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Vieira B, Amaral J, Pereira MJ, Domingues I. Cyanobacterial Blooms in City Parks: A Case Study Using Zebrafish Embryos for Toxicity Characterization. Microorganisms 2024; 12:2003. [PMID: 39458312 PMCID: PMC11509529 DOI: 10.3390/microorganisms12102003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
Cyanobacteria are photosynthetic prokaryotes that play an important role in the ecology of aquatic ecosystems. However, they can also produce toxins with negative effects on aquatic organisms, wildlife, livestock, domestic animals, and humans. With the increasing global temperatures, urban parks, renowned for their multifaceted contributions to society, have been largely affected by blooms of toxic cyanobacteria. In this work, the toxicity of two different stages of development of a cyanobacterial bloom from a city park was assessed, evaluating mortality, hatching, development, locomotion (total distance, slow and rapid movements, and path angles) and biochemical parameters (oxidative stress, neurological damage, and tissue damage indicators) in zebrafish embryos/larvae (Danio rerio). Results showed significant effects for the samples with more time of evolution at the developmental level (early hatching for low concentrations (144.90 mg/L), delayed hatching for high concentrations (significant values above 325.90 mg/L), and delayed development at all concentrations), behavioral level (hypoactivity), and biochemical level (cholinesterase (ChE)) activity reduction and interference with the oxidative stress system for both stages of evolution). This work highlights the toxic potential of cyanobacterial blooms in urban environments. In a climate change context where a higher frequency of cyanobacterial proliferation is expected, this topic should be properly addressed by competent entities to avoid deleterious effects on the biodiversity of urban parks and poisoning events of wildlife, pets and people.
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Affiliation(s)
- Bruna Vieira
- Department of Biology, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
| | - João Amaral
- Department of Biology, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
| | - Mário Jorge Pereira
- Department of Biology & CESAM, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
| | - Inês Domingues
- Department of Biology & CESAM, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;
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2
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Zhang Y, Sun W, Wang B, Liu Z, Liu Z, Zhang X, Wang B, Han Y, Zhang H. Metabolomics reveals the lipid metabolism disorder in Pelophylax nigromaculatus exposed to environmentally relevant levels of microcystin-LR. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 358:124458. [PMID: 38942276 DOI: 10.1016/j.envpol.2024.124458] [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: 02/13/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
Cyanobacterial blooms have emerged as a significant environmental issue worldwide in recent decades. However, the toxic effects of microcystin-LR (MC-LR) on aquatic organisms, such as frogs, have remained poorly understood. In this study, frogs (Pelophylax nigromaculatus) were exposed to environmentally relevant concentrations of MC-LR (0, 1, and 10 μg/L) for 21 days. Subsequently, we assessed the impact of MC-LR on the histomorphology of the frogs' livers and conducted a global MS-based nontarget metabolomics analysis, followed by the determination of substances involved in lipid metabolism. Results showed that MC-LR significantly induced histological alterations in the frogs' hepatopancreas. Over 200 differentially expressed metabolites were identified, primarily enriched in lipid metabolism. Biochemical analysis further confirmed that MC-LR exposure led to a disorder in lipid metabolism in the frogs. This study laid the groundwork for a mechanistic understanding of MC-LR toxicity in frogs and potentially other aquatic organisms.
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Affiliation(s)
- Yinan Zhang
- Hangzhou Normal University, Hangzhou, 310018, China
| | - Wenhui Sun
- Hangzhou Normal University, Hangzhou, 310018, China
| | - Bingyi Wang
- Hangzhou Normal University, Hangzhou, 310018, China
| | - Zhiqun Liu
- Hangzhou Normal University, Hangzhou, 310018, China
| | - Zhiquan Liu
- Hangzhou Normal University, Hangzhou, 310018, China; Hangzhou International Urbanology Research Center, Hangzhou, 311121, China
| | | | - Binhao Wang
- Hangzhou Normal University, Hangzhou, 310018, China
| | - Yu Han
- Hangzhou Normal University, Hangzhou, 310018, China
| | - Hangjun Zhang
- Hangzhou Normal University, Hangzhou, 310018, China; Hangzhou International Urbanology Research Center, Hangzhou, 311121, China.
