Blotting 2.7.蛋白质印迹法

Total protein samples were extracted based on the previous protocol. (38,39) The protein of brain tissues was extracted using RIPA lysis solution (APExBIO, Houston, USA; MeilunBio, China) and supplemented with a protease inhibitor cocktail (MedChem Express, HY-K0010, USA). The proteins were separated with the standard SDS-PAGE procedure and transferred to nitrocellulose membranes, which were subsequently incubated using the primary antibody (Affinity, USA; Proteintech, USA; GeneTex, USA; ABclonal Technology, China; Bioss, China) at 4 °C overnight. At last, the members were incubated with the secondary antibody. The protein bands were imaged with Amersham Imager 600 (GE, Switzerland) and processed with ImageJ software.
根据之前的方案提取总蛋白样品。 (38,39)使用 RIPA 裂解液(APExBIO,休斯顿,美国;美伦生物,中国)提取脑组织蛋白质,并补充蛋白酶抑制剂混合物(MedChem Express,HY-K0010,美国)。使用标准 SDS-PAGE 程序分离蛋白质并转移到硝酸纤维素膜上,随后使用一抗(Affinity,美国;Proteintech,美国;GeneTex,美国;ABclonal Technology,中国;Bioss,中国)在 4° 下孵育C过夜。最后,将成员与二抗一起孵育。使用 Amersham Imager 600(GE,瑞士)对蛋白质条带进行成像并使用 ImageJ 软件进行处理。

2.8. Immunofluorescence 2.8.免疫荧光

Immunofluorescence (IF) was performed according to our previous study. (40,41) The IF staining of brain tissues is described in detail in Supporting Information Methods 1.2 and 1.3 and analyzed using a fluorescence microscope (Leica, Germany).
免疫荧光(IF)是根据我们之前的研究进行的。 (40,41)脑组织的 IF 染色在支持信息方法 1.2 和 1.3 中有详细描述,并使用荧光显微镜(Leica,德国)进行分析。

2.9. Statistical Analysis
2.9.统计分析

All statistical analyses were carried out using GraphPad Prism 8 and t tests at the significance level of 0.05. Data are expressed as mean ± SD from at least three independent experiments. Correlation analysis was performed using R programming language. Principal component analysis (PCA) and redundancy analysis (RDA) were performed using the OmicStudio tools at https://www.omicstudio.cn/tool. The search tool for the retrieval of the interacting proteins database (http://string-db.org) was used for predicting protein networks.
所有统计分析均使用 GraphPad Prism 8 和显着性水平 0.05 的t检验进行。数据表示为至少三个独立实验的平均值±SD。使用R编程语言进行相关性分析。使用 OmicStudio 工具进行主成分分析 (PCA) 和冗余分析 (RDA),网址为https://www.omicstudio.cn/tool 。用于检索相互作用蛋白质数据库的搜索工具( http://string-db.org )用于预测蛋白质网络。

3. Results 3. 结果

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3.1. DEHP Caused Structure Damage and Dysfunction in Mouse Brain
3.1. DEHP 导致小鼠大脑结构损伤和功能障碍

To explore the possible effect of DEHP on the brain structure and function, we set out to perform an animal experiment of the treatment with DEHP (Figure 1A). The brain has varieties of functions, and its structures are very closely related with one another (Figure 1B). We first performed the forced swim and balance beam tests to assess depressive-like behavior and motor coordination. The balance beam test showed that the mice of the DEHP exposure group took an obviously longer time to traverse the balance beam compared to that of the Con group (Figure 1G). Moreover, the forced swim test suggested that the mice of the DEHP exposure group exhibited a decreased immobility time compared to that of the Con group (Figure 1H).
为了探讨DEHP对大脑结构和功能的可能影响,我们着手进行DEHP治疗的动物实验(图1A )。大脑具有多种功能,其结构彼此密切相关(图1B )。我们首先进行强迫游泳和平衡木测试,以评估抑郁样行为和运动协调性。平衡木测试显示,与Con组相比,DEHP暴露组小鼠跨越平衡木的时间明显更长(图1G )。此外,强迫游泳测试表明,与 Con 组相比,DEHP 暴露组的小鼠表现出减少的不动时间(图 1 H)。

Figure 1 图1

Figure 1. DEHP caused structure damage and dysfunction in mouse brain. (A) Mice were treated with DEHP by oral gavage for 28 days. (B) Brain structure image. (C) Histopathology of brain with H&E, silver, and Nissi staining; yellow arrow: vacuolation or disordered arrangement; green arrow: vacuolation or disordered arrangement; red arrow: incomplete nerve fibers; ultrastructure of neuron; yellow: mitochondria; orange: ER. (D) Number of total cells in the CTX and HPC. (E) Number of neurons in the CTX and HPC. (F) Number of nerve fibers in the CTX and HPC. (G) Time of the balance beam. (H) Time of forced swim. Data are presented as the mean ± SD. Symbol for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.
图 1. DEHP 导致小鼠大脑结构损伤和功能障碍。 (A) 小鼠经口灌胃 DEHP 治疗 28 天。 (B) 大脑结构图像。 (C) H&E、银染色和尼西染色的脑组织病理学;黄色箭头:空泡或无序排列;绿色箭头:空泡或无序排列;红色箭头:不完整的神经纤维;神经元超微结构;黄色:线粒体;橙色:急诊室。 (D) CTX 和 HPC 中的总细胞数。 (E) CTX 和 HPC 中的神经元数量。 (F) CTX 和 HPC 中的神经纤维数量。 (G) 平衡木的时间。 (H) 强迫游泳的时间。数据以平均值±标准差表示。 Con组和DEHP组之间差异显着性的符号:** P < 0.01,*** P < 0.001。

