|
1
|
Zhao Y, Wang XQ, Liu RQ, Jiang FW, Wang JX, Chen MS, Zhang H, Cui JG, Chang YH, Li JL. SLC7A11 as a therapeutic target to attenuate phthalates-driven testosterone level decline in mice. J Adv Res 2025; 71:369-381. [PMID: 38797476 DOI: 10.1016/j.jare.2024.05.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/23/2024] [Accepted: 05/23/2024] [Indexed: 05/29/2024] Open
Abstract
INTRODUCTION Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined. OBJECTIVES Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis. METHODS We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe2+ levels and glutathione system to confirm the occurrence of ferroptosis. RESULTS In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin. CONCLUSION Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and "The Global Plastic Toxicity Debt".
Collapse
Affiliation(s)
- Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xue-Qi Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Rui-Qi Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Fu-Wei Jiang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jia-Xin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Ming-Shan Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yuan-Hang Chang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
2
|
Zhang H, Cui JG, Chen MS, Wang JX, Sun XH, Zhao Y, Li JL. TNF/TNFR1 Signaling Mediates DEHP-Induced Hepatocyte Pyroptosis via the GSDMD-mtROS Axis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:7432-7444. [PMID: 39999303 DOI: 10.1021/acs.jafc.4c11022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2025]
Abstract
Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial reactive oxygen species (mtROS) were overproduced. MEHP exposure activates pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated pyroptosis in mitochondrial damage and confirms that the regulation of pyroptosis is helpful in maintaining normal mitochondrial function.
Collapse
Affiliation(s)
- Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Ming-Shan Chen
- 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. China
| | - Xiao-Han Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - 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
| | - 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
| |
Collapse
|
|
3
|
Li XL, Li QM, Zheng YZ, Hu D, Cai XY, Yin K, Qi YY, Cheng ZY, Ning X, Cai Y, Wu W, Lin TY, Xu T, Zhao LL. Di (2-ethylhexyl) phthalate reduces sperm motility by decreasing sperm tail energy supply. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 290:117811. [PMID: 39879685 DOI: 10.1016/j.ecoenv.2025.117811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 01/24/2025] [Accepted: 01/24/2025] [Indexed: 01/31/2025]
Abstract
Di (2-ethylhexyl) phthalate (DEHP) is widespread in the environment. It can impair sperm function through damaging the sperm development process. However, few studies have focused on the sperm tail that is directly related to sperm motility. In this study, we demonstrate that DEHP impedes the conversion of riboflavin in the mitochondrial sheath in the midsection of the sperm tail, resulting in reduced ATP (adenosine triphosphate) synthesis, thereby inhibiting sperm motility. The results of HPLC-MS/MS showed that DEHP metabolites were transported to the testes and epididium, indicating that MEHP (Mono-2-ethylexyl phthalate) could directly affect the espermatozoa of mature. Sperm motility analysis determined that sperm motility decreased with increasing DEHP concentration. The movement of sperm is mainly dependent on the tail motility, which is largely determined by tail structure and energy supply. Electron microscopy images illustrate that there are no observable changes in the basic kinematic structure of the sperm tail. However, DEHP causes a decrease in complex II activity of mitochondrial respiratory chain by interfering with the synthesis of the cofactor FAD (Flavin adenine dinucleotide), which leads to a decrease in ATP concentration. Therefore, DEHP exposure can reduce sperm motility by decreasing sperm tail energy supply. This study exemplifies the importance of the sperm tail in sperm dysfunction caused by environmental pollutants.
Collapse
Affiliation(s)
- Xiao-Lu Li
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Qi-Meng Li
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Yuan-Zhuo Zheng
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Die Hu
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Xiao-Yue Cai
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Ke Yin
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Yin-Yin Qi
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Zi Yu Cheng
- School of Biology, Food and Environment, Hefei University, Hefei 230601, China
| | - Xia Ning
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Yang Cai
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Wei Wu
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Ting-Yuan Lin
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China
| | - Tao Xu
- School of Biology, Food and Environment, Hefei University, Hefei 230601, China.
| | - Ling-Li Zhao
- Department of Toxicology, School of Public Health; Suzhou Hospital of Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei 230032, China.
| |
Collapse
|
|
4
|
Zhao Y, Hu ZY, Lou M, Jiang FW, Huang YF, Chen MS, Wang JX, Liu S, Shi YS, Zhu HM, Li JL. AQP1 Deficiency Drives Phthalate-Induced Epithelial Barrier Disruption through Intestinal Inflammation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:15334-15344. [PMID: 38916549 DOI: 10.1021/acs.jafc.4c03764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.
Collapse
Affiliation(s)
- 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
| | - Zi-Yan Hu
- 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
| | - Yi-Feng Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Ming-Shan Chen
- 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. China
| | - 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
| | - 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
| |
Collapse
|
|
5
|
Lu J, Liu G, Sun W, Jia G, Zhao H, Chen X, Wang J. Dietary α-Ketoglutarate Alleviates Escherichia coli LPS-Induced Intestinal Barrier Injury by Modulating the Endoplasmic Reticulum-Mitochondrial System Pathway in Piglets. J Nutr 2024; 154:2087-2096. [PMID: 38453028 DOI: 10.1016/j.tjnut.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 02/20/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND α-Ketoglutarate (AKG) plays a pivotal role in mitigating inflammation and enhancing intestinal health. OBJECTIVES This study aimed to investigate whether AKG could protect against lipopolysaccharide (LPS)-induced intestinal injury by alleviating disorders in mitochondria-associated endoplasmic reticulum (MAM) membranes, dysfunctional mitochondrial dynamics, and endoplasmic reticulum (ER) stress in a piglet model. METHODS Twenty-four piglets were subjected to a 2 × 2 factorial design with dietary factors (basal diet or 1% AKG diet) and LPS treatment (LPS or saline). After 21 d of consuming either the basal diet or AKG diet, piglets received injections of LPS or saline. The experiment was divided into 4 treatment groups [control (CON) group: basal diet + saline; LPS group: basal diet +LPS; AKG group: AKG diet + saline; and AKG_LPS group: AKG + LPS], each consisting of 6 piglets. RESULTS The results demonstrated that compared with the CON group, AKG enhanced jejunal morphology, antioxidant capacity, and the messenger RNA and protein expression of tight junction proteins. Moreover, it has shown a reduction in serum diamine oxidase activity and D-lactic acid content in piglets. In addition, fewer disorders in the ER-mitochondrial system were reflected by AKG, as evidenced by AKG regulating the expression of key molecules of mitochondrial dynamics (mitochondrial calcium uniporter, optic atrophy 1, fission 1, and dynamin-related protein 1), ER stress [activating transcription factor (ATF) 4, ATF 6, CCAAT/enhancer binding protein homologous protein, eukaryotic initiation factor 2α, glucose-regulated protein (GRP) 78, and protein kinase R-like ER kinase], and MAM membranes [mitofusin (Mfn)-1, Mfn-2, GRP 75, and voltage-dependent anion channel-1]. CONCLUSIONS Dietary AKG can prevent mitochondrial dynamic dysfunction, ER stress, and MAM membrane disorder, ultimately alleviating LPS-induced intestinal damage in piglets.
Collapse
Affiliation(s)
- Jiajia Lu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Chengdu, Sichuan, China
| | - Guangmang Liu
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Chengdu, Sichuan, China.
| | - Weixiao Sun
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Chengdu, Sichuan, China
| | - Gang Jia
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Chengdu, Sichuan, China
| | - Hua Zhao
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Chengdu, Sichuan, China
| | - Xiaoling Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China; Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Chengdu, Sichuan, China
| | - Jing Wang
- Maize Research Institute, Sichuan Agricultural University, Chengdu, Sichuan, China
| |
Collapse
|
|
6
|
Shi YS, Yang TN, Wang YX, Ma XY, Liu S, Zhao Y, Li JL. Melatonin Mitigates Atrazine-Induced Renal Tubular Epithelial Cell Senescence by Promoting Parkin-Mediated Mitophagy. RESEARCH (WASHINGTON, D.C.) 2024; 7:0378. [PMID: 38766643 PMCID: PMC11098712 DOI: 10.34133/research.0378] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 04/14/2024] [Indexed: 05/22/2024]
Abstract
The accumulation of senescent cells in kidneys is considered to contribute to age-related diseases and organismal aging. Mitochondria are considered a regulator of cell senescence process. Atrazine as a triazine herbicide poses a threat to renal health by disrupting mitochondrial homeostasis. Melatonin plays a critical role in maintaining mitochondrial homeostasis. The present study aims to explore the mechanism by which melatonin alleviates atrazine-induced renal injury and whether parkin-mediated mitophagy contributes to mitigating cell senescence. The study found that the level of parkin was decreased after atrazine exposure and negatively correlated with senescent markers. Melatonin treatment increased serum melatonin levels and mitigates atrazine-induced renal tubular epithelial cell senescence. Mechanistically, melatonin maintains the integrity of mitochondrial crista structure by increasing the levels of mitochondrial contact site and cristae organizing system, mitochondrial transcription factor A (TFAM), adenosine triphosphatase family AAA domain-containing protein 3A (ATAD3A), and sorting and assembly machinery 50 (Sam50) to prevent mitochondrial DNA release and subsequent activation of cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate synthase pathway. Furthermore, melatonin activates Sirtuin 3-superoxide dismutase 2 axis to eliminate the accumulation of reactive oxygen species in the kidney. More importantly, the antisenescence role of melatonin is largely determined by the activation of parkin-dependent mitophagy. These results offer novel insights into measures against cell senescence. Parkin-mediated mitophagy is a promising drug target for alleviating renal tubular epithelial cell senescence.
Collapse
Affiliation(s)
- Yu-Sheng Shi
- College of Veterinary Medicine,
Northeast Agricultural University, Harbin 150030, P.R. China
| | - Tian-Ning Yang
- College of Veterinary Medicine,
Northeast Agricultural University, Harbin 150030, P.R. China
| | - Yu-Xiang Wang
- College of Veterinary Medicine,
Northeast Agricultural University, Harbin 150030, P.R. China
| | - Xiang-Yu Ma
- College of Veterinary Medicine,
Northeast Agricultural University, Harbin 150030, P.R. China
| | - Shuo Liu
- College of Veterinary Medicine,
Northeast Agricultural University, Harbin 150030, P.R. China
| | - 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
| | - 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
| |
Collapse
|
|
7
|
Fan X, Zhang D, Hou T, Zhang Q, Tao L, Bian C, Wang Z. Mitochondrial DNA Stress-Mediated Health Risk to Dibutyl Phthalate Contamination on Zebrafish ( Danio rerio) at Early Life Stage. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:7731-7742. [PMID: 38662601 DOI: 10.1021/acs.est.3c10175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Plastics contaminations are found globally and fit the exposure profile of the planetary boundary threat. The plasticizer of dibutyl phthalate (DBP) leaching has occurred and poses a great threat to human health and the ecosystem for decades, and its toxic mechanism needs further comprehensive elucidation. In this study, environmentally relevant levels of DBP were used for exposure, and the developmental process, oxidative stress, mitochondrial ultrastructure and function, mitochondrial DNA (mtDNA) instability and release, and mtDNA-cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway with inflammatory responses were measured in zebrafish at early life stage. Results showed that DBP exposure caused developmental impairments of heart rate, hatching rate, body length, and mortality in zebrafish embryo. Additionally, the elevated oxidative stress damaged mitochondrial ultrastructure and function and induced oxidative damage to the mtDNA with mutations and instability of replication, transcription, and DNA methylation. The stressed mtDNA leaked into the cytosol and activated the cGAS-STING signaling pathway and inflammation, which were ameliorated by co-treatment with DBP and mitochondrial reactive oxygen species (ROS) scavenger, inhibitors of cGAS or STING. Furthermore, the larval results suggest that DBP-induced mitochondrial toxicity of energy disorder and inflammation were involved in the developmental defects of impaired swimming capability. These results enhance the interpretation of mtDNA stress-mediated health risk to environmental contaminants and contribute to the scrutiny of mitochondrial toxicants.