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3
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Tornabene BJ, Smalling KL, Hossack BR. Effects of Harmful Algal Blooms on Amphibians and Reptiles are Under-Reported and Under-Represented. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2024; 43:1936-1949. [PMID: 38967263 DOI: 10.1002/etc.5941] [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: 03/29/2024] [Revised: 05/07/2024] [Accepted: 06/03/2024] [Indexed: 07/06/2024]
Abstract
Harmful algal blooms (HABs) are a persistent and increasing problem globally, yet we still have limited knowledge about how they affect wildlife. Although semi-aquatic and aquatic amphibians and reptiles have experienced large declines and occupy environments where HABs are increasingly problematic, their vulnerability to HABs remains unclear. To inform monitoring, management, and future research, we conducted a literature review, synthesized the studies, and report on the mortality events describing effects of cyanotoxins from HABs on freshwater herpetofauna. Our review identified 37 unique studies and 71 endpoints (no-observed-effect and lowest-observed-effect concentrations) involving 11 amphibian and 3 reptile species worldwide. Responses varied widely among studies, species, and exposure concentrations used in experiments. Concentrations causing lethal and sublethal effects in laboratory experiments were generally 1 to 100 µg/L, which contains the mean value of reported HAB events but is 70 times less than the maximum cyanotoxin concentrations reported in the environment. However, one species of amphibian was tolerant to concentrations of 10,000 µg/L, demonstrating potentially immense differences in sensitivities. Most studies focused on microcystin-LR (MC-LR), which can increase systemic inflammation and harm the digestive system, reproductive organs, liver, kidneys, and development. The few studies on other cyanotoxins illustrated that effects resembled those of MC-LR at similar concentrations, but more research is needed to describe effects of other cyanotoxins and mixtures of cyanotoxins that commonly occur in the environment. All experimental studies were on larval and adult amphibians; there were no such studies on reptiles. Experimental work with reptiles and adult amphibians is needed to clarify thresholds of tolerance. Only nine mortality events were reported, mostly for reptiles. Given that amphibians likely decay faster than reptiles, which have tissues that resist decomposition, mass amphibian mortality events from HABs have likely been under-reported. We propose that future efforts should be focused on seven major areas, to enhance our understanding of effects and monitoring of HABs on herpetofauna that fill important roles in freshwater and terrestrial environments. Environ Toxicol Chem 2024;43:1936-1949. Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
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Affiliation(s)
- Brian J Tornabene
- Northern Rocky Mountain Science Center, US Geological Survey, Missoula, Montana
| | - Kelly L Smalling
- New Jersey Water Science Center, US Geological Survey, Lawrenceville, New Jersey
| | - Blake R Hossack
- Northern Rocky Mountain Science Center, US Geological Survey, Missoula, Montana
- Wildlife Biology Program, W. A. Franke College of Forestry and Conservation, University of Montana, Missoula, Montana, USA
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4
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Ge K, Du X, Liu H, Meng R, Wu C, Zhang Z, Liang X, Yang J, Zhang H. The cytotoxicity of microcystin-LR: ultrastructural and functional damage of cells. Arch Toxicol 2024; 98:663-687. [PMID: 38252150 DOI: 10.1007/s00204-023-03676-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024]
Abstract
Microcystin-LR (MC-LR) is a toxin produced by cyanobacteria, which is widely distributed in eutrophic water bodies and has multi-organ toxicity. Previous cytotoxicity studies have mostly elucidated the effects of MC-LR on intracellular-related factors, proteins, and DNA at the molecular level. However, there have been few studies on the adverse effects of MC-LR on cell ultrastructure and function. Therefore, research on the cytotoxicity of MC-LR in recent years was collected and summarized. It was found that MC-LR can induce a series of cytotoxic effects, including decreased cell viability, induced autophagy, apoptosis and necrosis, altered cell cycle, altered cell morphology, abnormal cell migration and invasion as well as leading to genetic damage. The above cytotoxic effects were related to the damage of various ultrastructure and functions such as cell membranes and mitochondria. Furthermore, MC-LR can disrupt cell ultrastructure and function by inducing oxidative stress and inhibiting protein phosphatase activity. In addition, the combined toxic effects of MC-LR and other environmental pollutants were investigated. This review explored the toxic targets of MC-LR at the subcellular level, which will provide new ideas for the prevention and treatment of multi-organ toxicity caused by MC-LR.
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Affiliation(s)
- Kangfeng Ge
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Haohao Liu
- Department of Public Health, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Ruiyang Meng
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Chunrui Wu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Zongxin Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiao Liang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Jun Yang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
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Wang Y, Guo Y, Liu H, Du X, Shi L, Wang W, Zhang S. Hawthorn fruit extract protect against MC-LR-induced hepatotoxicity by attenuating oxidative stress and apoptosis. ENVIRONMENTAL TOXICOLOGY 2023; 38:1239-1250. [PMID: 36880395 DOI: 10.1002/tox.23760] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/28/2023] [Accepted: 02/20/2023] [Indexed: 05/18/2023]
Abstract
Microcystins (MCs) is a class of cyclic heptapeptide compounds with biological activity. There is no effective treatment for liver injury caused by MCs. Hawthorn is a medicinal and edible plant traditional Chinese medicine with hypolipidemic, reducing inflammation and oxidative stress in the liver. This study discussed the protective effect of hawthorn fruit extract (HFE) on liver damage caused by MC-LR and the underlying molecular mechanism. After MC-LR exposure, pathological changes were observed and hepatic activity of ALT, AST and ALP were increased obviously, but they were remarkably restored with HFE administration. In addition, MC-LR could significantly reduce SOD activity and increase MDA content. Importantly, MC-LR treatment resulted in mitochondrial membrane potential decreased, and Cytochrome C release, eventually leading to cell apoptosis rate increase. HFE pretreatment could significantly alleviate the above abnormal phenomena. To examine the mechanism of protection, the expression of critical molecules in the mitochondrial apoptosis pathway was examined. The levels of Bcl-2 was inhibited, and the levels of Bax, Caspase-9, Cleaved Caspase-9, and Cleaved caspase-3 were upregulated after MC-LR treatment. HFE reduced MC-LR-induced apoptosis via reversing the expression of key proteins and genes in the mitochondrial apoptotic pathway. Hence, HFE could alleviate MC-LR induced hepatotoxicity by reducing oxidative stress and apoptosis.