Then, we used HE, Nissl, and Bielschowsky silver staining to observe the morphological changes in the cerebral cortex (CTX) and hippocampus (HPC) of brain (Figure 1C). HE and Nissl staining showed that the cerebral CTX and HPC neurons were in neat rows, close together, and of normal cell morphology and size in the Con group. However, irregular neuronal arrangement, cellular vacuolation, nuclear pyknosis, and cellular vacuolization were observed in the cerebral CTX and HPC neurons of the DEHP exposure group. The silver-plated staining results showed that nerve fibers were intact, and the arrangement was uniform and orderly in the Con group. However, incomplete nerve fibers and disordered arrangement were shown in the DEHP exposure group. We then further quantitatively analyzed the number of total cells, neurons, and nerve fibers. An obviously reduced number of total cells and neurons in the CTX and HPC was observed in the DEHP exposure group compared with the Con group (Figure 1D,E). There was a visible reduction in the number of nerve fibers in the CTX and HPC in the DEHP exposure group (Figure 1F). To further explore the effect of DEHP on the neuronal structure, we employed TEM to examine the ultrastructure of ER and mitochondria. Ultrastructural analysis showed that the morphologies of mitochondria and ER were normal in neurons of the Con group. However, the mitochondria underwent swelling and vacuolation, the ER had slight swelling, and mitochondrial cristae were broken in neurons of the DEHP exposure group (Figure 1C). Consequently, these data indicated that DEHP could cause morphological changes, motor deficits, and cognitive impairments in the brain.
然后,我们使用HE、Nissl和Bielschowsky银染色观察大脑大脑皮层(CTX)和海马(HPC)的形态变化(图1C )。 HE和尼氏染色显示Con组脑CTX和HPC神经元排列整齐、紧密相连,细胞形态和大小正常。然而,DEHP暴露组的大脑CTX和HPC神经元中观察到神经元排列不规则、细胞空泡化、核固缩和细胞空泡化。镀银染色结果显示Con组神经纤维完整,排列均匀有序。但DEHP暴露组神经纤维不完整、排列紊乱。然后我们进一步定量分析了总细胞、神经元和神经纤维的数量。与 Con 组相比,DEHP 暴露组的 CTX 和 HPC 中总细胞和神经元数量明显减少(图 1 D、E)。 DEHP 暴露组中 CTX 和 HPC 中的神经纤维数量明显减少(图 1 F)。为了进一步探讨DEHP对神经元结构的影响,我们采用TEM观察ER和线粒体的超微结构。超微结构分析显示Con组神经元线粒体和内质网形态正常。然而,DEHP暴露组神经元的线粒体出现肿胀和空泡化,内质网轻微肿胀,线粒体嵴破裂(图1C )。因此,这些数据表明 DEHP 可能会导致大脑形态变化、运动缺陷和认知障碍。
The BBB is a natural barrier that prevents harmful substances in the blood from entering into contact with the brain. To explore the effect of DEHP on BBB damage in brain, we detected BBB permeability using Evans Blue staining and critical tight junction (TJ) proteins at the BBB. Here, we found that TJ-related protein (claudin-1, claudin-5, occludin, and ZO-1) levels were downregulated in the DEHP exposure group (Figure 2A–E). Consistent with the western blotting(WB) data, the IF results suggested a significant decrease in claudin-1, claudin-5, occludin, and ZO-1 in response to DEHP exposure. Therefore, IF showed that claudin-1 and claudin-5 and occludin and ZO-1 were colocalized in mouse brain tissue (Figure 2F,G). Furthermore, the leakage of Evans blue in the brain tissue was markedly increased by DEHP exposure relative to the Con group (Figure S1A). These data indicated that DEHP causes structure damage and dysfunction in mouse brain.
血脑屏障是一道天然屏障,可防止血液中的有害物质进入大脑。为了探索 DEHP 对大脑 BBB 损伤的影响,我们使用伊文思蓝染色和 BBB 上的关键紧密连接 (TJ) 蛋白检测了 BBB 通透性。在这里,我们发现 DEHP 暴露组中 TJ 相关蛋白(claudin-1、claudin-5、occludin 和 ZO-1)水平下调(图 2 A-E)。与蛋白质印迹 (WB) 数据一致,IF 结果表明,暴露于 DEHP 后,claudin-1、claudin-5、occludin 和 ZO-1 显着减少。因此,IF显示claudin-1和claudin-5以及occludin和ZO-1在小鼠脑组织中共定位(2F,G)。此外,相对于Con组,DEHP暴露使脑组织中伊文思蓝的渗漏显着增加(图S1A )。这些数据表明DEHP会导致小鼠大脑结构损伤和功能障碍。

Figure 2 图2

Figure 2. DEHP impaired BBB permeability and induced BBB dysfunction in mouse brain. (A) Protein levels of claudin 1, claudin 5, occludin, and ZO-1. (B) Protein relative level of claudin 1. (C) Protein relative level of claudin 5. (D) Protein relative level of occludin. (E) Protein relative level of ZO-1. (F) Representative IF images of claudin 1 and claudin 5 on the brain. (G) Representative IF images of occludin and ZO-1 on the brain. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.
图 2. DEHP 损害小鼠大脑中的 BBB 通透性并诱导BBB 功能障碍。 (A) 密蛋白 1、密蛋白 5、occludin 和 ZO-1 的蛋白质水平。 (B) 密蛋白 1 的蛋白质相对水平。(C) 密蛋白 5 的蛋白质相对水平。(D) 密蛋白 5 的蛋白质相对水平。 (E) ZO-1 的蛋白质相对水平。 (F) 大脑中紧密蛋白 1 和紧密蛋白 5 的代表性 IF 图像。 (G) occludin 和 ZO-1 在大脑上的代表性 IF 图像。数据以平均值±标准差表示。 Con组和DEHP组之间差异显着性的符号:** P < 0.01,*** P < 0.001。

3.2. DEHP Resulted in the Disruption of MAM Integrity and Function in the Mouse Brain
3.2. DEHP 导致小鼠大脑中 MAM 完整性和功能的破坏

The structural and functional integrity of MAMs contributes to the maintenance of Ca2+ homeostasis and determines the normal communication between the mitochondria and ER. (42) To further determine the effect of DEHP on the MAM integrity, we detected the levels of proteins involved in MAM formation. MAMs modulate Ca2+ transfer from ER to mitochondria via formatting a macromolecular complex comprising GRP75 and VDAC1. Here, we first utilized WB and found the levels of proteins. Both GRP75 and VDAC1 were significantly increased after exposure to DEHP (Figure 3A). Consistent with the previous findings, (10) the IF results suggested a significant increase in GRP75 and VDAC1 in response to DEHP exposure. Therefore, IF showed that GRP75 and VDAC1 were colocalized in mouse brain tissue (Figure 3B). qPCR demonstrated that the mRNA expression levels of MAM-related proteins (IP3R, VDAC1, GRP75, ERP44, S100B, Presenilin-2, Sigma1-R, PACS2, PSS1, PSS2, DGAT2, and ACAT1) were significantly upregulated from Con to DEHP exposure (Figures 3C and S2). The parameters of MAM-related proteins (IP3R, VDAC1, GRP75, ERP44, S100B, Presenilin-2, Sigma1-R, PACS2, PSS1, PSS2, DGAT2, and ACAT1) were examined by using PCA, which further verified that DEHP induced MAM formation disorder (Figure 3D,E). The data indicated that DEHP could cause the disruption of MAM integrity and function in mouse brain.
MAM 的结构和功能完整性有助于维持 Ca 2+稳态并决定线粒体和 ER 之间的正常通讯。 (42)为了进一步确定 DEHP 对 MAM 完整性的影响,我们检测了参与 MAM 形成的蛋白质水平。 MAM 通过形成包含 GRP75 和 VDAC1 的大分子复合物来调节 Ca 2+从 ER 到线粒体的转移。在这里,我们首先利用 WB 来确定蛋白质的水平。暴露于 DEHP 后,GRP75 和 VDAC1 均显着增加(图 3 A)。与之前的研究结果一致, (10) IF 结果表明,DEHP 暴露后 GRP75 和 VDAC1 显着增加。因此,IF 显示 GRP75 和 VDAC1 在小鼠脑组织中共定位(图 3 B)。 qPCR 证明,MAM 相关蛋白( IP3RVDAC1GRP75ERP44S100BPresenilin-2Sigma1-RPACS2PSS1PSS2DGAT2ACAT1 )的 mRNA 表达水平从 Con 暴露到 DEHP 显着上调(图3CS2 )。利用PCA检测MAM相关蛋白( IP3RVDAC1GRP75ERP44S100BPresenilin-2Sigma1-RPACS2PSS1PSS2DGAT2ACAT1 )参数,进一步验证DEHP诱导MAM形成紊乱(3D、E)。 数据表明,DEHP 可能会破坏小鼠大脑中 MAM 的完整性和功能。