Collapse
Affiliation(s)
- Xiaoteng Fan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Dingfu Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Tingting Hou
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Qianqing Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Lu Tao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chongqian Bian
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Zaizhao Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| |
Collapse
|
|
8
|
Singh J, Jangra A, Kumar D. Recent advances in toxicological research of di-(2-ethylhexyl)-phthalate: Focus on endoplasmic reticulum stress pathway. CHEMOSPHERE 2024; 356:141922. [PMID: 38593956 DOI: 10.1016/j.chemosphere.2024.141922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 01/01/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
The plasticizer di-(2-ethylhexyl)-phthalate (DEHP) is the most significant phthalate in production, usage, and environmental occurrence. DEHP is found in products such as personal care products, furniture materials, cosmetics, and medical devices. DEHP is noncovalently bind with plastic therefore, repeated uses lead to leaching out of it. Exposure to DEHP plasticizers leads to toxicity in essential organs of the body through various mechanisms. The main objective of this review article is to focus on the DEHP-induced endoplasmic reticulum (ER) stress pathway implicated in the testis, brain, lungs, kidney, heart, liver, and other organs. Not only ER stress, PPAR-related pathways, oxidative stress and inflammation, Ca2+ homeostasis disturbances in mitochondria are also identified as the relative mechanisms. ER is involved in various critical functions of the cell such as Protein synthesis, protein folding, calcium homeostasis, and lipid peroxidation but, DEHP exposure leads to augmentation of misfolded/unfolded protein. This review complies with various recently reported DEHP-induced toxicity studies and some pharmacological interventions that have been shown to be effective through ER stress pathway. DEHP exposure does assess health risks and vulnerability to populations across the globe. This study offers possible targets and approaches for addressing various DEHP-induced toxicity.
Collapse
Affiliation(s)
- Jiten Singh
- Department of Pharmaceutical Sciences, School of Interdisciplinary and Applied Sciences, Central University of Haryana, Mahendergarh, 123031, Haryana, India
| | - Ashok Jangra
- Department of Pharmaceutical Sciences, School of Interdisciplinary and Applied Sciences, Central University of Haryana, Mahendergarh, 123031, Haryana, India.
| | - Dinesh Kumar
- Department of Pharmaceutical Sciences, School of Interdisciplinary and Applied Sciences, Central University of Haryana, Mahendergarh, 123031, Haryana, India.
| |
Collapse
|
|
9
|
Jiang FW, Guo JY, Lin J, Zhu SY, Dai XY, Saleem MAU, Zhao Y, Li JL. MAPK/NF-κB signaling mediates atrazine-induced cardiorenal syndrome and antagonism of lycopene. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 922:171015. [PMID: 38369134 DOI: 10.1016/j.scitotenv.2024.171015] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/08/2024] [Accepted: 02/14/2024] [Indexed: 02/20/2024]
Abstract
Atrazine (ATZ) is the most prevalent herbicide that has been widely used in agriculture to control broadleaf weeds and improve crop yield and quality. The heavy use of ATZ has caused serious environmental pollution and toxicity to human health. Lycopene (LYC), is a carotenoid that exhibits numerous health benefits, such as prevention of cardiovascular diseases and nephropathy. However, it remains unclear that whether ATZ causes cardiorenal injury or even cardiorenal syndrome (CRS) and the beneficial role of LYC on it. To test this hypothesis, mice were treated with LYC and/or ATZ for 21 days by oral gavage. This study demonstrated that ATZ exposure caused cardiorenal morphological alterations, and several inflammatory cell infiltrations mediated by activating NF-κB signaling pathways. Interestingly, dysregulation of MAPK signaling pathways and MAPK phosphorylation caused by ATZ have been implicated in cardiorenal diseases. ATZ exposure up-regulated cardiac and renal injury associated biomarkers levels that suggested the occurrence of CRS. However, these all changes were reverted, and the phenomenon of CAR was disappeared by LYC co-treatment. Based on our findings, we postulated a novel mechanism to elucidate pesticide-induced CRS and indicated that LYC can be a preventive and therapeutic agent for treating CRS by targeting MAPK/NF-κB signaling pathways.
Collapse
Affiliation(s)
- Fu-Wei Jiang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jian-Ying Guo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jia Lin
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, PR China
| | - Shi-Yong Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; College of Animal Science and Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, PR China
| | - Xue-Yan Dai
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, PR China
| | | | - Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
10
|
Song X, Sun J, Liu H, Mushtaq A, Huang Z, Li D, Zhang L, Chen F. Lycopene Alleviates Endoplasmic Reticulum Stress in Steatohepatitis through Inhibition of the ASK1-JNK Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:7832-7844. [PMID: 38544357 DOI: 10.1021/acs.jafc.3c08108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Lycopene has been proven to alleviate nonalcoholic steatohepatitis (NASH), but the precise mechanisms are inadequately elucidated. In this study, we found a previously unknown regulatory effect of lycopene on the apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in both in vivo and in vitro models. Lycopene supplementation (3 and 6 mg/kg/day) exhibited a significant reduction in lipid accumulation, inflammation, and fibrosis of the liver in mice fed with a high-fat/high-cholesterol diet or a methionine-choline-deficient diet. RNA sequencing uncovered that the mitogen-activated protein kinases signaling pathway, which is closely associated with inflammation and endoplasmic reticulum (ER) stress, was significantly downregulated by lycopene. Furthermore, we found lycopene ameliorated ER swelling and decreased the expression levels of ER stress markers (i.e., immunoglobulin heavy chain binding protein, C/EBP homologous protein, and X-box binding protein 1s). Especially, the inositol-requiring enzyme 1α involved in the ASK1 phosphorylation was inhibited by lycopene, resulting in the decline of the subsequent c-Jun N-terminal kinase (JNK) signaling cascade. ASK1 inhibitor DQOP-1 eliminated the lycopene-induced inhibition of the ASK1-JNK pathway in oleic acid and palmitic acid-induced HepG2 cells. Molecular docking further indicated hydrophobic interactions between lycopene and ASK1. Collectively, our research indicates that lycopene can alleviate ER stress and attenuate inflammation cascades and lipid accumulation by inhibiting the ASK1-JNK pathway.
Collapse
Affiliation(s)
- Xunyu Song
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture; Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Jun Sun
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture; Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Hanxiong Liu
- School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian 116034, China
| | - Aroosa Mushtaq
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture; Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Zhoumei Huang
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture; Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Daotong Li
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture; Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Lujia Zhang
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture; Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Fang Chen
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture; Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| |
Collapse
|
|
11
|
Zhao Y, Chang YH, Ren HR, Lou M, Jiang FW, Wang JX, Chen MS, Liu S, Shi YS, Zhu HM, Li JL. Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum-Mitochondria Interaction. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:7411-7422. [PMID: 38390847 DOI: 10.1021/acs.jafc.3c07752] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2024]
Abstract
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.
Collapse
Affiliation(s)
- 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
| | - 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. China
| | - Ming-Shan Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - 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
| | - 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
| |
Collapse
|
|
12
|
Ge XR, Zhao Y, Ren HR, Jiang FW, Liu S, Lou M, Huang YF, Chen MS, Wang JX, Li JL. Phthalate drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 346:123610. [PMID: 38382728 DOI: 10.1016/j.envpol.2024.123610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/03/2024] [Accepted: 02/17/2024] [Indexed: 02/23/2024]
Abstract
As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form of cell death induced by activating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and implicated in pathogenesis of numerous inflammatory diseases. The current study aimed to explore the impact of DEHP on immune inflammatory response in mouse spleen. In this study, the male ICR mice were treated with DEHP (200 mg/kg) for 28 days. Here, DEHP exposure caused abnormal pathohistological and ultrastructural changes, accompanied by inflammatory cells infiltration in mouse spleen. DEHP exposure arouse heat shock response that involves increase of heat shock proteins 60 (HSP60) expression. DEHP also elevated the expressions of toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) proteins, as well as the activation of NF-κB pathway. Moreover, DEHP promoted NLRP3 inflammasome activation and triggered NLRP3 inflammasome-induced pyroptosis. Mechanistically, DEHP drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. Our findings reveal that targeting HSP60-mediated TLR4/NLRP3 signaling axis may be a promising strategy for inflammatory diseases treatment.
Collapse
Affiliation(s)
- Xin-Ran Ge
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China.
| | - Hao-Ran Ren
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Fu-Wei Jiang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Shuo Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Ming Lou
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Yi-Feng Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Ming-Shan Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jia-Xin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China.
| |
Collapse
|
|
13
|
Wang L, Zhang D, Jiang B, Ding H, Feng S, Zhao C, Wang X, Wu J. 4-Phenylbutyric Acid Attenuates Soybean Glycinin/β-Conglycinin-Induced IPEC-J2 Cells Apoptosis by Regulating the Mitochondria-Associated Endoplasmic Reticulum Membrane and NLRP-3. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:5926-5934. [PMID: 38457471 DOI: 10.1021/acs.jafc.3c09630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Glycinin (11S) and β-conglycinin (7S) from soybean (glycine max) cause diarrhea and intestinal barrier damage in young animals. Understanding the mechanisms underlying the damage caused by 7S and 11S, it is vital to develop strategies to eliminate allergenicity. Consequently, we investigated 7S/11S-mediated apoptosis in porcine intestinal epithelial (IPEC-J2) cells. IPEC-J2 cells suffered endoplasmic reticulum stress (ERS) in response to 7S and 11S, activating protein kinase RNA-like ER kinase, activating transcription factor 6, C/EBP homologous protein, and inositol-requiring enzyme 1 alpha. 4-Phenylbutyric acid (4-PBA) treatment alleviated ERS; reduced the NLR family pyrin domain containing 3, interleukin-1β, and interleukin-18 levels; inhibited apoptosis; increased mitofusin 2 expression; and mitigated Ca2+ overload and mitochondria-associated ER membrane (MAM) dysfunction, thereby ameliorating IPEC-J2 injury. We demonstrated the pivotal role of ERS in MAM dysfunction and 7S- and 11S-mediated apoptosis, providing insights into 7S- and 11S-mediated intestinal barrier injury prevention and treatment.