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Affiliation(s)
- Yongshui Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Yao Guo
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Linjia Shi
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Wenjun Wang
- College of Nursing, Jining Medical University, Jining, Shandong, China
| | - Shenshen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
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6
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Wang W, Zhang H, Wei L, Ma Y, Jiang H, Yuen CNT, Zhang J, Wu H, Shu Y. Microcystin-leucine arginine causes brain injury and functional disorder in Lithobates catesbeianus tadpoles by oxidative stress and inflammation. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2023; 258:106509. [PMID: 36989925 DOI: 10.1016/j.aquatox.2023.106509] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 06/19/2023]
Abstract
Microcystin-leucine arginine (MC-LR) is a toxin commonly found in eutrophic waters worldwide, but its potential effects on amphibian brain toxicity and exposure mechanisms are unclear. In this study, Lithobates catesbeianus tadpoles were exposed to MC-LR for 30 days at realistic ambient concentrations (0, 0.5, and 2 µg/L) to reveal its effects on brain health. The MC-LR bioaccumulation in the brain increased in dependence on the concentration of MC-LR exposure. Exposure to 0.5 and 2 µg/L MC-LR resulted in a significant down-regulation of the expression of structural components of the blood-brain barrier (CLDN1), while the expression of genes associated with inflammation (NLRP3, TNF, IL-1β, and CXCL12) was significantly up-regulated with increased number of eosinophils. In the hippocampal and hypothalamic regions, the number of vacuolated neuropils increased with increasing MC-LR exposure concentration, while the expression of genes associated with neuronal development (LGALS1, CACNA2D2, and NLGN4X) and neurotransmitter transmission (SLC6A13 and AChE) was significantly down-regulated. Moreover, the levels of neurotransmitters (5-HT, glutamate, GABA, and ACh) were significantly reduced. These results provide strong evidence that MC-LR exposure at realistic ambient concentrations of 0.5 and 2 µg/L can break the blood-brain barrier and raise the accumulation of MC-LR in the brain tissue, causing structural damage and functional disorder to brain neurons. Further, based on transcriptomic and biochemical analysis, it was revealed that MC-LR exposure induces DNA damage through oxidative stress and may be an important pathway causing brain structural damage and functional disorder. Overall, this study demonstrates the significant effects of MC-LR on the brain tissue of amphibians, highlighting the sensitivity of amphibians to MC-LR.
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Affiliation(s)
- Wenchao Wang
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China
| | - Huijuan Zhang
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China
| | - Luting Wei
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China
| | - Yi Ma
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China
| | - Huiling Jiang
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China
| | - Calista N T Yuen
- State Key Laboratory in Marine Pollution Department of Chemistry, City University of Hong Kong, Hong Kong, China
| | - Jihui Zhang
- School of Food Science and Biology Engineering, Wuhu Institute of Technology, Wuhu, Anhui 241000, China
| | - Hailong Wu
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China.
| | - Yilin Shu
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China.
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7
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Si W, Zhao M, Che H, Wu Z, Xiao Y, Xie X, Duan J, Shen T, Xu D, Zhao S. Microcystin-LR induced transgenerational effects of thyroid disruption in zebrafish offspring by endoplasmic reticulum stress-mediated thyroglobulin accumulation and apoptosis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 322:121117. [PMID: 36690294 DOI: 10.1016/j.envpol.2023.121117] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/09/2023] [Accepted: 01/17/2023] [Indexed: 06/17/2023]
Abstract
MC-LR can interfere with thyroid function in fish, but the underlying mechanism is still unclear. Current study focuses to study the intergenerational inheritance of MC-LR-induced thyroid toxicity in zebrafish and in rat thyroid cells. In vivo experiments, adult female zebrafish (F0) were exposed to MC-LR (0, 5, and 25 μg/L) for 90 days and mated with male zebrafish without MC-LR exposure to generate F1 generation. F1 embryos were allowed to develop normally to 7 days post-fertilization (dpf) in clear water. In the F0 generation, MC-LR induced disturbance of the hypothalamic-pituitary-thyroid (HPT) axis, leading to a decrease in the production of thyroid hormones. Maternal MC-LR exposure also induced growth inhibition by altering thyroid hormones (THs) homeostasis and interfering with thyroid metabolism and development in F1 offspring. Mechanistically, MC-LR caused excessive accumulation of ROS and induced ER stress that further lead to activation of UPR in the F0 and F1 offspring of zebrafish. Interestingly, our findings suggested that MC-LR exposure hampered thyroglobulin turnover by triggering IRE1 and PERK pathway in zebrafish and FRTL-5 thyroid cells, thus disturbing the thyroid endocrine system and contributing to the thyroid toxicity from maternal to its F1 offspring of zebrafish. Particularly, inhibition of the IRE1 pathway by siRNA could alleviate thyroid development injury induced by MC-LR in FRTL-5 cells. In addition, MC-LR induced thyroid cell apoptosis by triggering ER stress. Taken together, our results demonstrated that maternal MC-LR exposure causes thyroid endocrine disruption by ER stress contributing to transgenerational effects in zebrafish offspring.