Figure 3 图3

Figure 3. DEHP resulted in the disruption of MAM integrity and function in mouse brain. (A) Protein relative levels of GRP75 and VDAC1. (B) Representative IF images of GRP75 and VDAC1 on the brain. (C) Heatmap presentation of relative mRNA levels of MAM-related proteins. (D) PCA. (E) MAM pathway. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.
图 3. DEHP 导致小鼠大脑中 MAM 完整性和功能的破坏。 (A) GRP75 和 VDAC1 的蛋白质相对水平。 (B) GRP75 和 VDAC1 在大脑上的代表性 IF 图像。 (C) MAM 相关蛋白相对 mRNA 水平的热图呈现。 (D) 主成分分析。 (E) MAM 途径。数据以平均值±标准差表示。 Con组和DEHP组之间差异显着性的符号:** P < 0.01,*** P < 0.001。

3.3. DEHP Led to the Disorder of Mitochondrial Dynamics in Mouse Brain
3.3. DEHP导致小鼠大脑线粒体动力学紊乱

Mitochondrial dynamics contributes to maintaining mitochondrial integrity and refers to the constant remodeling of mitochondria by fusion and fission events. To identify the effect of DEHP on the mitochondrial dynamics, we detected the levels of mitochondrial dynamics-related proteins. We found that the proteins levels of Mfn2, Mfn1, and OPA1 were obviously reduced, and the Drp1 protein level was clearly upregulated in the DEHP exposure group by WB analysis (Figure 4A–E). Consistently, the mRNA levels of mitochondrial fusion-related proteins (Mfn2, Mfn1, and OPA1) were obviously reduced, and mitochondrial fission-related proteins (Drp1, Fis1, and MFF) were clearly increased in the DEHP exposure group compared to the Con group (Figure 4F–K). RDA of MAMs and mitochondrial dynamics-related factors showed that MAMs were highly negatively correlated with mitochondrial fusion and highly positively correlated with mitochondrial fission and further verified that DEHP induced mitochondrial dynamics disorder (Figure 4L,M). All these data indicated that DEHP could induce disorder of mitochondrial dynamics, which might be related to disrupted MAM integrity and function in mouse brain.
线粒体动力学有助于维持线粒体完整性,是指通过融合和裂变事件不断重塑线粒体。为了确定 DEHP 对线粒体动力学的影响,我们检测了线粒体动力学相关蛋白的水平。通过WB分析发现,DEHP暴露组中Mfn2、Mfn1和OPA1的蛋白水平明显降低,Drp1蛋白水平明显上调(图4A -E)。一致地,与 Con 组相比,DEHP 暴露组中线粒体融合相关蛋白( Mfn2Mfn1OPA1 )的 mRNA 水平明显降低,线粒体分裂相关蛋白( Drp1Fis1MFF )明显增加。 (图 4 F–K)。 MAMs和线粒体动力学相关因子的RDA显示,MAMs与线粒体融合呈高度负相关,与线粒体裂变呈高度正相关,进一步验证了DEHP引起线粒体动力学紊乱(4L,M)。所有这些数据表明DEHP可引起线粒体动力学紊乱,这可能与小鼠大脑中MAM完整性和功能的破坏有关。

Figure 4 图4

Figure 4. DEHP led to disorder of mitochondrial dynamics in mouse brain. (A) Protein levels of Mfn2, Mfn1, OPA1, and Drp1. (B) Protein relative level of Mfn2. (C) Protein relative level of Mfn1. (D) Protein relative level of OPA1. (E) Protein relative level of Drp1. (F) mRNA relative level of Mfn2. (G) mRNA relative level of Mfn1. (H) mRNA relative level of OPA1. (I) mRNA relative level of Drp1. (J) mRNA relative level of Fis1. (K) mRNA relative level of MFF. (L) RDA for the relevance of mitochondrial dynamics and MAMs. (M) Mitochondrial dynamics pathway. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: *P < 0.05, **P < 0.01, ***P < 0.001.
图4. DEHP导致小鼠大脑线粒体动力学紊乱。 (A) Mfn2、Mfn1、OPA1 和 Drp1 的蛋白质水平。 (B) Mfn2 的蛋白质相对水平。 (C) Mfn1 的蛋白质相对水平。 (D) OPA1 的蛋白质相对水平。 (E) Drp1 的蛋白质相对水平。 (F) Mfn2 的 mRNA 相对水平。 (G) Mfn1 的 mRNA 相对水平。 (H) OPA1 mRNA 相对水平。 (I) Drp1 mRNA相对水平。 (J) Fis1 的 mRNA 相对水平。 (K) MFF 的 mRNA 相对水平。 (L) RDA 与线粒体动力学和 MAM 的相关性。 (M) 线粒体动力学途径。数据以平均值±标准差表示。 Con组和DEHP组之间差异显着性的符号:* P < 0.05,** P < 0.01,*** P < 0.001。

3.4. DEHP Induces ER Stress and Activates UPR in Mouse Brain
3.4. DEHP诱导小鼠大脑内质网应激并激活 UPR

Numerous studies have found that ER stress always accompanies mitochondrial dysfunction. To identify whether ER stress is involved in DEHP-induced mitochondrial dynamics and MAM disorders, we detected the levels of UPR-related proteins. Here, we found that ER stress-related protein (p-PERK, p-eIF2a, ATF4, and GRP78) levels were upregulated in the DEHP exposure group (Figure 5A–E). We also demonstrated that the mRNA levels of UPR-related proteins (XBP1, ATF4, ATF6, PERK, IRE1, CHOP, GRP78, GRP94, and eIF2a) were increased with DEHP exposure compared with the Con group (Figures 5F and S3). The parameters of UPR-related proteins were examined by using PCA, which further verified that DEHP triggered ER stress and activated UPR (Figure 5G,H). The data indicated that DEHP could cause ER stress and activate UPR in mouse brain.
大量研究发现,内质网应激总是伴随着线粒体功能障碍。为了确定 ER 应激是否与 DEHP诱导的线粒体动力学和 MAM 紊乱有关,我们检测了 UPR 相关蛋白的水平。在这里,我们发现 DEHP 暴露组中内质网应激相关蛋白(p-PERK、p-eIF2a、ATF4 和 GRP78)水平上调(图 5 A-E)。我们还证明,与Con组相比,UPR相关蛋白( XBP1ATF4ATF6PERKIRE1CHOPGRP78GRP94eIF2a )的mRNA水平随着DEHP暴露而增加(图5FS3 )。利用PCA对UPR相关蛋白的参数进行检测,进一步验证了DEHP触发了ER应激并激活了UPR(5G,H)。数据表明DEHP可以引起ER应激并激活小鼠大脑中的UPR。