Collapse
Affiliation(s)
- Lei Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Daoliang Zhang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Benzheng Jiang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Hongyan Ding
- Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, Institute of Animal Science and Veterinary Medicine, Anhui Academy of Agricultural Sciences, Hefei 230031, China
| | - Shibin Feng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Chang Zhao
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Xichun Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| | - Jinjie Wu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230061, China
| |
Collapse
|
|
14
|
Zhao BC, Wang TH, Chen J, Qiu BH, Xu YR, Li JL. Essential oils improve nursery pigs' performance and appetite via modulation of intestinal health and microbiota. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 16:174-188. [PMID: 38357573 PMCID: PMC10864218 DOI: 10.1016/j.aninu.2023.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 07/22/2023] [Accepted: 10/12/2023] [Indexed: 02/16/2024]
Abstract
Optimal intestinal health and functionality are essential for animal health and performance, and simultaneously intestinal nutrient transporters and intestinal peptides are also involved in appetite and feed intake control mechanisms. Given the potential of essential oil (EO) in improving animal performance and improving feed palatability, we hypothesized that dietary supplementation of cinnamaldehyde and carvacrol could improve performance and appetite of nursery pigs by modulating intestinal health and microbiota. Cinnamaldehyde (100 mg/kg), carvacrol (100 mg/kg), and their mixtures (including 50 mg/kg cinnamaldehyde and 50 mg/kg carvacrol) were supplemented into the diets of 240 nursery pigs for 42 d, and data related to performance were measured. Thereafter, the influence of EO on intestinal health, appetite and gut microbiota and their correlations were explored. EO supplementation increased (P < 0.05) the body weight, average daily gain (ADG) and average daily feed intake (ADFI) of piglets, and reduced (P < 0.05) diarrhea rates in nursery pigs. Furthermore, EO increased (P < 0.05) the intestinal absorption area and the abundance of tight junction proteins, and decreased (P < 0.05) intestinal permeability and local inflammation. In terms of intestinal development and the mucus barrier, EO promoted intestinal development and increased (P < 0.05) the number of goblet cells. Additionally, we found that piglets in the EO-supplemented group had upregulated (P < 0.05) levels of transporters and digestive enzymes in the intestine, which were significantly associated with daily gain and feed utilization. In addition, EO supplementation somewhat improved appetite in nursery pigs, increased the diversity of the gut microbiome and the abundance of beneficial bacteria, and there was a correlation between altered bacterial structure and appetite-related hormones. These findings indicate that EO is effective in promoting growth performance and nutrient absorption as well as in regulating appetite by improving intestinal health and bacterial structure.
Collapse
Affiliation(s)
- Bi-Chen Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Tian-Hao Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Jian Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Bai-Hao Qiu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Ya-Ru Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, China
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, China
| |
Collapse
|
|
15
|
Wang X, Li D, Zheng X, Hong Y, Zhao J, Deng W, Wang M, Shen L, Long C, Wei G, Wu S. Di-(2-ethylhexyl) phthalate induces ferroptosis in prepubertal mouse testes via the lipid metabolism pathway. ENVIRONMENTAL TOXICOLOGY 2024; 39:1747-1758. [PMID: 38050670 DOI: 10.1002/tox.24065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 09/07/2023] [Accepted: 11/16/2023] [Indexed: 12/06/2023]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, has been shown to cause reproductive toxicity, but the precise mechanism remains unclear. This study aimed to investigate the possible molecular mechanism of DEHP-induced testicular damage. In vivo study, we administered different doses of DEHP (0, 250, and 500 mg/kg/day) to male C57BL/6 mice from 22 and 35 days after birth. We found that DEHP exposure induced histopathological alterations in prepubertal testes, and testicular lipidomics indicated notable alterations in lipid metabolism and significant enrichment of ferroptosis. Further tests showed that ferrous iron (Fe2+ ) and malondialdehyde (MDA) levels significantly increased after DEHP exposure. Western blotting revealed that DEHP exposure reduced glutathione peroxidase 4 (GPX4) expression, and elevated acyl coenzyme A synthetase long-chain member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) expression. The in vitro results were consistent with the in vivo results. When Leydig cells and Sertoli cells were treated with ferrostatin-1 and monoethylhexyl phthalate (MEHP), MEHP-induced increases in Fe2+ and MDA levels, accumulation of lipid reactive oxygen species, downregulation of GPX4, and upregulation of ACSL4 and LPCAT3 were reversed. Collectively, our findings suggested that aberrant lipid metabolism and ferroptosis may be involved in prepubertal DEHP exposure-induced testicular damage.
Collapse
Affiliation(s)
- Xia Wang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Dinggang Li
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Xiangqin Zheng
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yifan Hong
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Jie Zhao
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Wei Deng
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Mingxin Wang
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Lianju Shen
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Chunlan Long
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Guanghui Wei
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Shengde Wu
- Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China
| |
Collapse
|
|
16
|
Zhang H, Yi X, Hu W, Zhu G, Fu X, Jin W, Qin L, Li M. MEHP activates JNK to inhibit the migration of human foreskin fibroblasts. Syst Biol Reprod Med 2023; 69:423-434. [PMID: 37812750 DOI: 10.1080/19396368.2023.2262082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 09/11/2023] [Indexed: 10/11/2023]
Abstract
This study aimed to investigate the impact of mono(2-ethylhexyl) phthalate (MEHP) on the proliferation, apoptosis, and migration of human foreskin fibroblast cells (HFF-1) and the role of the JNK signaling pathway in cell migration. HFF-1 cells were randomly assigned to the control group with 0 MEHP exposure (M0) or the experimental groups with 25, 50, 100, 200, and 400 μmol/L MEHP exposure (M25, M50, M100, M200, and M400, respectively). After 24 and 48 h of MEHP exposure, the proliferation of HFF-1 cells in any group had no significant change. However, compared with the M0 group, the M200 and M400 groups presented substantially increased apoptosis of HFF-1 cells. Moreover, cell migration ability significantly decreased in all groups (p < 0.05). Additionally, the transcription and phosphorylated protein activation of JNK kinase in HFF-1 cells were substantially upregulated with the increase in MEHP exposure. Subsequently, HFF-1 cells were randomly divided into three groups: the DMSO blank control group, the 100 μM MEHP experimental group (M100), and the 100 μM MEHP plus 10 μM SP600125 (specific JNK inhibitor) experimental group (S10). The activation of JNK protein in HFF-1 cells was substantially downregulated in the S10 group. HFF-1 cells were also divided into the blank control group (M0). They were treated with 100 μM MEHP and varying concentrations of SP600125 (5, 10, and 15 μM for S5, S10, and S15, respectively). As the concentration of the antagonist increased, the migration ability of HFF-1 cells was returned to normal. Finally, the ROS in HFF-1 cells increased under MEHP exposure. This finding indicates that the regulation of cell migration by the JNK signaling pathway may be important in the occurrence of hypospadias.
Collapse
Affiliation(s)
- Hu Zhang
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Xuan Yi
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Wei Hu
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Guoqiang Zhu
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Xiaowen Fu
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Wei Jin
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Long Qin
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Mingyong Li
- Urology Department, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| |
Collapse
|
|
17
|
Zhang Y, Li G, Zhao Y, Dai X, Hu M, Cao H, Huang K, Yang F. Inhibition of calcium imbalance protects hepatocytes from vanadium exposure-induced inflammation by mediating mitochondrial-associated endoplasmic reticulum membranes in ducks. Poult Sci 2023; 102:103013. [PMID: 37856907 PMCID: PMC10591013 DOI: 10.1016/j.psj.2023.103013] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 07/31/2023] [Accepted: 08/04/2023] [Indexed: 10/21/2023] Open
Abstract
Vanadium (V) is an essential mineral element in animals, but excessive V can lead to many diseases, affecting the health of humans and animals. However, the molecular crosstalk between mitochondria-associated endoplasmic reticulum membranes (MAMs) and inflammation under V exposure is still at the exploratory stage. This study was conducted to determine the molecular crosstalk between MAMs and inflammation under V exposure in ducks. In this study, duck hepatocytes were treated with NaVO3 (0 μM, 100 μM, and 200 μM) and 2-aminoethyl diphenyl borate (2-APB) (IP3R inhibitor) alone or in combination for 24 h. The data showed that V exposure-induced cell vacuolization, enlarged intercellular space, and decreased density and viability. Meanwhile, hydrogen peroxide (H2O2), malonaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and reactive oxygen species (ROS) levels were upregulated under V treatment. In addition, excessive V could lead to a marked reduction in the MAMs structure, destruction of the membrane structure and overload of intracellular Ca2+ and mitochondrial Ca2+. Moreover, V treatment resulted in notable upregulation of the levels of MAMs-relevant factors (IP3R, Mfn2, Grp75, MCU, VDAC1) but downregulated the levels of IL-18, IL-1β, and lactate dehydrogenase (LDH) in the cell supernatant. Additionally, it also significantly elevated the levels of inflammation-relevant factors (NLRP3, ASC, caspase-1, MAVS, IL-18, IL-1β, and TXNIP). However, the inhibition of IP3R expression attenuated the V-induced variations in the above indicators. Collectively, our results revealed that the maintenance of calcium homeostasis could protect duck hepatocytes from V-induced inflammation injury via MAMs.
Collapse
Affiliation(s)
- Yiling Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China; Department of Animal Science and Technology, Jiangxi Biotech Vocational College, Nanchang 330200, China
| | - Guyue Li
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Yanqing Zhao
- The Second People's Hospital, Jingdezhen 333099, China
| | - Xueyan Dai
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Mingwen Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Kai Huang
- Jiangxi Agricultural Engineering College, Zhangshu 331200, China
| | - Fan Yang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China.
| |
Collapse
|
|
18
|
Wang HR, Li MZ, Cui JG, Zhang H, Zhao Y, Li JL. Lycopene Prevents Phthalate-Induced Cognitive Impairment via Modulating Ferroptosis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:16727-16738. [PMID: 37871231 DOI: 10.1021/acs.jafc.3c04801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is frequently used as a plasticizer in industrial and agricultural products. DEHP can cause severe neurotoxicity, such as impaired learning and memory function. Lycopene (LYC) as a carotenoid exerts excellent antioxidant capacity and therapeutic effects in neurodegenerative diseases. However, whether LYC can prevent the cognitive impairment induced by DEHP and the specific mechanisms are unclear. In the present study, the behavioral test results suggested that LYC alleviated the learning and memory impairment induced by DEHP. The histopathological data revealed that LYC attenuated DEHP-induced disordered arrangement of the neurons in the CA1 and CA3 regions of the hippocampus tissue. Moreover, LYC inhibited the occurrence of DEHP-induced ferroptosis via regulating iron metabolism, inhibiting lipid peroxidation, and activating the cysteine transporter and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NrF2/HO-1) signaling pathway. Overall, the study contributes novel perspectives into the potential mechanisms of LYC preventing phthalate-induced cognitive impairment in the hippocampus.