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Affiliation(s)
- Weirong Si
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Mengjie Zhao
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Huimin Che
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Zaiwei Wu
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Yuchun Xiao
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Xinxin Xie
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Jiayao Duan
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Tong Shen
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Dexiang Xu
- School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Sujuan Zhao
- School of Public Health, Anhui Medical University, Hefei, 230032, China.
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8
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Veerabadhran M, Manivel N, Sarvalingam B, Seenivasan B, Srinivasan H, Davoodbasha M, Yang F. State-of-the-art review on the ecotoxicology, health hazards, and economic loss of the impact of microcystins and their ultrastructural cellular changes. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2023; 256:106417. [PMID: 36805195 DOI: 10.1016/j.aquatox.2023.106417] [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: 09/03/2022] [Revised: 11/30/2022] [Accepted: 01/04/2023] [Indexed: 06/18/2023]
Abstract
Cyanobacteria are ubiquitously globally present in both freshwater and marine environments. Ample reports have been documented by researchers worldwide for pros and cons of cyanobacterial toxins. The implications of cyanobacterial toxin on health have received much attention in recent decades. Microcystins (MCs) represent the unique class of toxic metabolites produced by cyanobacteria. Although the beneficial aspects of cyanobacterial are numerous, the deleterious effect of MCs overlooked. Several studies on MCs evidently reported that MCs exhibit a plethora of harmful effect on animals, plants, and cell lines. Accordingly, numerous histopathological studies have also found that MCs cause detrimental effects to cells by damaging cellular organelles, including nuclear envelope, Golgi apparatus, endoplasmic reticulum, mitochondria, plastids, flagellum, pilus membrane structures and integrity, vesicle structures, and autolysosomes and autophagosomes. Such ultrastructural cellular damages holistically influence the morphological, biochemical, physiological, and genetic status of the host. Indeed, MCs have also been found to cause the deleterious effect to different animals and plants. Such deleterious effects of MCs have greater impact on agriculture, public health which in turn influences ecotoxicology and economic consequences. The impairments correspond to oxidative stress, organ failure, carcinogenesis, aquaculture loss, with an emphasis for blooms and respective bioaccumulation prospects. The preservation of mortality among life forms is addressed in a critical cellular perspective for multitude benefits. The comprehensive cellular assessment could provide opportunity to develop strategy for therapeutic implications.
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Affiliation(s)
- Maruthanayagam Veerabadhran
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang, China; Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Hunan 410078, China
| | - Nagarajan Manivel
- ICAR-Central Marine Fisheries Research Institute, Chennai 600 0028, India
| | - Barathkumar Sarvalingam
- National Centre for Coastal Research (NCCR), Ministry of Earth Science, NIOT Campus, Chennai 600100, India
| | - Boopathi Seenivasan
- Department of Biotechnology, College of Science and Humanities, SRM Institute of Science and Technology, Chennai, India
| | - Hemalatha Srinivasan
- School of Life Sciences, B.S. Abdur Rahman Crescent Institute of Science and Technology, Chennai 600 0048, India
| | - MubarakAli Davoodbasha
- School of Life Sciences, B.S. Abdur Rahman Crescent Institute of Science and Technology, Chennai 600 0048, India.
| | - Fei Yang
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, School of Public Health, University of South China, Hengyang, China.
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Wang X, Zhu Y, Lu W, Guo X, Chen L, Zhang N, Chen S, Ge C, Xu S. Microcystin-LR-induced nuclear translocation of cGAS promotes mutagenesis in human hepatocytes by impeding homologous recombination repair. Toxicol Lett 2022; 373:94-104. [PMID: 36435412 DOI: 10.1016/j.toxlet.2022.11.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/11/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022]
Abstract
Microcystin-LR (MC-LR) has been recognized as a typical hepatotoxic cyclic peptides produced by cyanobacteria. Nowadays, due to the frequent occurrence of cyanobacterial blooms, the underlying hepatotoxic mechanism of MC-LR has become the focus of attention. In our present work, the mutagenic effect of MC-LR on human normal hepatic (HL-7702) cells regulated by cGAS was mainly studied. Here, we showed that exposure to MC-LR for 1-4 days could activate the cGAS-STING signaling pathway and then trigger immune response in HL-7702 cells. Notably, relative to the treatment with 1 μM MC-LR for 1-3 days, it was observed that when HL-7702 cells were exposed to 1 μM MC-LR for 4 days, the mutation frequency at the Hprt locus was remarkably increased. In addition, cGAS in HL-7702 cells was also found to complete the nuclear translocation after 4-day exposure. Moreover, co-immunoprecipitation and homologous recombination (HR)-directed DSB repair assay were applied to show that homologous recombination repair was inhibited after 4-day exposure. However, the intervention of the nuclear translocation of cGAS by transfecting BLK overexpression plasmid restored homologous recombination repair and reduced the mutation frequency at the Hprt locus in HL-7702 cells exposed to MC-LR. Our study unveiled the distinct roles of cGAS in the cytoplasm and nucleus of human hepatocytes as well as potential mutagenic mechanism under the early and late stage of exposure to MC-LR, and provided a novel insight into the prevention and control measures about the hazards of cGAS-targeted MC-LR.