Figure 5 图5

Figure 5. DEHP induces ER stress and activates UPR in mouse brain. (A) Protein levels of PERK, p-PERK, eIF2a, p-eIF2a, ATF4, and GRP78. (B) Protein relative level of p-PERK. (C) Protein relative level of p-eIF2a. (D) Protein relative level of ATF4. (E) Protein relative level of GRP78. (F) Heatmap presentation of relative mRNA levels of UPR-related proteins. (G) PCA. (H) UPR pathway. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.
图 5. DEHP 在小鼠大脑中诱导ER 应激并激活 UPR。 (A) PERK、p-PERK、eIF2a、p-eIF2a、ATF4 和 GRP78 的蛋白质水平。 (B) p-PERK 的蛋白质相对水平。 (C) p-eIF2a 的蛋白质相对水平。 (D) ATF4 的蛋白质相对水平。 (E) GRP78 的蛋白质相对水平。 (F) UPR 相关蛋白相对 mRNA 水平的热图呈现。 (G)主成分分析。 (H)UPR途径。数据以平均值±标准差表示。 Con组和DEHP组之间差异显着性的符号:** P < 0.01,*** P < 0.001。

3.5. DEHP Caused Disruption of the ER–Mitochondria Interaction by Inhibiting the Mfn2-PERK Axis
3.5. DEHP 通过抑制Mfn2 - PERK轴引起 ER-线粒体相互作用的破坏

Some studies have found that ER stress and mitochondrial dysfunction could induce apoptosis. (43) Consistently, the TUNEL staining results indicated that TUNEL positive rates in the DEHP exposure group were obviously increased compared with the Con group (Figure S1B). Moreover, the protein expression of Bcl2 was clearly decreased and Bax was increased, and the Bax/Bcl2 ratio was significantly elevated after exposure to DEHP (Figure S1C). In MAMs, the interaction of Mfn2 with PERK could affect mitochondrial Ca2+ levels and mitochondrial morphology. (44) To further identify whether the Mfn2-PERK axis is involved in DEHP-induced MAM disorders, we performed IF colocalization analysis. Here, IF results showed that Mfn2 was colocalized with PERK. Consistently, the level of Mfn2 was reduced and PERK was upregulated in the DEHP exposure group compared to the Con group, respectively (Figure 6A). From the results of correlation analysis and the PPI network, it could be observed that Mfn2 is significantly negatively correlated with PERK (Figure 6B,C). To confirm the possible interaction between DEHP and Mfn2 at the molecular level, we carried out the protein ligand docking analysis, which suggested a stable combination (Figure 6D). In summary, we unraveled a mechanism of DEHP-induced disruption of the ER–mitochondria interaction by inhibiting the Mfn2-PERK axis in mouse brain (Figure 7).
一些研究发现内质网应激和线粒体功能障碍可以诱导细胞凋亡。 (43)一致地,TUNEL染色结果表明DEHP暴露组的TUNEL阳性率较Con组明显升高(图S1B )。而且,暴露于DEHP后,Bcl2蛋白表达明显降低,Bax蛋白表达增加,Bax/Bcl2比值显着升高(图S1C )。在 MAM 中,Mfn2 与 PERK 的相互作用可能影响线粒体 Ca 2+水平和线粒体形态。 (44)为了进一步确定Mfn2 - PERK轴是否参与 DEHP诱导的MAM 疾病,我们进行了 IF 共定位分析。此处,IF 结果显示 Mfn2 与 PERK 共定位。一致地,与 Con 组相比,DEHP 暴露组的 Mfn2 水平降低,PERK 水平上调(图 6 A)。从相关性分析和PPI网络的结果可以看出,Mfn2与PERK呈显着负相关(6B、C)。为了在分子水平上确认DEHP和Mfn2之间可能存在的相互作用,我们进行了蛋白质配体对接分析,结果表明存在稳定的组合(图6D )。总之,我们揭示了 DEHP 通过抑制小鼠大脑中的Mfn2 - PERK轴而诱导ER-线粒体相互作用破坏的机制(图 7 )。

Figure 6 图6

Figure 6. DEHP caused disruption of the ER–mitochondria interaction by inhibiting Mfn2-PERK axis in mouse brain. (A) Representative IF images of Mfn2 and PERK on the brain. (B) Correlation analysis of mitochondrial dynamics, MAMs, and UPR. (C) PPI network of mitochondrial dynamics, MAMs, and UPR. (D) Molecular docking simulation for the ligand–protein binding of DEHP with Mfn2.
图 6. DEHP 通过抑制小鼠大脑中的Mfn2 - PERK轴来破坏 ER-线粒体相互作用。 (A) Mfn2 和 PERK 在大脑上的代表性 IF 图像。 (B) 线粒体动力学、MAM 和 UPR 的相关性分析。 (C) 线粒体动力学、MAM 和 UPR 的 PPI 网络。 (D) DEHP 与 Mfn2 配体-蛋白质结合的分子对接模拟。

Figure 7 图7

Figure 7. DEHP induced neurotoxicity by disrupting the Mfn2-PERK axis-mediated ER–mitochondria interaction.
图 7. DEHP 通过破坏Mfn2 - PERK介导的ER-线粒体相互作用来诱导神经毒性