Collapse
Affiliation(s)
- Hao-Ran Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Mu-Zi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - 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
| | - 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
| |
Collapse
|
|
19
|
Shi H, Zhao XH, Peng Q, Zhou XL, Liu SS, Sun CC, Cao QY, Zhu SP, Sun SY. Green tea polyphenols alleviate di-(2-ethylhexyl) phthalate-induced liver injury in mice. World J Gastroenterol 2023; 29:5054-5074. [PMID: 37753369 PMCID: PMC10518738 DOI: 10.3748/wjg.v29.i34.5054] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/19/2023] [Accepted: 08/21/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Di (2-ethylhexyl) phthalate (DEHP) is a common plasticizer known to cause liver injury. Green tea is reported to exert therapeutic effects on heavy metal exposure-induced organ damage. However, limited studies have examined the therapeutic effects of green tea polyphenols (GTPs) on DEHP-induced liver damage. AIM To evaluate the molecular mechanism underlying the therapeutic effects of GTPs on DEHP-induced liver damage. METHODS C57BL/6J mice were divided into the following five groups: Control, model [DEHP (1500 mg/kg bodyweight)], treatment [DEHP (1500 mg/kg bodyweight) + GTP (70 mg/kg bodyweight), oil, and GTP (70 mg/kg bodyweight)] groups. After 8 wk, the liver function, blood lipid profile, and liver histopathology were examined. Differentially expressed micro RNAs (miRNAs) and mRNAs in the liver tissues were examined using high-throughput sequencing. Additionally, functional enrichment analysis and immune infiltration prediction were performed. The miRNA-mRNA regulatory axis was elucidated using the starBase database. Protein expression was evaluated using immunohistochemistry. RESULTS GTPs alleviated DHEP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, liver fibrosis, and mitochondrial and endoplasmic reticulum lesions in mice. The infiltration of macrophages, mast cells, and natural killer cells varied between the model and treatment groups. mmu-miR-141-3p (a differentially expressed miRNA), Zcchc24 (a differentially expressed mRNA), and Zcchc24 (a differentially expressed protein) constituted the miRNA-mRNA-protein regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage in mice. CONCLUSION This study demonstrated that GTPs mitigate DEHP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, and partial liver fibrosis, and regulate immune cell infiltration. Additionally, an important miRNA-mRNA-protein molecular regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage was elucidated.
Collapse
Affiliation(s)
- Heng Shi
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 522000, Guangdong Province, China
- Department of Gastroenterology, The Central Hospital of Shaoyang, Shaoyang 422000, Hunan Province, China
| | - Xin-Hai Zhao
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 522000, Guangdong Province, China
| | - Qin Peng
- Department of Gastroenterology, The Central Hospital of Shaoyang, Shaoyang 422000, Hunan Province, China
| | - Xian-Ling Zhou
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 522000, Guangdong Province, China
| | - Si-Si Liu
- Department of Pathology, The Central Hospital of Shaoyang, Shaoyang 422000, Hunan Province, China
| | - Chuan-Chuan Sun
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 522000, Guangdong Province, China
| | - Qiu-Yu Cao
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 522000, Guangdong Province, China
| | - Shi-Ping Zhu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 522000, Guangdong Province, China
| | - Sheng-Yun Sun
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 522000, Guangdong Province, China
| |
Collapse
|
|
20
|
Zhao YX, Li XN, Tang YX, Talukder M, Zhao Y, Li JL. Cadmium Transforms Astrocytes into the A1 Subtype via Inducing Gap Junction Protein Connexin 43 into the Nucleus. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:12043-12051. [PMID: 37471304 DOI: 10.1021/acs.jafc.3c02963] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/22/2023]
Abstract
Cadmium is highly toxic and present in the environment and can be accumulated among various levels of the food chain. Both humans and animals are at risk from toxicity associated with cadmium. However, the neurological endpoint caused by cadmium has not been revealed. The aim of our research is to explore the potential target of cadmium attack when causing neurotoxicity. 80 male chickens (one day old, weighing 36.49 ± 2.88 g) were randomly divided into four groups and independently treated with 0, 35, 70, or 140 mg/kg CdCl2 in diet for 90 days. The result showed that the striatum was damaged due to a high dose of cadmium in the brain, which was characterized by degeneration of neurons and astrocyte dysfunction. Transcriptome analysis demonstrated that striatal astrocytes were transformed into the A1 state under cadmium exposure. Deeper investigation revealed that the internalization of gap junction protein connexin 43 was responsible for this transformation. Eventually, we can conclude that the internalized gap junction protein connexin 43 of astrocytes is the target of cadmium anchoring, and this process was accompanied by the transformation of astrocytes into the A1 subtype. This study provides a new direction for exploring the effects of cadmium on the nervous system and the treatment of subsequent nervous system diseases.
Collapse
Affiliation(s)
| | - Xue-Nan Li
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P. R. China
| | | | | | - Yi Zhao
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Jin-Long Li
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, P. R. China
| |
Collapse
|
|
21
|
Li CX, Talukder M, Xu YR, Zhu SY, Zhao YX, Li JL. Cadmium aggravates the blood-brain barrier disruption via inhibition of the Wnt7A/β-catenin signaling axis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 324:121400. [PMID: 36878275 DOI: 10.1016/j.envpol.2023.121400] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 06/18/2023]
Abstract
Cadmium (Cd) is a non-biodegradable widespread environmental pollutant, which can cross the blood-brain barrier (BBB) and cause cerebral toxicity. However, the effect of Cd on the BBB is still unclear. In this study, a total of 80 (1-day-old) Hy-Line white variety chicks (20 chickens/group) were selected and randomly divided into four (4) groups: the control group (Con group) (fed with a basic diet, n = 20), the Cd 35 group (basic diet with 35 mg/kg CdCl2, n = 20), the Cd 70 group (basic diet with 70 mg/kg CdCl2, n = 20) and the Cd 140 group (basic diet with 140 mg/kg CdCl2, n = 20), and fed for 90 days. The pathological changes, factors associated with the BBB, oxidation level and the levels of Wingless-type MMTV integration site family, member 7 A (Wnt7A)/Wnt receptor Frizzled 4 (FZD4)/β-catenin signaling axis-related proteins in brain tissue were detected. Cd exposure induced capillary damage and neuronal swelling, degeneration and loss of neurons. Gene Set Enrichment Analysis (GSEA) showed the weakened Wnt/β-catenin signaling axis. The protein expression of the Wnt7A, FZD4, and β-catenin was decreased by Cd expusure. Inflammation generation and BBB dysfunction were induced by Cd, as manifested by impaired tight junctions (TJs) and adherens junctions (AJs) formation. These findings underscore that Cd induced BBB dysfunction via disturbing Wnt7A/FZD4/β-catenin signaling axis.
Collapse
Affiliation(s)
- Chen-Xi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Ya-Ru Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Shi-Yong Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Ying-Xin Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
| |
Collapse
|
|
22
|
Ma XY, Zhu Y, Xu YR, Saleem MAU, Jian PA, Yi BJ, Li XN, Li JL. Mitocytosis Is Critical for Phthalate-Induced Injury to the Ovarian Granulosa Cell Layer in Quail ( Coturnix japonica). JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:5745-5755. [PMID: 36977485 DOI: 10.1021/acs.jafc.2c08601] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Phthalates are widely used synthetic chemicals that determine endocrine disruption effects on female reproductivity and oviposition. Our study demonstrated that the mitochondrial quality in ovarian granulosa cells (GCs) is associated with a poor prognosis in female reproduction. However, the molecular mechanism of di-(2-ethylhexyl) phthalate (DEHP) exposure on the quail ovarian GC layer is still unknown. To validate the effects of DEHP on the GC layer, 8 days' old 150 female Japanese quail were treated orally with DEHP (250, 500, and 750 mg/kg BW/day) for 45 days to explore the toxic effects of DEHP on the ovarian GC layer. Histopathological assessment and ultrastructure observation found that DEHP decreased the thickness of the GC layer, resulted in mitochondrial damage, and activated mitocytosis. Additionally, the results further suggested that DEHP impacted the secretion of steroid hormones (reduced FSH, E2, and T levels and boosted Prog, PRL, and LH levels) by triggering mitocytosis (enhanced transcription of MYO19 and protein of KIF5B levels), mitochondrial dynamics (increasing mRNA and protein levels of OPA1, DRP1, MFN1, and MFN2), mitophagy (increasing mRNA and protein levels of Parkin, LC3B, and P62), and inducing GC function disorder. In conclusion, our research provided a new idea to explain the mechanism of DEHP toxicity of the ovarian GC layer in quail and presented insights into the role of mitocytosis in DEHP-induced ovarian GC layer injury.
Collapse
Affiliation(s)
- Xiang-Yu Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Yu Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Ya-Ru Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | | | - Ping-An Jian
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Bao-Jin Yi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Xue-Nan 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
- Heilongjiang Provincial Key Laboratory of Pathogenic Mechanism for Animal Disease and Comparative Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - 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
| |
Collapse
|
|
23
|
Hu Z, Liao J, Zhang K, Huang K, Li Q, Lei C, Han Q, Zhang H, Guo J, Hu L, Pan J, Li Y, Tang Z. Effects of Long-Term Exposure to Copper on Mitochondria-Mediated Apoptosis in Pig Liver. Biol Trace Elem Res 2023; 201:1726-1739. [PMID: 35666388 DOI: 10.1007/s12011-022-03303-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/26/2022] [Indexed: 11/02/2022]
Abstract
Copper (Cu) is listed as one of the main heavy metal pollutants, which poses potential health risks to humans. Excessive intake of Cu has shown toxic effects on the organs of many animals, and the liver is one of the most important organs to metabolize it. In this study, pigs, the mammal with similar metabolic characteristics to humans, were selected to assess the effects of long-term exposure to Cu on mitochondria-mediated apoptosis, which are of great significance for studying the toxicity of Cu to humans. Pigs were fed a diet with different contents of Cu (10, 125, and 250 mg/kg) for 80 days. Samples of blood and liver tissue were collected on days 40 and 80. Experimental results demonstrated that the accumulation of Cu in the liver was increased in a dose-dependent and time-dependent manner. Meanwhile, the curve of pig's body weight showed that a 125 mg/kg Cu diet promoted the growth of pigs during the first 40 days and then inhibited it from 40 to 80 days, while the 250 mg/kg Cu diet inhibited the growth of pigs during 80 days of feeding. Additionally, the genes and protein expression levels of Caspase-3, p53, Bax, Bak1, Bid, Bad, CytC, and Drp1 in the treatment group were higher than that in the control group, while Bcl-2, Bcl-xL, Opa1, Mfn1, and Mfn2 were decreased. In conclusion, these results indicated that long-term excessive intake of Cu could inhibit the growth of pigs and induced mitochondria-mediated apoptosis by breaking the mitochondrial dynamic balance. Synopsis: Long-term exposure to high doses of Cu could lead to mitochondrial dysfunction by breaking the mitochondrial dynamic balance, which ultimately induced mitochondria-mediated apoptosis in the liver of pigs. This might be closely related to the growth inhibition and liver damage in pigs.