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Affiliation(s)
- Xiaofei Wang
- School of Biology, Food and Environment, Hefei University, Hefei 230601, PR China
| | - Yuchen Zhu
- School of Biology, Food and Environment, Hefei University, Hefei 230601, PR China
| | - Wenzun Lu
- School of Biology, Food and Environment, Hefei University, Hefei 230601, PR China
| | - Xiaoying Guo
- Institute of Agricultural Engineering, Anhui Academy of Agricultural Science, Hefei 230031, PR China
| | - Liuzeng Chen
- School of Biology, Food and Environment, Hefei University, Hefei 230601, PR China
| | - Ning Zhang
- School of Biology, Food and Environment, Hefei University, Hefei 230601, PR China
| | - Shaopeng Chen
- School of Public Health, Wannan Medical College, Wuhu 241002, PR China
| | - Chunmei Ge
- School of Biology, Food and Environment, Hefei University, Hefei 230601, PR China.
| | - Shengmin Xu
- Information Materials and Intelligent Sensing Laboratory of Anhui Province, Anhui University, Hefei 230601, PR China.
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10
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Li J, Sun H, Wang C, Li S, Cai Y. Subchronic Toxicity of Microcystin-LR on Young Frogs (Xenopus laevis) and Their Gut Microbiota. Front Microbiol 2022; 13:895383. [PMID: 35633706 PMCID: PMC9134123 DOI: 10.3389/fmicb.2022.895383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 04/12/2022] [Indexed: 11/13/2022] Open
Abstract
Although toxic effects of microcystins (MCs) in mammals and fish have been extensively studied, the effects of MCs on the immune system and gut microbiota of amphibians have not received sufficient attention. As MCs cause general damage to the vertebrate liver and immune system and trigger an inflammatory response, and the gut microbiota is closely related to host metabolism and immunity, we speculated that MCs can cause changes in the immune system and gut microbiota of amphibians. To verify this, we examined the intestinal and liver injury of Xenopus laevis exposed to different microcystin-leucine-arginine (MC-LR) concentrations and the effects on the gut microbiota through high-throughput sequencing of 16S rDNA of the gut microbiota combined with histopathological analysis, enzyme activity determination, and qRT-PCR. Our results showed that MC-LR caused focal infiltration of inflammatory cells and increased the number of T cells and local congestion and vacuolization in X. laevis liver, but reduced the number, density, height, and regularity of villi. These liver and intestinal injuries became more obvious with an increase in MC-LR concentration. MC-LR significantly decreased the activities of malondialdehyde and alkaline phosphatase and the expression of TGF-β in the liver. Moreover, MC-LR significantly altered the gut microbiota of X. laevis. The relative abundance of Firmicutes and Bacteroidetes in high-concentration MC-LR groups was significantly reduced compared to that in low-concentration MC-LR groups, whereas Fusobacteria was significantly enriched. The metabolic gene composition of the gut microbiota in low-concentration MC-LR (≤5 μg/L) groups was significantly different from that in high-concentration MC-LR (≥20 μg/L) groups. These results deepen our understanding of the toxicity of MCs to aquatic organisms and assessment of the ecological risk of MCs in amphibians.