4. Discussion 4. 讨论

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DEHP, as an emerging agricultural organic pollutant in environmental science, can lead to accumulation in the soil, which is absorbed by plants and enters into the food chain cycle. (45) In recent years, several studies have described that DEHP has neurotoxic and neurobehavioral toxicity, but the concrete mechanism and its association with mitochondria or ER are not clear. To address this issue, we tested whether the dysfunctional mitochondria and/or ER are involved in DEHP-induced neurotoxicity. Here, we demonstrated that DEHP caused brain morphology and physiopathology injury. The results indicated that DEHP led to the disruption of MAM integrity and function, the disorder of mitochondrial dynamics, and ER stress in mouse brain. The MAM integrity disruption is likely through its direct interaction with Mfn2-mediated mitochondrial dynamics disorder and PERK-mediated ER stress. Therefore, we then confirmed the role of the Mfn2-PERK axis in DEHP-induced MAM disorder. At present, an increasing number of studies are focusing on the development and evaluation of novel treatment approaches of neurological diseases. (46−49) These observations render the Mfn2-PERK axis a promising target that exerts the potential to alleviate DEHP-induced neurotoxicity.
DEHP作为环境科学中新兴的农业有机污染物,可导致土壤中积累,被植物吸收并进入食物链循环。 (45)近年来,多项研究描述DEHP具有神经毒性和神经行为毒性,但具体机制及其与线粒体或ER的关系尚不清楚。为了解决这个问题,我们测试了功能失调的线粒体和/或 ER 是否与 DEHP诱导的神经毒性有关。在这里,我们证明 DEHP 会导致脑形态和病理生理学损伤。结果表明,DEHP 导致小鼠大脑 MAM 完整性和功能破坏、线粒体动力学紊乱和 ER 应激。 MAM 完整性破坏可能是通过其与 Mfn2 介导的线粒体动力学紊乱和 PERK 介导的 ER 应激的直接相互作用实现的。因此,我们随后证实了Mfn2 - PERK轴在 DEHP诱导的MAM 紊乱中的作用。目前,越来越多的研究集中在神经系统疾病新治疗方法的开发和评估上。 (46−49)这些观察结果使Mfn2 - PERK轴成为一个有希望的靶点,具有减轻 DEHP诱导的神经毒性的潜力。
The brain is separated into hippocampus and cerebral cortex tissues, which are the most damaged regions of the brain. The cerebral cortex of the brain is a central structure that enables higher cognitive functions or intellectual skills. The hippocampus of the brain is a key structure in many cognitive functions, especially episodic memory. (50) Therefore, the impaired development of the CTX and HPC, which play a crucial role in memory and learning, may lead to cognitive deficiency. In this study, DEHP exposure resulted in neuronal loss, damaged neurons, and decreased nerve fibers in the CTX and HPC of the brain. Recent studies reported that phthalates’ exposure could harm brain development and increase risks for learning, attention, and conduct disorders. (51) Consistently, our results indicated that DEHP exposure caused motor deficits and cognitive impairments in the brain. The BBB serves as a natural barrier between the central nervous system and bloodstream, protecting the brain against unwanted or harmful substances in the blood. TJ proteins are the main structural and functional components of BBB integrity. Some studies have reported that DEHP disrupts the BBB integrity and surrounding parenchyma in the medial preoptic area and triggers an inflammatory profile in the HPC. (52,53) A recent finding suggested that DEHP-induced neurotoxicity is possibly associated with BBB dysfunction and neuroinflammation. (54) In the present study, DEHP induced TJ protein changes and disrupted the integrity of the BBB, resulting in an increase in permeability. Then, DEHP crossed the BBB and directly contacted the nerve cells and eventually impaired the nervous system and induced neurotoxicity, such as motor deficits, cognitive impairments, neuronal loss, damaged neurons, and decreased nerve fibers. Thus, the current results indicated that DEHP could cause the damage or dysfunction of the nervous system.
大脑分为海马体和大脑皮层组织,这是大脑中受损最严重的区域。大脑的大脑皮层是实现更高认知功能或智力技能的中心结构。大脑的海马体是许多认知功能的关键结构,尤其是情景记忆。 (50)因此,在记忆和学习中起关键作用的 CTX 和 HPC 发育受损可能会导致认知缺陷。在这项研究中,DEHP 暴露导致大脑 CTX 和 HPC 中的神经元损失、神经元受损和神经纤维减少。最近的研究报告称,接触邻苯二甲酸盐可能会损害大脑发育,并增加学习、注意力和行为障碍的风险。 (51)我们的结果一致表明,DEHP 暴露会导致大脑运动缺陷和认知障碍。血脑屏障是中枢神经系统和血液之间的天然屏障,保护大脑免受血液中不需要或有害物质的侵害。 TJ 蛋白是 BBB 完整性的主要结构和功能成分。一些研究报告称,DEHP 会破坏内侧视前区的 BBB 完整性和周围实质,并引发 HPC 炎症。 (52,53)最近的一项发现表明,DEHP引起的神经毒性可能与 BBB 功能障碍和神经炎症有关。 (54)在本研究中,DEHP诱导TJ 蛋白变化并破坏 BBB 的完整性,导致通透性增加。 然后,DEHP穿过血脑屏障,直接接触神经细胞,最终损害神经系统并诱发神经毒性,如运动缺陷、认知障碍、神经元丢失、神经元受损和神经纤维减少等。因此,目前的结果表明DEHP可能会导致神经系统的损伤或功能障碍。
The physiology of the brain is regulated by the mitochondria, which may change during neuronal differentiation. The ER is a central hub for controlling protein homeostasis, affecting various cellular processes in brain function. MAMs mediate the communication between mitochondria and the ER and play a more pronounced role in neurons. Some advances have indicated that pathological changes in neurodegenerative diseases are related to changes in ER–mitochondria signaling, including MAM integrity injury, ER stress responses, mitochondrial dynamic disorder, and synaptic dysfunction. Recent reports suggested that MAMs are involved in inflammation and apoptosis and associate with traumatic brain injury. (55) Recent studies indicated that specialized contacts modulate neuron and synapse, and disturbances to MAMs result in neurodegenerative diseases. (56) Consistently, our data suggested that DEHP could change the proteins involved in MAM formation, which resulted in the disruption of MAM integrity in mouse brain. Taken together, the findings underscore the significance of MAM integrity in maintaining a healthy nervous system.
大脑的生理机能由线粒体调节,线粒体在神经元分化过程中可能会发生变化。内质网是控制蛋白质稳态的中枢,影响大脑功能中的各种细胞过程。 MAM 介导线粒体和 ER 之间的通讯,并在神经元中发挥更显着的作用。一些进展表明,神经退行性疾病的病理变化与内质网-线粒体信号的变化有关,包括MAM完整性损伤、内质网应激反应、线粒体动态紊乱和突触功能障碍。最近的报告表明,MAM 参与炎症和细胞凋亡,并与创伤性脑损伤有关。 (55)最近的研究表明,专门的接触调节神经元和突触,而对 MAM 的干扰会导致神经退行性疾病。 (56)我们的数据一致表明,DEHP 可以改变参与 MAM 形成的蛋白质,从而导致小鼠大脑中 MAM 完整性的破坏。总而言之,这些发现强调了 MAM 完整性在维持神经系统健康方面的重要性。