Collapse
Affiliation(s)
- Zhuoying Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Jianzhao Liao
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Kai Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Kunxuan Huang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Quanwei Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Chaiqin Lei
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Qingyue Han
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Hui Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Jianying Guo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Lianmei Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Jiaqiang Pan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Ying Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China
| | - Zhaoxin Tang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, People's Republic of China.
| |
Collapse
|
|
24
|
Lycopene ameliorates atrazine-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus of mice. Food Chem Toxicol 2023; 174:113655. [PMID: 36791905 DOI: 10.1016/j.fct.2023.113655] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/27/2023] [Accepted: 02/06/2023] [Indexed: 02/16/2023]
Abstract
Atrazine (ATR) is a commercially available herbicide that is used worldwide. The intensive use of ATR poses potential risks to animals' and humans' health. Lycopene (LYC) is an anti-oxidative phytochemical that normalizes health hazards triggered by environmental factors. In this study, we aimed to investigate the toxic effects of ATR on the hippocampus and its amelioration by LYC. Male mice were exposed to ATR (50 mg/kg/day or 200 mg/kg/d) and/or LYC (5 mg/kg/d) for 21 days. The results showed that ATR exposure induced hippocampus-dependent learning and memory impairments. ATR-induced ferroptosis in hippocampal cells affects the homeostasis of lipid metabolism, whereas LYC ameliorates the neurotoxic effects of ATR in the hippocampus. LYC inhibited ATR-induced ferroptosis by increasing the expression of HO-1, Nrf2 and SLC7A11. Therefore, this study established that LYC ameliorates ATR-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus and also provides a novel approach for the treatment in contradiction of environmental pollutants.
Collapse
|
|
25
|
Li MZ, Zhao Y, Dai XY, Talukder M, Li JL. Lycopene ameliorates DEHP exposure-induced renal pyroptosis through the Nrf2/Keap-1/NLRP3/Caspase-1 axis. J Nutr Biochem 2023; 113:109266. [PMID: 36610486 DOI: 10.1016/j.jnutbio.2022.109266] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/16/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023]
Abstract
Di (2-ethylhexyl) phthalate (DEHP) is commonly used as a plasticizer in plastic products, and due to its unique chemical composition, it frequently dissolves and enters the environment. Lycopene as a natural carotenoid has been shown to have powerful antioxidant capacity and strong kidney protection. This study aimed to investigate the role of the interplay between oxidative stress and the classical pyroptosis pathway in LYC alleviating DEHP-induced renal injury. ICR mice were given DEHP (500 mg/kg/d or 1000 mg/kg/d) and/or LYC (5 mg/kg/d) for 28 days to explore the underlying mechanisms of this hypothesis. Our results indicated that DEHP caused the shedding of renal tubular epithelial cells, increased the content of kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the tissue, the decrease of antioxidant activity markers and the increase of oxidative stress indexes. It is gratifying that LYC alleviates DEHP-induced renal injury. The expression of nuclear factor erythrocyte 2-related factor 2 (Nrf2) and its downstream target genes is improved in DEHP induced renal injury through LYC mediated protection. Meanwhile, LYC supplementation can inhibit DEHP-induced Caspase-1/NLRP3-dependent pyroptosis and inflammatory responses. Taken together, DEHP administration resulted in nephrotoxicity, but these changes ameliorated by LYC may through crosstalk between the Nrf2/Keap-1/NLRP3/Caspase-1 pathway. Our study provides new evidence that LYC protects against kidney injury caused by DEHP.
Collapse
Affiliation(s)
- Mu-Zi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilong Jiang, China
| | - Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilong Jiang, China
| | - Xue-Yan Dai
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilong Jiang, China
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilong Jiang, China; Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barisha, Bangladesh
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilong Jiang, China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, Heilong Jiang, China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, Heilong Jiang, China.
| |
Collapse
|
|
26
|
Bi SS, Talukder M, Sun XT, Lv MW, Ge J, Zhang C, Li JL. Cerebellar injury induced by cadmium via disrupting the heat-shock response. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:22550-22559. [PMID: 36301385 DOI: 10.1007/s11356-022-23771-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 10/18/2022] [Indexed: 06/16/2023]
Abstract
Cadmium (Cd) is a food contaminant that poses serious threats to animal health, including birds. It is also an air pollutant with well-known neurotoxic effects on humans. However, knowledge on the neurotoxic effects of chronic Cd exposure on chicken is limited. Thus, this study assessed the neurotoxic effects of chronic Cd on chicken cerebellum. Chicks were exposed to 0 (control), 35 (low), and 70 (high) mg/kg of Cd for 90 days, and the expression of genes related to the heat-shock response was investigated. The chickens showed clinical symptoms of ataxia, and histopathology revealed that Cd exposure decreased the number of Purkinje cells and induced degeneration of Purkinje cells with pyknosis, and some dendrites were missing. Moreover, Cd exposure increased the expression of heat-shock factors, HSF1, HSF2, and HSF3, and heat-shock proteins, HSP60, HSP70, HSP90, and HSP110. These changes indicate that HSPs improve the tolerance of the cerebellum to Cd. Conversely, the expressions of HSP10, HSP25, and HSP40 were decreased significantly, which indicated that Cd inhibits the expression of small heat-shock proteins. However, HSP27 and HSP47 were upregulated following low-dose Cd exposure, but downregulated under high-dose Cd exposure. This work sheds light on the toxic effects of Cd on the cerebellum, and it may provide evidence for health risks posed by Cd. Additionally, this work also identified a novel target of Cd exposure in that Cd induces cerebellar injury by disrupting the heat-shock response. Cd can be absorbed into chicken's cerebellum through the food chain, which eventually caused cerebellar injury. This study provided a new insight that chronic Cd-induced neurotoxicity in the cerebellum is associated with alterations in heat-shock response-related genes, which indicated that Cd through disturbing heat-shock response induced cerebellar injury.
Collapse
Affiliation(s)
- Shao-Shuai Bi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
- College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, 237012, People's Republic of China
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
- Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Xue-Tong Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Mei-Wei Lv
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Jing Ge
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Cong Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
| |
Collapse
|
|
27
|
Hu Z, Shi S, Ou Y, Hu F, Long D. Mitochondria-associated endoplasmic reticulum membranes: A promising toxicity regulation target. Acta Histochem 2023; 125:152000. [PMID: 36696877 DOI: 10.1016/j.acthis.2023.152000] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/24/2023]
Abstract
Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic suborganelle membranes that physically couple endoplasmic reticulum (ER) and mitochondria to provide a platform for exchange of intracellular molecules and crosstalk between the two organelles. Dysfunctions of mitochondria and ER and imbalance of intracellular homeostasis have been discovered in the research of toxics. Cellular activities such as oxidative stress, ER stress, Ca2+ transport, autophagy, mitochondrial fusion and fission, and apoptosis mediated by MAMs are closely related to the toxicological effects of various toxicants. These cellular activities mediated by MAMs crosstalk with each other. Regulating the structure and function of MAMs can alleviate the damage caused by toxicants to some extent. In this review, we discuss the relationships between MAMs and the mechanisms of toxicological effects, and highlight MAMs as a potential target for protection against toxicants.
Collapse
Affiliation(s)
- Zehui Hu
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, PR China
| | - Shengyuan Shi
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, PR China
| | - Yiquan Ou
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, PR China
| | - Fangyan Hu
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, PR China
| | - Dingxin Long
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, PR China.
| |
Collapse
|
|
28
|
Wang JX, Zhao Y, Chen MS, Zhang H, Cui JG, Li JL. Heme-oxygenase-1 as a target for phthalate-induced cardiomyocytes ferroptosis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 317:120717. [PMID: 36423886 DOI: 10.1016/j.envpol.2022.120717] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/09/2022] [Accepted: 11/19/2022] [Indexed: 06/16/2023]
Abstract
Phthalates as a large group of environmental pollutants are used primarily as plasticizers and solvents, which have become a growing problem worldwide. Epidemiological results show that severity of heart disease is related to degree of environmental contamination. As the most usually used phthalate, di(2-ethylhexyl) phthalate (DEHP) has toxic effects on organism health and is also a major cause of heart damage. Ingestion of food, liquid, or dust contaminated with DEHP are major routes of exposure. The purpose of the present research was to determine the mechanism of cardiotoxicity in mice after exposure to DEHP. Here, male mice were treated by gavage with three different doses of (50, 200 and 500 mg/kg b.w.) DEHP for 28 days. Our research showed that DEHP brought about histopathological changes involving cardiomyocyte lysis and rupture, and ultrastructural damage such as dissolution and loss of mitochondrial cristae. Furthermore, DEHP induced oxidative stress and a significant decline in the antioxidant function, which activates nuclear factor E2-related factor 2 (Nrf2)/heme-oxygense-1 (HO-1) signaling pathways. Interestingly, DEHP resulted in lipid peroxidation and increased ferrous ion content, suggesting that ferroptosis occurred in mouse hearts. Therefore, our findings demonstrated that DEHP could induce cardiac ferroptosis via upregulation of HO-1. The present study provides novel evidence of HO-1 as a target for DEHP-induced cardiotoxicity.
Collapse
Affiliation(s)
- Jia-Xin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Ming-Shan Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
| |
Collapse
|
|
29
|
Shi YS, Zhao Y, Li XN, Li MZ, Li JL. Xenobiotic-sensing nuclear receptors as targets for phthalates-induced lung injury and antagonism of lycopene. CHEMOSPHERE 2023; 312:137265. [PMID: 36403809 DOI: 10.1016/j.chemosphere.2022.137265] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/06/2022] [Accepted: 11/14/2022] [Indexed: 06/16/2023]
Abstract
Phthalates are extensively used in the production of plastics products and have been verified to induce lung injury. Lycopene (LYC) has proved an effective preventive and can be utilized to prevent phthalates-induced toxicity. However, the role of phthalate in pathogenesis of lung injury remain poorly researched, and little work has been devoted whether LYC could alleviate phthalate-induced lung toxicity via modulating nuclear xenobiotic receptors (NXRs) response. Here, di (2-ethylhexyl) phthalate (DEHP) is used as the representative of phthalates for further studies on toxicity of phthalates and the antagonistic role of LYC in phthalates-induced lung injury. We found that DEHP exposure caused alveoli destruction and alveolar epithelial cells type II damage. Mechanistically, DEHP exposure increased nuclear accumulation of aryl hydrocarbon receptor (AHR) and its downstream genes level, including cytochrome P450-dependent monooxygenase (CYP) 1A1 and CYP1B1. Constitutive androstane receptor (CAR) and their downstream gene level, including CYP2E1 are also increased after phthalates exposure. Significantly, LYC supplementation relieves lung injury from DEHP exposure by inhibiting the activation of NXRs. We confirm that NXRs plays a key role in phthalates-induced lung injury. Our study showed that LYC may have a positive role in alleviating the toxicity effects of phthalates, which provides an effective strategy for revising phthalates-induced injury.