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Affiliation(s)
- Jinjin Li
- School of Life Sciences, Qilu Normal University, Jinan, China
- *Correspondence: Jinjin Li,
| | - Hongzhao Sun
- School of Life Sciences, Qilu Normal University, Jinan, China
| | - Chun Wang
- School of Ecology and Environment, Beijing Technology and Business University, Beijing, China
| | - Shangchun Li
- School of Public Health, Southwest Medical University, Luzhou, China
| | - Yunfei Cai
- School of Life Sciences, Qilu Normal University, Jinan, China
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11
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Xu G, Luo Y, Xu D, Ma Y, Chen Y, Han X. Male reproductive toxicity induced by Microcystin-leucine-arginine (MC-LR). Toxicon 2022; 210:78-88. [DOI: 10.1016/j.toxicon.2022.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/20/2022] [Accepted: 02/08/2022] [Indexed: 11/30/2022]
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He J, Shu Y, Dai Y, Gao Y, Liu S, Wang W, Jiang H, Zhang H, Hong P, Wu H. Microcystin-leucine arginine exposure induced intestinal lipid accumulation and MC-LR efflux disorder in Lithobates catesbeianus tadpoles. Toxicology 2022; 465:153058. [PMID: 34863901 DOI: 10.1016/j.tox.2021.153058] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 11/05/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022]
Abstract
Few studies exist on the toxic effects of chronic exposure to microcystins (MCs) on amphibian intestines, and the toxicity mechanisms are unclear. Here, we evaluated the impact of subchronic exposure (30 days) to environmentally realistic microcystin-leucine arginine (MC-LR) concentrations (0 μg/L, 0.5 μg/L and 2 μg/L) on tadpole (Lithobates catesbeianus) intestines by analyzing the histopathological and subcellular microstructural damage, the antioxidative and oxidative enzyme activities, and the transcriptome levels. Histopathological results showed severe damage accompanied by inflammation to the intestinal tissues as the MC-LR exposure concentration increased from 0.5 μg/L to 2 μg/L. RNA-sequencing analysis identified 634 and 1,147 differentially expressed genes (DEGs) after exposure to 0.5 μg/L and 2 μg/L MC-LR, respectively, compared with those of the control group (0 μg/L). Biosynthesis of unsaturated fatty acids and the peroxisome proliferator-activated receptor (PPAR) signaling pathway were upregulated in the intestinal tissues of the exposed groups, with many lipid droplets being observed on transmission electron microscopy, implying that MC-LR may induce lipid accumulation in frog intestines. Moreover, 2 μg/L of MC-LR exposure inhibited the xenobiotic and toxicant biodegradation related to detoxification, implying that the tadpoles' intestinal detoxification ability was weakened after exposure to 2 μg/L MC-LR, which may aggravate intestinal toxicity. Lipid accumulation and toxin efflux disorder may be caused by MC-LR-induced endoplasmic reticular stress. This study presents new evidence that MC-LR harms amphibians by impairing intestinal lipid metabolism and toxin efflux, providing a theoretical basis for evaluating the health risks of MC-LR to amphibians.
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Affiliation(s)
- Jun He
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Yilin Shu
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Yue Dai
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Yuxin Gao
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Shuyi Liu
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Wenchao Wang
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Huiling Jiang
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Huijuan Zhang
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
| | - Pei Hong
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China; State Key Laboratory of Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
| | - Hailong Wu
- Collaborative Innovation Center of Recovery and Reconstruction of Degraded Ecosystem in Wanjiang Basin Co-founded by Anhui Province and Ministry of Education, School of Ecology and Environment, Anhui Normal University, Wuhu 241002, Anhui Province, China.
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13
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Tian Z, Liu H, Chen X, Losiewicz MD, Wang R, Du X, Wang B, Ma Y, Zhang S, Shi L, Guo X, Wang Y, Zhang B, Yuan S, Zeng X, Zhang H. The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 227:112919. [PMID: 34715501 DOI: 10.1016/j.ecoenv.2021.112919] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/14/2021] [Accepted: 10/17/2021] [Indexed: 06/13/2023]
Abstract
Microcystin-LR (MC-LR) is an intracellular toxin with multi-organ toxicity and the testis is one of its important target organs. Although there is increasing research on MC-LR in male reproductive toxicity, the association between DNA damage and autophagy induced by MC-LR in male germ cells are still unclear. Therefore, it is important to explore the mechanism of MC-LR-induced DNA damage and the role of the activated ATM/p53 signaling pathway in testicular toxicity. The present study showed that MC-LR exposure significantly reduced gonadal index and induced pathological damage of the testes in mice. In addition, MC-LR increased the oxidative stress-related indicator hydroxyl radical, accompanied by increased levels of DNA damage-related indicators gamma-H2AX, 8-hydroxy-2'-deoxyguanosine, the olive tail moment (OTM) and DNA content of comet tail (TailDNA%) in trailing cells. Moreover, MC-LR activated the ATM/p53 pathway by enhancing the phosphorylation levels of ATM, CHK2 and p53 proteins, and then led to cell autophagy, ultimately triggering disrupted testicular cell arrangement, reduced sperm count and spermatogenic cell shedding. Importantly, after pretreatment with the antioxidant NAC, the expression levels of DNA damage-related indicators and the extent of damage in male germ cells were significantly reduced. Furthermore, pretreatment with the ATM inhibitor KU55933 could reduce the occurrence of autophagy and mitigate testicular toxicity of MC-LR through inhibiting the activation of the ATM/p53 pathway. These results indicate that MC-LR-induced oxidative stress can activate the DNA damage-mediated ATM/p53 signalling pathway to induce autophagy in male germ cells. This study provides a novel insight to further clarify the reproductive toxicity caused by MC-LR and to protect male reproductive health.