Mitochondrial dynamics, as a quality control mechanism, can be combined with multiple functions in response to alterations in physiology, which contributes to mitochondrial function and quality control. The interaction of mitochondrial fusion and fission brings a wide range of benefits on mitochondria, such as efficient transport and energy production. Although mitochondrial fission and fusion as well as the proteins controlling the processes are ubiquitous, related diseases are mainly neurological disorders. Recent studies found that inhibition of the proteins involved in mitochondrial dynamics could cause defects in brain development and functioning. (57) Moreover, some findings revealed that mitochondrial dynamics play a vital role in mature neurons and brain development, especially during the process of neurogenesis. (58) This study revealed that DEHP promoted mitochondrial fission and suppressed mitochondrial fusion, resulting in brain mitochondrial dysfunction. The findings of numerous studies showed that Mfn2, as a critical factor, maintains mitochondrial dynamics balance and mitochondrial function. (59) Mfn2 is considered to be a potential therapeutic target for treating neurological disorders through actions on medium spiny neuron structures and functions. (60) A recent study suggested that Mfn2 mutations can lead to neurodegenerative Charcot-Marie-Tooth disease type 2A. (61) Similarly, we demonstrated here that DEHP inhibited mitochondrial fusion by downregulating the Mfn2 protein level, ultimately leading to mitochondrial fragmentation and dysfunction in neural cells. Overall, we showed that DEHP caused mitochondrial alterations and mitochondrial dynamics disorder through Mfn2 ablation.
线粒体动力学作为一种质量控制机制,可以与多种功能结合以响应生理变化,这有助于线粒体功能和质量控制。线粒体融合和裂变的相互作用给线粒体带来了广泛的好处,例如有效的运输和能量生产。尽管线粒体裂变和融合以及控制该过程的蛋白质无处不在,但相关疾病主要是神经系统疾病。最近的研究发现,抑制参与线粒体动力学的蛋白质可能会导致大脑发育和功能缺陷。 (57)此外,一些研究结果表明,线粒体动力学在成熟神经元和大脑发育中发挥着至关重要的作用,特别是在神经发生过程中。 (58)这项研究表明,DEHP 促进线粒体裂变并抑制线粒体融合,导致脑线粒体功能障碍。大量研究结果表明,Mfn2作为维持线粒体动力学平衡和线粒体功能的关键因子。 (59) Mfn2 被认为是通过作用于中棘神经元结构和功能来治疗神经系统疾病的潜在治疗靶点。 (60)最近的一项研究表明,Mfn2 突变可导致神经退行性腓骨肌萎缩症 2A 型。 (61)同样,我们在此证明 DEHP 通过下调 Mfn2 蛋白水平来抑制线粒体融合,最终导致神经细胞线粒体断裂和功能障碍。 总体而言,我们表明 DEHP 通过 Mfn2 消除引起线粒体改变和线粒体动力学紊乱。
ER stress is the stress response of the body to external stimuli, which results in the massive accumulation of unfolded proteins. Recent research studies indicated that presynaptic store-operated calcium entry is related to ER stress and increased neurotransmission, which could accelerate the process of neurodegeneration. (62) Some findings showed that ER stress facilitates neuronal autophagy and results in neuronal cell death, which might be a promising therapeutic strategy for intracerebral hemorrhage. (63) Our data revealed that DEHP could induce disruptions of ER homeostasis and result in ER stress in mouse brain. As an ER stress sensor, PERK initiates signaling pathways that influence ER quality control through various mechanisms. When ER stress occurs, the activation of PERK/eIF2A results in ATF4 translation and CHOP upregulation. Recent reports suggested that PERK is used as a marker of neuronal activation in central and peripheral nervous systems. (64) Furthermore, the activation of PERK leads to motor capacity disorder, indicating that PERK is detrimental to Charcot–Marie–Tooth disease type 1B neuropathy. (65) In our study, the results showed that DEHP caused GRP78 dissociation from PERK and activated PERK protein. Above all, we propose that DEHP caused ER stress and triggered UPR activation by mainly activating PERK/eIF2a/ATF4 signaling.
内质网应激是机体对外界刺激的应激反应,导致未折叠蛋白大量积累。最近的研究表明,突触前库操纵的钙进入与内质网应激和神经传递增加有关,这可能会加速神经退行性变的过程。 (62)一些研究结果表明,内质网应激促进神经元自噬并导致神经元细胞死亡,这可能是脑出血的一种有前景的治疗策略。 (63)我们的数据显示,DEHP 可能会破坏ER 稳态,并导致小鼠大脑中的 ER 应激。作为 ER 压力传感器,PERK 启动信号通路,通过各种机制影响 ER 质量控制。当 ER 应激发生时,PERK/eIF2A 的激活导致 ATF4 翻译和 CHOP 上调。最近的报告表明 PERK 被用作中枢和周围神经系统神经元激活的标志物。 (64)此外,PERK 的激活会导致运动能力障碍,表明 PERK 对夏科-玛丽-图思病 1B 型神经病有害。 (65)在我们的研究中,结果表明 DEHP 导致 GRP78 从 PERK 解离并激活 PERK 蛋白。最重要的是,我们认为 DEHP 主要通过激活 PERK/eIF2a/ATF4 信号传导来引起 ER 应激并触发 UPR 激活。
ER stress and mitochondrial dysfunction have been identified as the most crucial two pathways that could trigger neuronal apoptosis. A recent study suggested that DEHP exposure could induce apoptosis, mitochondrial membrane permeability, and caspase-3 activation. (66) Here, we showed that DEHP caused apoptosis through ER stress and mitochondrial dysfunction. Mfn2 is widely proposed as the main MAM component in various cell types, promoting transfer of Ca2+ from the ER to mitochondria. Some findings showed that Mfn2 ablation increased the MAMs and upregulated close contacts between the ER and mitochondria. (67) A recent report showed that Mfn2 facilitates neuronal degeneration and ultimately necrosis through the disruption of MAMs. (68) PERK, as a crucial ER stress sensor of the UPR, is enriched uniquely in the MAMs, which establishes a physical and functional association between the ER and the mitochondria. Recent studies indicated that dysfunctional MAMs might be mainly involved in the neuronal apoptosis and neurological deficits, which is associated with the activation of the PERK pathway. (69) Among the proteins of MAM formation, Mfn2 interacts with PERK to stabilize ER–mitochondrial contacts and involves in mitochondrial fusion and Ca2+ transport from the ER to mitochondria. Some studies suggested that Mfn2-silenced cells showed mitochondrial dysfunction, MAM decrease, and podocyte apoptosis via activating the PERK/eIF2α/ATF4 pathway. (23) Our findings were consistent with those of other studies; this study showed that the Mfn2-PERK axis mediates the damage to morphology and functions in MAMs and mitochondria, and subsequently exerts nervous system toxicity.
内质网应激和线粒体功能障碍已被确定为触发神经元凋亡的最重要的两条途径。最近的一项研究表明,DEHP 暴露可诱导细胞凋亡、线粒体膜通透性和 caspase-3 激活。 (66)在此,我们证明 DEHP 通过 ER 应激和线粒体功能障碍引起细胞凋亡。 Mfn2 被广泛认为是各种细胞类型中的主要 MAM 成分,促进 Ca 2+从内质网转移到线粒体。一些研究结果表明,Mfn2 消融增加了 MAM,并上调了 ER 和线粒体之间的紧密接触。 (67)最近的一份报告表明,Mfn2 通过破坏 MAM 促进神经元变性并最终坏死。 (68) PERK 作为 UPR 的关键 ER 应激传感器,在 MAM 中独特富集,从而在 ER 和线粒体之间建立了物理和功能关联。最近的研究表明,功能失调的MAMs可能主要参与神经元凋亡和神经功能缺损,这与PERK通路的激活有关。 (69)在 MAM 形成的蛋白质中,Mfn2 与 PERK 相互作用以稳定 ER-线粒体接触,并参与线粒体融合和 Ca 2+从 ER 到线粒体的转运。一些研究表明,Mfn2 沉默的细胞通过激活 PERK/eIF2α/ATF4 途径表现出线粒体功能障碍、MAM 减少和足细胞凋亡。 (23)我们的研究结果与其他研究结果一致;这项研究表明, Mfn2 - PERK轴介导 MAM 和线粒体形态和功能的损伤,并随后产生神经系统毒性。
In conclusion, the results suggest that DEHP induces functional and structural deficiencies in the nervous system through the ER stress and mitochondrial dynamics imbalance. We also identify the Mfn2-PERK axis as a regulator of the MAMs and ER–mitochondria interaction. Therefore, our study validates that the Mfn2-PERK pathway mediates ER stress and mitochondrial dysfunction and ultimately MAM integrity injury and dysfunction. It also provides critical evidence that targeting the Mfn2-PERK interaction may represent a potential approach for phthalate-induced neurological diseases.
总之,结果表明 DEHP 通过 ER 应激和线粒体动力学失衡诱导神经系统功能和结构缺陷。我们还确定了Mfn2 - PERK轴作为 MAM 和 ER-线粒体相互作用的调节因子。因此,我们的研究证实Mfn2 - PERK通路介导 ER 应激和线粒体功能障碍,并最终介导 MAM 完整性损伤和功能障碍。它还提供了关键证据,表明针对Mfn2 - PERK相互作用可能是治疗邻苯二甲酸盐诱发的神经系统疾病的潜在方法。