Collapse
Affiliation(s)
- Yu-Sheng Shi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Mu-Zi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
| |
Collapse
|
|
30
|
Lei Y, Zhang W, Gao M, Lin H. Mechanism of evodiamine blocking Nrf2/MAPK pathway to inhibit apoptosis of grass carp hepatocytes induced by DEHP. Comp Biochem Physiol C Toxicol Pharmacol 2023; 263:109506. [PMID: 36368504 DOI: 10.1016/j.cbpc.2022.109506] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/24/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022]
Abstract
Di (2-ethylhexyl) phthalate (DEHP) is often used as a plasticizer for plastic products, and its excessive use can cause irreversible damage to aquatic animals and humans. Evodiamine (EVO) is an alkaloid component in the fruit of Evodia rutaecarpa, which has antioxidant and detoxification functions. To investigate the toxic mechanism of DEHP on grass carp (Ctenopharyngodon idellus) hepatocyte cell line (L8824) and the therapeutic effect of evodiamine, an experimental model of L8824 cells exposed to 800 μM DEHP and/or 10 μM EVO for 24 h was established. Flow cytometry, AO/EB fluorescence staining, real-time quantitative PCR, and western blot were used to detect the degree of cell injury, oxidative stress level, MAPK signaling pathway relative genes, and the expression of apoptosis-related molecules. The results showed that DEHP exposure could significantly increase the level of reactive oxygen species (ROS), inhibit the activities of antioxidant enzymes (CAT, SOD, GSH-Px), and cause the accumulation of MDA. DEHP also activated MAPK signaling pathway-related molecules (JNK, ERK, P38 MAPK), and then up-regulated the expression of pro-apoptotic factors Bcl-2-Associated X (Bax) and caspase 3, while inhibiting the anti-apoptotic factor B-cell lymphoma-2 (Bcl-2). In addition, EVO can also promote the dissociation of nuclear factor-E2-related factor 2 (Nrf2) into the nucleus, reduce the level of ROS and the occurrence of oxidative stress in grass carp hepatocytes, down-regulate the MAPK pathway, alleviate DEHP-induced apoptosis, and restore the expression of antioxidant genes. These results indicated that evodiamine could block Nrf2/MAPK pathway to inhibit DEHP-induced apoptosis of grass carp hepatocytes.
Collapse
Affiliation(s)
- Yutian Lei
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Wenyue Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Meichen Gao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hongjin Lin
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
31
|
Khan NG, Eswaran S, Adiga D, Sriharikrishnaa S, Chakrabarty S, Rai PS, Kabekkodu SP. Integrated bioinformatic analysis to understand the association between phthalate exposure and breast cancer progression. Toxicol Appl Pharmacol 2022; 457:116296. [PMID: 36328110 DOI: 10.1016/j.taap.2022.116296] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 10/22/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022]
Abstract
Phthalates have been extensively used as plasticizers while manufacturing plastic-based consumer products. Estradiol mimicking properties and association studies suggest phthalates may contribute to breast cancer (BC). We performed an in-silico analysis and functional studies to understand the association between phthalate exposure and BC progression. Search for phthalate-responsive genes using the comparative toxicogenomics database identified 20 genes as commonly altered in response to multiple phthalates exposure. Of the 20 genes, 12 were significantly differentially expressed between normal and BC samples. In BC samples, 9 out of 20 genes showed a negative correlation between promoter methylation and its expression. AHR, BAX, BCL2, CAT, ESR2, IL6, and PTGS2 expression differed significantly between metastatic and non-metastatic BC samples. Gene set enrichment analysis identified metabolism, ATP-binding cassette transporters, insulin signaling, and type II diabetes as highly enriched pathways. The diagnostic assessment based on 20 genes expression suggested a sensitivity and a specificity >0.91. The aberrantly expressed phthalate interactive gene influenced the overall survival of BC patients. Drug-gene interaction analysis identified 14 genes and 523 candidate drugs, including 19 BC treatment-approved drugs. Di(2-ethylhexyl) phthlate (DEHP) exposure increased the growth, proliferation, and migration of MCF-7 and MDA-MB-231 cells in-vitro. DEHP exposure induced morphological changes, actin cytoskeletal remodeling, increased ROS content, reduced basal level lipid peroxidation, and induced epithelial to mesenchymal transition (EMT). The present approach can help to explore the potentially damaging effects of environmental agents on cancer risk and understand the underlined pathways and molecular mechanisms.
Collapse
Affiliation(s)
- Nadeem G Khan
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sangavi Eswaran
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - S Sriharikrishnaa
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; Centre for DNA repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Padmalatha S Rai
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; Centre for DNA repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
| |
Collapse
|
|
32
|
Yang TN, Li XN, Wang YX, Ma XY, Li JL. Disrupted microbiota-barrier-immune interaction in phthalates-mediated barrier defect in the duodenum. CHEMOSPHERE 2022; 308:136275. [PMID: 36058374 DOI: 10.1016/j.chemosphere.2022.136275] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/15/2022] [Accepted: 08/27/2022] [Indexed: 06/15/2023]
Abstract
As one of the most used phthalates, Di (2-ethylhexyl) phthalate (DEHP) is a widespread environmental contaminant. Extremely persistent plastic can enter the food chain of animals through the aquatic environment, affect metabolic pathways and cause damage to the digestive system. But the molecular mechanism of its toxic effects on the duodenum in birds has not been elucidated. To investigate the toxicity of phthalates in the duodenum, quails were gavaged with 250, 500, and 750 mg/kg doses of DEHP for 45 days, and water and oil control groups were retained. This study revealed that subchronic exposure to DEHP could lead to duodenal barrier defect in quail. The damage to duodenum was reflected in a reduction in V/C and tight junction proteins. Moreover, DEHP also led to a breakdown of antimicrobial defenses through the flora derangement, which acted as a biological barrier. The massive presence of Lipopolysaccharide (LPS) led to the activation of TLR4 receptors. In addition, DEHP activated oxidative stress, which synergized the inflammatory response induced by the TLR4-NFκB pathway, and further promoted duodenum damage. This study provides a base for the further effect of phthalates on the microbiota-barrier-immune interaction.
Collapse
Affiliation(s)
- Tian-Ning Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yu-Xiang Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xiang-Yu Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
| |
Collapse
|
|
33
|
Promising hepatoprotective effects of lycopene in different liver diseases. Life Sci 2022; 310:121131. [PMID: 36306869 DOI: 10.1016/j.lfs.2022.121131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/13/2022] [Accepted: 10/23/2022] [Indexed: 11/07/2022]
|
|
34
|
Bi SS, Talukder M, Jin HT, Lv MW, Ge J, Zhang C, Li JL. Nano-selenium alleviates cadmium-induced cerebellar injury by activating metal regulatory transcription factor 1 mediated metal response. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2022; 11:402-412. [PMID: 36382201 PMCID: PMC9636061 DOI: 10.1016/j.aninu.2022.06.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 04/22/2022] [Accepted: 06/22/2022] [Indexed: 05/21/2023]
Abstract
This study aims to investigate the role of metal regulatory transcription factor 1 (MTF1)-mediated metal response in cadmium (Cd)-induced cerebellar injury, and to evaluate the antagonistic effects of nano-selenium (Nano-Se) against Cd toxicity. A total of 80 chicks (1 d old, male, Hy-Line Variety White) were randomly allocated to 4 treatment groups for 3 months: the control group (fed with a basic diet, n = 20), the Nano-Se group (basic diet with 1 mg/kg nano-Se 1 mg/kg Nano-Se in basic diet, n = 20), the Nano-Se + Cd group (basic diet with 1 mg/kg Nano-Se and 140 mg/kg CdCl2, n = 20) and the Cd group (basic diet with 140 mg/kg CdCl2 , n = 20). The results of the experiment showed that the Purkinje cells were significantly decreased with their degradation and indistinct nucleoli after Cd exposure. Moreover, exposure to Cd caused a significant accumulation of Cd and cupper. However, the contents of Se, iron, and zinc were decreased, thereby disturbing the metal homeostasis in the cerebellum. The Cd exposure also resulted in high levels of malondialdehyde (MDA) and down regulation of selenoprotein transcriptome. Furthermore, the expressions of MTF1, metallothionein 1 (MT1), MT2, zinc transporter 3 (ZNT3), ZNT5, ZNT10, zrt, irt-like protein 8 (ZIP8), ZIP10, transferrin (TF), ferroportin 1 (FPN1), ATPase copper transporting beta (ATP7B), and copper uptake protein 1 (CTR1) were inhibited by Cd exposure. However, all these changes were significantly alleviated by the supplementation of Nano-Se. This study proved that Cd could disorder metal homeostasis and induce oxidative stress, whereas Nano-Se could relieve all these negative effects caused by Cd via activating the MTF1-mediated metal response in the cerebellum of chicken.
Collapse
Affiliation(s)
- Shao-Shuai Bi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- College of Biotechnology and Pharmaceutical Engineering of West Anhui University, Lu’an 237012, China
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Hai-Tao Jin
- Quality and Safety Institute of Agricultural Products, Heilongjiang Academy of Agricultural Sciences, Harbin 150010, China
| | - Mei-Wei Lv
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jing Ge
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Cong Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
- Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, China
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
- Corresponding author. College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
| |
Collapse
|
|
35
|
Dai XY, Lin J, Zhu SY, Guo JY, Cui JG, Li JL. Atrazine-induced oxidative damage via modulating xenobiotic-sensing nuclear receptors and cytochrome P450 systems in cerebrum and antagonism of lycopene. Food Chem Toxicol 2022; 170:113462. [DOI: 10.1016/j.fct.2022.113462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/17/2022] [Accepted: 10/04/2022] [Indexed: 11/07/2022]
|
|
36
|
Role of ER Stress in Xenobiotic-Induced Liver Diseases and Hepatotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4640161. [PMID: 36388166 PMCID: PMC9652065 DOI: 10.1155/2022/4640161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/12/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
The liver is a highly metabolic organ and plays a crucial role in the transportation, storage, and/or detoxication of xenobiotics. Liver damage induced by xenobiotics (e.g., heavy metal, endocrine disrupting chemicals, Chinese herbal medicine, or nanoparticles) has become a pivotal reason for liver diseases, leading to great clinical challenge and much attention for the past decades. Given that endoplasmic reticulum (ER) is the prominent organelle involved in hepatic metabolism, ER dysfunction, namely, ER stress, is clearly observed in various liver diseases. In response to ER stress, a conserved adaptive signaling pathway known as unfolded protein response (UPR) is activated to restore ER homeostasis. However, the prolonged ER stress with UPR eventually leads to the death of hepatocytes, which is a pathogenic event in many hepatic diseases. Therefore, analyzing the perturbation in the activation or inhibition of ER stress and the UPR signaling pathway is likely an effective marker for investigating the molecular mechanisms behind the toxic effects of xenobiotics on the liver. We review the role of ER stress in hepatic diseases and xenobiotic-induced hepatotoxicity, which not only provides a theoretical basis for further understanding the pathogenesis of liver diseases and the mechanisms of hepatotoxicity induced by xenobiotics but also presents a potential target for the prevention and treatment of xenobiotic-related liver diseases.
Collapse
|
|
37
|
Yang TN, Li XN, Li XW, Li JY, Huang YQ, Li JL. DEHP triggers a damage severity grade increase in the jejunum in quail (Coturnix japonica) by disturbing nuclear xenobiotic receptors and the Nrf2-mediated defense response. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 96:104012. [PMID: 36372389 DOI: 10.1016/j.etap.2022.104012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 07/18/2022] [Accepted: 11/08/2022] [Indexed: 06/16/2023]
Abstract
As a plasticizer, di-2-ethylhexyl phthalate (DEHP) has been listed as a potential endocrine disruptor by The World Health Organization. The toxicity of DEHP has been widely studied, but its toxicity on the digestive tract of birds has not been clarified. Female quail were treated by gavage with DEHP (250, 500, 750 mg/kg), with the blank and vehicle control groups reserved. The result showed that DEHP raised the damage severity grade, and decreased the ratio of villus length to crypt depth. The content and activity of cytochrome P450 system (CYP450s) were increased by DEHP. DEHP interfered with the transcription of nuclear xenobiotic receptors (NXRs), CYP isoforms, and the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway. This study revealed DEHP could cause the imbalance in CYP450s mediated by NXRs, and then promote Nrf2 mediated antioxidant defense. This study provided new evidence about the mechanisms of DEHP-induced toxic effects on digestive tract.