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Affiliation(s)
- Zhihui Tian
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Xinghai Chen
- Department of Chemistry and Biochemistry, St Mary's University, San Antonio, TX, USA
| | - Michael D Losiewicz
- Department of Chemistry and Biochemistry, St Mary's University, San Antonio, TX, USA
| | - Rui Wang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Bingqian Wang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Ya Ma
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Shiyu Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Linjia Shi
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Xing Guo
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Yongshui Wang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Bingyu Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Shumeng Yuan
- College of Public Health, Zhengzhou University, Zhengzhou, PR China
| | - Xin Zeng
- College of Public Health, Zhengzhou University, Zhengzhou, PR China.
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, PR China.
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Mehinto AC, Smith J, Wenger E, Stanton B, Linville R, Brooks BW, Sutula MA, Howard MDA. Synthesis of ecotoxicological studies on cyanotoxins in freshwater habitats - Evaluating the basis for developing thresholds protective of aquatic life in the United States. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 795:148864. [PMID: 34328929 DOI: 10.1016/j.scitotenv.2021.148864] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 06/13/2023]
Abstract
In recent decades, cyanobacteria harmful algal blooms (cyanoHABs) have increased in magnitude, frequency, and duration in freshwater ecosystems. CyanoHABs can impact water quality by the production of potent toxins known as cyanotoxins. Environmental exposure to cyanotoxins has been associated with severe illnesses in humans, domestic animals, and wildlife. However, the effects of sustained exposure to cyanotoxins on aquatic life are poorly understood. In this study, over 150 peer-reviewed articles were critically evaluated to better understand the ecotoxicity of 5 cyanotoxin classes (microcystins, cylindrospermopsin, anatoxin-a, saxitoxins, nodularin) on fish, amphibians, aquatic invertebrates, and birds exclusively feeding in freshwater habitats. The systemic review demonstrated that microcystins, and more specifically microcystin-LR, were the most studied cyanotoxins. Ecotoxicological investigations were typically conducted using a fish or aquatic invertebrate model, with mortality, bioaccumulation, and biochemical responses as the most frequently measured endpoints. After excluding the studies that did not meet our acceptability criteria, remaining studies were examined to identify the no-observed and lowest observed effect concentrations (NOEC and LOEC) for microcystins; the limited amount of data for other cyanotoxins did not allow for analysis. The published ecotoxicity data suggests that the U.S. EPA recreational water quality criteria for microcystin (8 μg/L) may be protective of acute toxicity in aquatic organisms but does not appear to protect against chronic toxicity. Individual U.S. states have developed more stringent recreational health-based thresholds, such as 0.8 μg/L in California. Comparisons of this threshold to the chronic NOEC and LOEC data indicate that more restrictive microcystins thresholds may be required to be protective of aquatic life. Additional research is needed to evaluate the sublethal effects of a wider array of microcystin congeners and other cyanotoxins on organisms relevant to U.S. watersheds to better support nationwide thresholds protective of aquatic life.
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Affiliation(s)
- Alvine C Mehinto
- Southern California Coastal Water Research Project Authority, Costa Mesa, CA, United States of America.
| | - Jayme Smith
- Southern California Coastal Water Research Project Authority, Costa Mesa, CA, United States of America
| | - Ellie Wenger
- Southern California Coastal Water Research Project Authority, Costa Mesa, CA, United States of America
| | - Beckye Stanton
- California Environmental Protection Agency, Office of Environmental Health Hazard Assessment (OEHHA), Sacramento, CA, United States of America
| | - Regina Linville
- California Environmental Protection Agency, Office of Environmental Health Hazard Assessment (OEHHA), Sacramento, CA, United States of America
| | - Bryan W Brooks
- Baylor University, Department of Environmental Science, Waco, TX, United States of America
| | - Martha A Sutula
- Southern California Coastal Water Research Project Authority, Costa Mesa, CA, United States of America
| | - Meredith D A Howard
- Central Valley Regional Water Quality Control Board, Rancho Cordova, CA, United States of America
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Zhang Y, Wu D, Fan Z, Li J, Gao L, Wang Y, Wang L. Microcystin-LR induces ferroptosis in intestine of common carp (Cyprinus carpio). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 223:112610. [PMID: 34365207 DOI: 10.1016/j.ecoenv.2021.112610] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/27/2021] [Accepted: 08/03/2021] [Indexed: 06/13/2023]
Abstract
Previous studies provide comprehensive evidence of the environmental hazards and intestinal toxicity of microcystin-LR (MC-LR) exposure. However, little is known about the mechanisms underlying the injury of intestine exposed to MC-LR. Juvenile common carp (Cyprinus carpio) were exposed to MC-LR (0 and 10 μg/L) for 15 days. The results suggest that organic anion-transporting polypeptides 3a1, 4a1, 2b1, and 1d1 mediate MC-LR entry into intestinal tissues. Lesion morphological features (vacuolization, deformation and dilation of the endoplasmic reticulum [ER], absence of mitochondrial cristae in mid-intestine), up-regulated mRNA expressions of ER stress (eukaryotic translation initiation factor 2-alpha kinase 3, endoplasmic reticulum to nucleus signaling 1, activating transcription factor [ATF] 6, ATF4, DNA damage-inducible transcript 3), iron accumulation, and down-regulated activity of glutathione peroxidase (GPx) and glutathione (GSH) content were all typical characteristics of ferroptosis in intestinal tissue following MC-LR exposure. GSH levels in intestinal tissue corroborated as the most influential GSH/GPx 4- related metabolic pathway in response to MC-LR exposure. Verrucomicrobiota, Planctomycetes, Bdellovibrionota, Firmicutes and Cyanobacteria were correlated with the ferroptosis-related GSH following MC-LR exposure. These findings provide new perspectives of the ferroptosis mechanism of MC-LR-induced intestinal injury in the common carp.