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The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
当前研究期间使用和/或分析的数据集可根据合理要求从相应作者处获得。

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支持信息可免费获取: https://pubs.acs.org/doi/10.1021/acs.jafc.3c07752 如果:5.7 Q1

  • Sequences of oligonucleotide primers for qRT-PCR; DEHP-induced cell apoptosis in mouse brain; mRNA levels of MAM-related proteins; mRNA levels of UPR-related proteins; and details of Materials and Methods (PDF)
    qRT-PCR 寡核苷酸引物序列; DEHP诱导小鼠脑细胞凋亡; MAM相关蛋白的mRNA水平; UPR相关蛋白的mRNA水平;以及材料和方法的详细信息( PDF

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum–Mitochondria Interaction

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Supplemental Materials
1
Phthalates Induce Neurotoxicity by Disrupting
the
Mfn2
-
PERK Axis
-
Mediated
2
Endoplasmic Reticulum
-
Mitochondria Interaction
3
Yi Zhao
†,‡,
§,#
, Y
uan
-
Hang Chang
†,#
, Hao
-
Ran Ren
†,#
, M
ing
Lou
, Fu
-
Wei Jiang
, Jia
-
Xin Wang
,
4
Ming
-
Shan Chen
,
Shuo Liu
, Yu
-
Sheng Shi
, H
ong
-
Mei Zhu
, Jin
-
Long Li
†,‡,
§,*
5
College of Veterinary Medicine, Northeast Agricultural University, Harbin
150030
, P.R. China
6
Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal
7
Disease
Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P.R.
8
China
9
§
Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast
10
Agricultural University, Harbin 150030, P.R. China
11
#
These authors contributed e
qually to this study.
12
*Corresponding author.
13
Jin
-
Long Li
14
Address:
College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P.
15
R. China
16
Tel: +86 451 55190407; fax: +86 451 55190407. E
-
mail address: Jinlongli@neau.edu.cn (J.L.
17
Li)
18
19
S
2
Table S1. Sequences of oligonucleotide primers for qRT
-
PCR.
20
Gene Names
Sequence (5'
→ 3')
NCBI Reference
Sequence
Amplicon size
(bp)
GADPH
AAGGTCGGTGTGAACGGATT
CAACAATCTCCACTTTGCCACT
NM_001289726.1
82
Mfn1
TTCTGAGTTTCATCCTACCCC
CGATCAGCCAAATTTCTTCCCA
NM_024200.4
96
Mfn2
AGCAAGTTGACATCACCCGAGA
AAGTGAATCCAGAGCCTCGAC
NM_001285920.1
80
OPA1
CCGCTTCATGACAGAACCCAA
CCTCGGCAAAGTCGTTCCAC
NM_001199177.1
113
Fis1
ACGCAATTTGAATATGCCTGGT
CGCTGTTCCTCTTTGCTCCC
NM_025562.3
113
Drp1
CAAGAAAACTGTCTGCCCGAGA
TTACTGCCTTTGGGACACTG
NM_152816.3
114
MFF
ACAACGTCAGGTATGGCATT
GAAGCTGCATCTACCACAGT
NM_029409.3
82
VDAC1
TCTGCCAACACGGAAACCAC
TTCTCTGTAAACGTCAGCCCAT
NM_001362693.1
86
GRP75
AGCCAGGTGTTTTCTACTGC
TGTCTCCAGCCATCTCTCG
NM_010481.2
8
5
ERp44
TCACCAATCTTGATCGCAGT
GAAGGCACAGTCATCATGCAA
NM_029572.3
1
16
IP3R
ATATGGCAACGTGATCCAGCTC
TCATGGCGTTCTTCTCTAGCAA
NM_010585.5
9
5
PACS
-
2
AAAGAACTCCTGTCCGTGGT
GTCCACTAGGAGGCAACACA
NM_001291444.1
9
1
Presenilin
-
2
ATCATGCTATTCGTGCCTGT
CTGCCCGTTCTTCTCAGTGT
NM_011183.3
9
0
IRE1
TCCTGCCTCCAGCTACCAA
TTTCCCCACATACAGTGTCA
NM_012016.3
82
S
100B
AGCTTATCAACAACGAGCTCT
CCATCTTCGTCCAGCGTCT
NM_009115.3
9
1
Sigma
-
1
GGGCACTCAAAACTTCGTCT
AGCTCCACGATCAGCCGAGA
NM_011014.3
1
05

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Author Information

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  • Corresponding Author
    • Jin-Long Li - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. ChinaKey Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P. R. ChinaHeilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, P. R. ChinaOrcidhttps://orcid.org/0000-0002-5133-9165 Email: Jinlongli@neau.edu.cn
  • Authors
    • Yi Zhao - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. ChinaKey Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P. R. ChinaHeilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, P. R. ChinaOrcidhttps://orcid.org/0000-0002-3270-4526
    • Yuan-Hang Chang - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    • Hao-Ran Ren - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    • Ming Lou - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    • Fu-Wei Jiang - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    • Jia-Xin Wang - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. ChinaOrcidhttps://orcid.org/0009-0000-6116-1594
    • Ming-Shan Chen - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. ChinaOrcidhttps://orcid.org/0009-0002-0798-2230
    • Shuo Liu - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    • Yu-Sheng Shi - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
    • Hong-Mei Zhu - College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
  • Author Contributions

    Y.Z., Y.-H.C., and H.-R.R. contributed equally to this study. Yi Zhao: conceptualization, investigation, writing-original draft. Yuan-Hang Chang, Hao-Ran Ren, Ming Lou: methodology. Fu-Wei Jiang, Jia-Xin Wang: formal analysis. Ming-Shan Chen, Shuo Liu: visualization. Yu-Sheng Shi, Hong-Mei Zhu: methodology. Jin-Long Li: writing-review and editing, data curation, supervision.