Collapse
Affiliation(s)
- Tian-Ning Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiao-Wei Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jin-Yang Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yue-Qiang Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
38
|
Zhao Y, Li XN, Zhang H, Cui JG, Wang JX, Chen MS, Li JL. Phthalate-induced testosterone/androgen receptor pathway disorder on spermatogenesis and antagonism of lycopene. JOURNAL OF HAZARDOUS MATERIALS 2022; 439:129689. [PMID: 36104915 DOI: 10.1016/j.jhazmat.2022.129689] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 06/15/2023]
Abstract
Male infertility is an attracting growing concern owing to decline in sperm quality of men worldwide. Phthalates, in particular to di (2-ethylhexyl) phthalate (DEHP) or its main metabolite mono-2-ethylhexyl phthalate (MEHP), affect male reproductive development and function, which mainly accounts for reduction in male fertility. Lycopene (LYC) is a natural antioxidant agent that has been recognized as a possible therapeutic option for treating male infertility. Testosterone (T)/androgen receptor (AR) signaling pathway is involved in maintaining spermatogenesis and male fertility. How DEHP causes spermatogenesis disturbance and whether LYC could prevent DEHP-induced male reproductive toxicity have remained unclear. Using in vivo and vitro approaches, we demonstrated that DEHP caused T biosynthesis reduction in Leydig cell and secretory function disorder in Sertoli cell, and thereby resulted in spermatogenic impairment. Results also showed that MEHP caused mitochondrial damage and oxidative damage, which imposes a serious threat to the progress of spermatogenesis. However, LYC supplement reversed these changes. Mechanistically, DEHP contributed to male infertility via perturbing T/AR signaling pathway during spermatogenesis. Overall, our study reveals critical role for T/AR signal transduction in male fertility and provides promising insights into the protective role of LYC in phthalate-induced male reproductive disorders.
Collapse
Affiliation(s)
- Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jia-Xin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Ming-Shan Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
39
|
Zhao Y, Chen MS, Wang JX, Cui JG, Zhang H, Li XN, Li JL. Connexin-43 is a promising target for lycopene preventing phthalate-induced spermatogenic disorders. J Adv Res 2022:S2090-1232(22)00203-X. [PMID: 36087924 DOI: 10.1016/j.jare.2022.09.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Male infertility is a multifactorial pathological condition and may be a harbinger of future health. Phthalates are ubiquitous environmental contaminants that have been implicated in the global decline in male fertility. Among them, di-(2-ethylhexyl) phthalate (DEHP) is the most prevalently used. Lycopene (LYC) is a possible preventive and therapeutic agent for male infertility owing to its antioxidant properties. The blood-testis barrier (BTB) is formed between Sertoli cells where it creates a unique microenvironment for spermatogenesis. OBJECTIVES We hypothesize that phthalate caused male infertility and LYC plays an important role in phthalate-induced male fertility disorders. METHODS Hematoxylin-eosin (H&E) staining, ultrastructure observation, and fluorescence microscopy were used to examine the morphological changes. RNA-Seq, and western blotting were conducted to detect gene and protein levels. Routine testing for sperm morphology and sperm-egg binding assay were conducted to examine the morphological structure and function of sperm. Cell scratch assay and transepithelial electrical resistance (TER) were used to detect cell migration capacity and barrier integrity. RESULTS In vivo experiments, we showed that LYC prevented DEHP-induced impairment of BTB integrity, which provided a guarantee for the smooth progress of spermatogenesis. LYC improved DEHP-induced change in sperm parameters and fertilization ability. Subsequent in vitro experiments, LYC alleviated MEHP-induced disruption of intercellular junctions in mouse Spermatogonia cells (GC-1 cells) and mouse Sertoli cells (TM4 cells). In MEHP-induced BTB impairment models of Sertoli cells, treatment with LYC or overexpressing connexin-43 (Cx43) promoted cell migration capacity and normalized BTB integrity. Cx43 knockdown inhibited cell migration capacity and perturbed BTB reassembly in LYC preventing DEHP-induced BTB impairment. CONCLUSION Our study provides evidence for the role of LYC in phthalates-induced spermatogenic disorders and points to Cx43 as a potential target for male fertility.
Collapse
Affiliation(s)
- Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Ming-Shan Chen
- 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. China
| | - Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P.R. China
| | - Xue-Nan 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
| | - 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.
| |
Collapse
|
|
40
|
Dai XY, Zhu SY, Chen J, Li MZ, Talukder M, Li JL. Role of Toll-like Receptor/MyD88 Signaling in Lycopene Alleviated Di-2-ethylhexyl Phthalate (DEHP)-Induced Inflammatory Response. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:10022-10030. [PMID: 35917506 DOI: 10.1021/acs.jafc.2c03864] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Lycopene (Lyc) has anti-inflammatory and antioxidant biological functions. Di-2-ethylhexyl phthalate (DEHP) is an extremely harmful and persistent environmental pollutant and is a threat to animal health. The toll-like receptor (TLR)/MyD88 pathway is an important pathway in the inflammatory response. To illustrate the potential antagonistic action of Lyc against DEHP by the TLR/MyD88 pathway, 140 ICR mice were randomly assigned groups and continuously gavaged with corn oil, distilled water, different DEHP concentrations (500 or 1000 mg/kg BW/day), and/or Lyc (5 mg/kg BW/day) for 28 days. The data show that Lyc effectively attenuates the DEHP-induced activation of the TLR/MyD88 pathway, the upregulation of JNK expression, the content of IL-6 and TNF-α, and the downregulation of the IL-10 content, which eventually inhibit the inflammatory response and mitochondrial injuries. These findings underline the TLR/MyD88 pathway as a potential therapeutic target in DEHP and Lyc as a new therapeutic method to inhibit DEHP toxicity.
Collapse
Affiliation(s)
- Xue-Yan Dai
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, P. R. China
| | | | | | | | - Milton Talukder
- Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal 8210, Bangladesh
| | | |
Collapse
|
|
41
|
How CM, Hsiu-Chuan Liao V. Chronic exposure to environmentally relevant levels of di(2-ethylhexyl) phthalate (DEHP) disrupts lipid metabolism associated with SBP-1/SREBP and ER stress in C. elegans. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 307:119579. [PMID: 35671893 DOI: 10.1016/j.envpol.2022.119579] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/24/2022] [Accepted: 06/02/2022] [Indexed: 06/15/2023]
Abstract
DEHP is commonly found in the environment, biota, food, and humans, raising significant health concerns. Whether developmental stage and exposure duration modify the obesogenic effects of DEHP is unclear, especially the underlying mechanisms by which chronic exposure to DEHP as well as its metabolites remain largely unknown. This study investigated the obesogenic effects of chronic DEHP exposure, with levels below environmentally-relevant amounts and provide the mechanism in Caenorhabditis elegans. We show that early-life DEHP exposure resulted in an increased lipid and triglyceride (TG) accumulation mainly attributed to DEHP itself, not its metabolite mono-2-ethylhexyl phthalate (MEHP). In addition, developmental stage and exposure timing influence DEHP-induced TG accumulation and chronic DEHP exposure resulted in the most significant effect. Analysis of fatty acid composition shows that chronic DEHP exposure altered fatty acid composition and TG, resulting in an increased ω-6/ω-3 ratio. The increased TG content by chronic DEHP exposure required lipogenic genes fat-6, fat-7, pod-2, fasn-1, and sbp-1. Moreover, chronic DEHP exposure induced XBP-1-mediated endoplasmic reticulum (ER) stress which might lead to up-regulation of sbp-1. This study suggests the possible involvement of ER stress and SBP-1/SREBP-mediated lipogenesis in chronic DEHP-induced obesogenic effects. Results from this study implies that chronic exposure to DEHP disrupts lipid metabolism, which is likely conserved across species due to evolutionary conservation of molecular mechanisms, raising concerns in ecological and human health.
Collapse
Affiliation(s)
- Chun Ming How
- Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 106, Taiwan
| | - Vivian Hsiu-Chuan Liao
- Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 106, Taiwan.
| |
Collapse
|
|
42
|
Dai XY, Zhu SY, Chen J, Li MZ, Zhao Y, Talukder M, Li JL. Lycopene alleviates di(2-ethylhexyl) phthalate-induced splenic injury by activating P62-Keap1-NRF2 signaling. Food Chem Toxicol 2022; 168:113324. [PMID: 35917956 DOI: 10.1016/j.fct.2022.113324] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 07/16/2022] [Accepted: 07/20/2022] [Indexed: 01/15/2023]
Abstract
Di(2-ethylhexyl) phthalate (DEHP) is an omnipresent environmental pollutant. It has been determined that DEHP is involved in multiple health disorders. Lycopene (Lyc) is a natural carotenoid pigment, with anti-inflammatory and antioxidant properties. However, it is not clear whether Lyc can protect the spleen from DEHP-induced oxidative damage. A total of 140 mice were randomly divided into seven groups (n = 20) and continuously gavaged with corn oil, distilled water, DEHP (500 or 1000 mg/kg BW/day) and/or Lyc (5 mg/kg BW/day) for 28 days. Histopathological and ultrastructural results showed a DEHP-induced inflammatory response and mitochondrial injuries. Moreover, DEHP exposure induced redox imbalance, which resulted in the up-regulation of ROS activity and MDA content, and the down-regulation of T-AOC, T-SOD and CAT in the DEHP groups. Simultaneously, our results also demonstrated that DEHP-induced kelch-like ECH-associated protein 1 (Keap1) expression was downregulated, and the expression levels of P62, nuclear factor erythroid 2-related factor (NRF2) and their downstream target genes were up-regulated. However, the supplementary Lyc reverted these changes to normal levels. Together, Lyc prevented DEHP-induced splenic injuries by regulating the P62-Keap1-NRF2 signaling pathway. Hence, the protective effects of Lyc might be a therapeutic strategy to ameliorate DEHP-induced splenic damage.