  • Funding

    This study received assistance from the National Natural Science Foundation of China (grant no. 32172932), Key Program of Natural Science Foundation of Heilongjiang Province of China (grant no. ZD2021C003), China Agriculture Research System of MOF and MARA (grant no. CARS-35), Outstanding Youth of Natural Science Foundation of Heilongjiang Province of China (grant no. YQ2023C017), Academic Backbone Project of Northeast Agricultural University (grant no. 54960212), Heilongjiang Postdoctoral Fund (grant no. LBH-Z23010), and China Postdoctoral Science Foundation (grant no. 2023MD744173).

  • Notes
    The authors declare no competing financial interest.

    The Northeast Agricultural University Animal Care and Use Committee gave the trial ethical approval. Written informed consent was provided by each participant. In regards to the publication of this paper, the authors have declared that there is no conflict of interest.

Acknowledgments

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We thank the BioRender website (app.biorender.com) for schematic diagrams and graphical abstract framing.

Abbreviations

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DEHP

di(2-ethylhexyl) phthalate

ER

endoplasmic reticulum

MAMs

mitochondria-associated ER membranes

USEPA

United States Environmental Protection Agency

AD

Alzheimer’s disease

PD

Parkinson’s disease

UPR

unfolded protein response

PERK

protein kinase R-like endoplasmic reticulum kinase

Mfn2

mitofusin-2

NEAU

Northeast Agricultural University

LD50

lethal dose 50

HE

hematoxylin and eosin

qRT–PCR

quantitative real-time PCR

IF

immunofluorescence

IP3R

inositol-14,5-triphosphate receptor

VDAC1

voltage-dependent anion channel protein 1

GRP75

glucose-regulated protein 75

ERP44

endoplasmic reticulum resident protein 44

S100B

S100 calcium-binding protein B

Sigma1-R

sigma1 receptor

PACS2

phosphofurin acidic cluster sorting protein 2

PSS1

phosphatidylserine synthases 1

DGAT2

diacylgycerol acyltransferase 2

ACAT1

acetyl-coA acetyltransferase 1

OPA1

optic atrophy 1

Drp1

dynamin-related protein 1

Fis1

fission 1

MFF

mitochondrial fission factor

RDA

redundancy analysis

XBP1

x-box-binding protein 1

ATF4

activating transcription factor 4

GRP78

glucose-regulated protein 78

IRE1

inosital-requiring enzyme-1

CHOP

C/EBP homologous protein

eIF2a

eukaryotic translation initiation factor 2a

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  • Abstract 抽象的

    Figure 1 图1

    Figure 1. DEHP caused structure damage and dysfunction in mouse brain. (A) Mice were treated with DEHP by oral gavage for 28 days. (B) Brain structure image. (C) Histopathology of brain with H&E, silver, and Nissi staining; yellow arrow: vacuolation or disordered arrangement; green arrow: vacuolation or disordered arrangement; red arrow: incomplete nerve fibers; ultrastructure of neuron; yellow: mitochondria; orange: ER. (D) Number of total cells in the CTX and HPC. (E) Number of neurons in the CTX and HPC. (F) Number of nerve fibers in the CTX and HPC. (G) Time of the balance beam. (H) Time of forced swim. Data are presented as the mean ± SD. Symbol for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.
    图 1. DEHP 导致小鼠大脑结构损伤和功能障碍。 (A) 小鼠经口灌胃 DEHP 治疗 28 天。 (B) 大脑结构图像。 (C) H&E、银染色和尼西染色的脑组织病理学;黄色箭头:空泡或无序排列;绿色箭头:空泡或无序排列;红色箭头:不完整的神经纤维;神经元超微结构;黄色:线粒体;橙色:急诊室。 (D) CTX 和 HPC 中的总细胞数。 (E) CTX 和 HPC 中的神经元数量。 (F) CTX 和 HPC 中的神经纤维数量。 (G) 平衡木的时间。 (H) 强迫游泳的时间。数据以平均值±标准差表示。 Con组和DEHP组之间差异显着性的符号:** P < 0.01,*** P < 0.001。

    Figure 2

    Figure 2. DEHP impaired BBB permeability and induced BBB dysfunction in mouse brain. (A) Protein levels of claudin 1, claudin 5, occludin, and ZO-1. (B) Protein relative level of claudin 1. (C) Protein relative level of claudin 5. (D) Protein relative level of occludin. (E) Protein relative level of ZO-1. (F) Representative IF images of claudin 1 and claudin 5 on the brain. (G) Representative IF images of occludin and ZO-1 on the brain. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.

    Figure 3

    Figure 3. DEHP resulted in the disruption of MAM integrity and function in mouse brain. (A) Protein relative levels of GRP75 and VDAC1. (B) Representative IF images of GRP75 and VDAC1 on the brain. (C) Heatmap presentation of relative mRNA levels of MAM-related proteins. (D) PCA. (E) MAM pathway. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.

    Figure 4

    Figure 4. DEHP led to disorder of mitochondrial dynamics in mouse brain. (A) Protein levels of Mfn2, Mfn1, OPA1, and Drp1. (B) Protein relative level of Mfn2. (C) Protein relative level of Mfn1. (D) Protein relative level of OPA1. (E) Protein relative level of Drp1. (F) mRNA relative level of Mfn2. (G) mRNA relative level of Mfn1. (H) mRNA relative level of OPA1. (I) mRNA relative level of Drp1. (J) mRNA relative level of Fis1. (K) mRNA relative level of MFF. (L) RDA for the relevance of mitochondrial dynamics and MAMs. (M) Mitochondrial dynamics pathway. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: *P < 0.05, **P < 0.01, ***P < 0.001.

    Figure 5

    Figure 5. DEHP induces ER stress and activates UPR in mouse brain. (A) Protein levels of PERK, p-PERK, eIF2a, p-eIF2a, ATF4, and GRP78. (B) Protein relative level of p-PERK. (C) Protein relative level of p-eIF2a. (D) Protein relative level of ATF4. (E) Protein relative level of GRP78. (F) Heatmap presentation of relative mRNA levels of UPR-related proteins. (G) PCA. (H) UPR pathway. Data are presented as the mean ± SD. Symbols for the significance of differences between the Con group and DEHP group: **P < 0.01, ***P < 0.001.

    Figure 6

    Figure 6. DEHP caused disruption of the ER–mitochondria interaction by inhibiting Mfn2-PERK axis in mouse brain. (A) Representative IF images of Mfn2 and PERK on the brain. (B) Correlation analysis of mitochondrial dynamics, MAMs, and UPR. (C) PPI network of mitochondrial dynamics, MAMs, and UPR. (D) Molecular docking simulation for the ligand–protein binding of DEHP with Mfn2.

    Figure 7

    Figure 7. DEHP induced neurotoxicity by disrupting the Mfn2-PERK axis-mediated ER–mitochondria interaction.

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    • Sequences of oligonucleotide primers for qRT-PCR; DEHP-induced cell apoptosis in mouse brain; mRNA levels of MAM-related proteins; mRNA levels of UPR-related proteins; and details of Materials and Methods (PDF)


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