Collapse
Affiliation(s)
- Xue-Yan Dai
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, PR China
| | - Shi-Yong Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Jian Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Mu-Zi Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
43
|
Cadmium-induced splenic lymphocytes anoikis is not mitigated by activating Nrf2-mediated antioxidative defense response. J Inorg Biochem 2022; 234:111882. [DOI: 10.1016/j.jinorgbio.2022.111882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/19/2022] [Accepted: 05/28/2022] [Indexed: 12/12/2022]
|
|
44
|
Chen J, Tang YX, Kang JX, Xu YR, Elsherbeni AIA, Gharib HBA, Li JL. Astragalus polysaccharide alleviates transport stress-induced heart injury in newly hatched chicks via ERS-UPR-Autophagy dependent pathway. Poult Sci 2022; 101:102030. [PMID: 35905545 PMCID: PMC9334333 DOI: 10.1016/j.psj.2022.102030] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/12/2022] [Accepted: 06/20/2022] [Indexed: 02/08/2023] Open
Abstract
Transport stress (TS) not only affects animal welfare but also eventually leads to higher morbidity and mortality. Moreover, TS could induce heart injury in animals, but the possible mechanism has yet to be fully explored. Astragalus polysaccharide (APS) is a main active component of Radix Astragali, which has an extensive anti-stress effect. However, the effect of APS on TS-induced heart injury has not yet been elucidated. In this study, a chick model of simulated TS was used. 240 newly hatched chicks were arranged into 4 groups: Control (Con), Transport group (T), Transport + water group (TW), and Transport + APS group (TA). Before transport, the chicks of the TW and TA groups were treated with deionized water and APS (0.25 mg/mL, 100 µL) by oral drops respectively. The histopathological analysis of myocardial tissue was assessed by hematoxylin and eosin staining. qRT-PCR and Western Blotting assays were employed to measure the expression of genes and proteins. Semiquantitative PCR was performed for the X box-binding protein-1 (XBP-1) mRNA splicing assay. The results indicated that APS significantly reduced TS-induced myocardial histopathological changes. Meanwhile, TS induced endoplasmic reticulum stress (ERS), evidenced by an activation of the unfolded protein response (UPR) signaling pathway and up-regulation of ERS-markers (P < 0.05). Moreover, TS markedly triggered autophagy induction by activating AMP-activated protein kinase (AMPK), reflected by augmented LC3-II/LC3-I, AMPK phosphorylation and autophagy-related genes (ATGs) expression (P < 0.05). Importantly, our study manifested that treatment of APS could reduce TS-induced ERS and AMPK-activated autophagy, accordingly alleviating heart injury of transported chicks. In summary, these findings indicate that TS induces heart injury in chicks via an ERS-UPR-autophagy-dependent pathway, and APS as an effective therapeutic method to alleviate it.
Collapse
Affiliation(s)
- Jian Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yi-Xi Tang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jian-Xun Kang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Ya-Ru Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | | | | | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
45
|
Liu X, Zhang Y, Sun X, Zhang W, Shi X, Xu S. Di-(2-ethyl hexyl) phthalate induced oxidative stress promotes microplastics mediated apoptosis and necroptosis in mice skeletal muscle by inhibiting PI3K/AKT/mTOR pathway. Toxicology 2022; 474:153226. [PMID: 35659966 DOI: 10.1016/j.tox.2022.153226] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/22/2022] [Accepted: 05/29/2022] [Indexed: 01/18/2023]
Abstract
The plastic decomposition product microplastics (MPs) and the plastic additive Di (2-ethylhexyl) phthalate (DEHP) in the environment can damage various organs of the organism by inducing oxidative stress. The PI3K/AKT/mTOR signaling pathway participate in toxin-induced apoptosis and necroptosis. However, the effects of DEHP/MPs alone and combined exposure on skeletal muscle cell injury in mice and the role of PI3K/AKT/mTOR axis remain unclear. To investigate the effect of DEHP or/and MPs on skeletal muscle in mice and its possible toxicological mechanism, 60 mice were randomly divided into control group, DEHP group (DEHP 200 mg/kg dissolved in 50 mL corn oil mixed with 2.5 kg diet), MPs group (10 mg/L MPs in drinking water) and combined exposure group. In vitro, C2C12 cells were exposed to DEHP 600 μM/MPs 800 μM alone or in combination for 24 h. The results showed that DEHP/MPs exposure alone or in combination increased MDA content, decreased activities of CAT, T-AOC, SOD and GSH-Px, increased mRNA and protein expressions of Caspase-3, BAX, RIPK1, RIPK3 and MLKL, and decreased BCL-2 expression. The expression of PI3K/AKT/mTOR signaling pathway was significantly down-regulated. All the above results showed that the combined exposure group was more toxic, and similar experimental results were obtained by DEHP/MPs exposure test of C2C12 cells in vitro. It is suggested that DEHP/MPs can induce apoptosis and necroptosis by activating oxidative stress and down-regulating PI3K/AKT/mTOR pathway. This study provides new evidence for clarifying the possible mechanism of toxicity of DEHP and MPs to skeletal muscle of mice.
Collapse
Affiliation(s)
- Xiaojing Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yilei Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xinyue Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Wenyue Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xu Shi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| |
Collapse
|
|
46
|
Zhao YX, Tang YX, Sun XH, Zhu SY, Dai XY, Li XN, Li JL. Gap Junction Protein Connexin 43 as a Target Is Internalized in Astrocyte Neurotoxicity Caused by Di-(2-ethylhexyl) Phthalate. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:5921-5931. [PMID: 35446567 DOI: 10.1021/acs.jafc.2c01635] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in plastic products, consumer products, and packaging materials. It is of great health concern in both animals and humans as it released into the environment and entered into the body from plastic products over time, thereby resulting in neurotoxicity. As a pivotal regulator of the central nervous system (CNS), astrocytes, are crucial for maintaining brain homeostasis. Nevertheless, the underlying reason for astrocyte neurotoxicity due to DEHP exposure remains incompletely understood. Here, using an in vivo model of neurotoxicity in quail, this study summarizes that Cx43 is internalized by phosphorylation and translocated to the nucleus as a consequence of DEHP exposure in astrocytes. This study further demonstrated that astrocytes transformed to pro-inflammatory status and induced the formation of autophagosomes. Of note, integrated immunofluorescent codetection approaches revealed an overexpression of the glial fibrillary acidic protein (GFAP) and down-expression of Cx43 in astrocytes. Therefore, in terms of neurotoxicity, this experiment in vivo models directly linked Cx43 internalization to autophagy and neuroinflammation and ultimately locked these changes to the astrocytes of the brain. These findings unveil a potential approach targeting Cx43 internalization for the treatment of neurodegeneration caused by DEHP exposure in astrocytes.
Collapse
Affiliation(s)
- Ying-Xin Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Yi-Xi Tang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Xiao-Han Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Shi-Yong Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Xue-Yan Dai
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China
| | - Xue-Nan 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
| | - 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
| |
Collapse
|
|
47
|
Huang YQ, Tang YX, Qiu BH, Talukder M, Li XN, Li JL. Di-2-ethylhexyl phthalate (DEHP) induced lipid metabolism disorder in liver via activating the LXR/SREBP-1c/PPARα/γ and NF-κB signaling pathway. Food Chem Toxicol 2022; 165:113119. [PMID: 35537648 DOI: 10.1016/j.fct.2022.113119] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 04/02/2022] [Accepted: 05/04/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Yue-Qiang Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yi-Xi Tang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Bai-Hao Qiu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
| |
Collapse
|
|
48
|
Cui JG, Zhao Y, Zhang H, Li XN, Li JL. Lycopene regulates the mitochondrial unfolded protein response to prevent DEHP-induced cardiac mitochondrial damage in mice. Food Funct 2022; 13:4527-4536. [PMID: 35348563 DOI: 10.1039/d1fo03054j] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lycopene (LYC), as a kind of carotene, has antioxidant effects. Di(2-ethylhexyl) phthalate (DEHP) was used to improve the flexibility of plastics. However, the potential role of LYC in DEHP induced cardiac injury in mice remains unclear. Therefore, the aim of this study was to investigate the role and mechanism of LYC in DEHP induced cardiac injury. Male ICR mice were treated with DEHP (500 or 1000 mg per kg BW per day) and/or LYC (5 mg per kg BW per day) for 28 days. The results of histopathology and ultrastructure showed that LYC relieved the decrease of mitochondrial volume density and myocardial fibre disorder induced by DEHP. Subsequently, LYC attenuated DEHP-induced mitochondrial damage, mitochondrial unfolded protein response (UPRmt) activation, nuclear factor erythroid 2-related factor 2 (Nrf2) mediated oxidative stress and heat shock response (HSR) activation induced by DEHP. LYC regulates UPRmt to prevent DEHP-induced cardiac mitochondrial damage. Thus, this study provided new evidence of UPRmt as a target for LYC treatment preventing DEHP-induced cardiac disease.
Collapse
Affiliation(s)
- Jia-Gen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Yi Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Hao Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.
| | - 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
| |
Collapse
|
|
49
|
Kim JK, Park SU. Recent insights into the biological and pharmacological activity of lycopene. EXCLI JOURNAL 2022; 21:415-425. [PMID: 35391916 PMCID: PMC8983849 DOI: 10.17179/excli2022-4714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 02/10/2022] [Indexed: 12/27/2022]
Affiliation(s)
- Jae Kwang Kim
- Division of Life Sciences and Bio?Resource and Environmental Center, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea
| | - Sang Un Park
- Department of Crop Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea.,Department of Smart Agriculture Systems, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Korea
| |
Collapse
|
|
50
|
Peng J, Peng C, Wang L, Cao H, Xing C, Li G, Hu G, Yang F. Endoplasmic reticulum-mitochondria coupling attenuates vanadium-induced apoptosis via IP 3R in duck renal tubular epithelial cells. J Inorg Biochem 2022; 232:111809. [PMID: 35421768 DOI: 10.1016/j.jinorgbio.2022.111809] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/14/2022] [Accepted: 03/24/2022] [Indexed: 11/28/2022]
Abstract
Vanadium (V) is necessary for the health and growth of animals, but excessive V has harmful effects on the ecosystem health. Endoplasmic reticulum (ER)-mitochondria coupling as a membrane structure connects the mitochondrial outer membrane with the ER. The mitochondria-associated ER membrane (MAM) is a region of the ER-mitochondria coupling and is essential for normal cell function. Currently, the crosstalk between ER-mitochondrial coupling and apoptosis in the toxic mechanism of V on duck kidney is still unclear. In this study, duck renal tubular epithelial cells were incubated with different concentrations of sodium metavanadate (NaVO3) and/or inositol triphosphate receptor (IP3R) inhibitor 2-aminoethyl diphenyl borate (2-APB) for 24 h. The results showed that V could significantly increase lactate dehydrogenase (LDH) release, the mitochondrial calcium level and the numbers of the fluorescent signal points of IP3R; shortened the length ER-mitochondria coupling and reduced its formation; markedly upregulate the mRNA levels of MAM-related genes and protein levels, causing MAM dysfunction. Additionally, V treatment appeared to upregulate pro-apoptotic genes and downregulate anti-apoptotic genes, followed by cell apoptosis. The V-induced changes were alleviated by treatment with IP3R inhibitor. In summary, V could induce the dysfunction of ER-mitochondrial coupling and apoptosis, and inhibition of ER-mitochondrial coupling could attenuate V-induced apoptosis in duck renal tubular epithelial cells.
Collapse
Affiliation(s)
- Junjun Peng
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China
| | - Chengcheng Peng
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China; Department of Pharmacy, School of Medicine, Guangxi University of Science and Technology, 257 Liu-shi Road, Liuzhou, 545005, Guangxi, PR China
| | - Li Wang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China
| | - Chenghong Xing
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China
| | - Guyue Li
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China
| | - Fan Yang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China.
| |
Collapse
|