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Affiliation(s)
- Yuanyuan Zhang
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
| | - Di Wu
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
| | - Ze Fan
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
| | - Jinnan Li
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
| | - Lei Gao
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
| | - Yu'e Wang
- Heilongjiang Provincial Key Laboratory of Laboratory Animal and Comparative Medicine, Laboratory Animal and Comparative Medicine, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China.
| | - Liansheng Wang
- Key Laboratory of Aquatic Animal Diseases and Immune Technology of Heilongjiang Province, Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 150070, China.
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16
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Zhou Y, Xue M, Jiang Y, Zhang M, Wang C, Wang X, Yu G, Tang Z. Beneficial Effects of Quercetin on Microcystin-LR Induced Tight Junction Defects. Front Pharmacol 2021; 12:733993. [PMID: 34566654 PMCID: PMC8462518 DOI: 10.3389/fphar.2021.733993] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/24/2021] [Indexed: 01/22/2023] Open
Abstract
Quercetin has numerous functions including antioxidant and anti-inflammatory effects. The beneficial effect of quercetin against microcystin-LR (MC-LR)-induced testicular tight junctions (TJs) defects in vitro and in vivo were investigated. Significant reductions in transepithelial electrical resistance, occludin, and zonula occludens-1(ZO-1) levels were detected in the MC-LR-treated TM4 cells, and quercetin attenuated these effects. Interestingly, quercetin suppressed MC-LR-induced phosphorylation of protein kinase B (AKT). It effectively inhibited the accumulation of reactive oxygen species (ROS) in cells stimulated by MC-LR. In addition, ROS inhibitors blocked the TJ damage that is dependent on the AKT signaling pathway induced by MC-LR. In conclusion, our results suggest that alleviates MC-LR-impaired TJs by suppressing the ROS-regulated activation of the AKT pathway.
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Affiliation(s)
- Yuan Zhou
- Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mei Xue
- College of Traditional Chinese Medicine·College of Intergrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yunfei Jiang
- Department of Emergency, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Miaomiao Zhang
- Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Changming Wang
- Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xuyang Wang
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, China
| | - Guang Yu
- Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zongxiang Tang
- Department of Physiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Refsnider JM, Garcia JA, Holliker B, Hulbert AC, Nunez A, Streby HM. Effects of harmful algal blooms on stress levels and immune functioning in wetland-associated songbirds and reptiles. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 788:147790. [PMID: 34034177 DOI: 10.1016/j.scitotenv.2021.147790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/11/2021] [Accepted: 05/11/2021] [Indexed: 06/12/2023]
Abstract
Harmful algal blooms (HABs), caused primarily by nutrient input from agricultural runoff, are a threat to freshwater systems worldwide, and are further predicted to increase in size, frequency, and intensity due to climate change. HABs occur annually in the Western Basin of Lake Erie (Ohio, USA), and these blooms become toxic when dominated by cyanobacteria that produce the liver toxin microcystin. Although we are making substantial inroads toward understanding how microcystin affects human health, less is known about effects of microcystin on wildlife exposed to HABs. Wetland-associated songbirds (barn swallows, Hirundo rustica, and red-winged blackbirds, Agelaius phoeniceus) and reptiles (Northern watersnakes, Nerodia sipedon, and painted turtles, Chrysemys picta) were sampled from wetlands exposed to chronically high microcystin levels due to a prolonged HAB event, and from unexposed, control wetlands. Physiological stress levels and several measures of immune functioning were compared between the HAB-exposed and control populations. Physiological stress levels, measured as heterophil:lymphocyte ratios, were higher in barn swallows, red-winged blackbirds, and Northern watersnakes exposed to a chronic HAB compared to unexposed, control individuals, but painted turtles did not differ in physiological stress levels between HAB-exposed and control individuals. Neither barn swallows nor red-winged blackbirds differed in immune functioning between populations, but HAB-exposed watersnakes had higher bactericidal capacity than control snakes, and HAB-exposed painted turtles had lower bactericidal capacity than control turtles. These results suggest that even when HABs do not cause direct mortality of exposed wildlife, they can potentially act as a physiological stressor across several taxa, and furthermore may compromise immune functioning in some species.
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Affiliation(s)
- Jeanine M Refsnider
- Department of Environmental Sciences, University of Toledo, Wolfe Hall Room 1235, 3050 West Towerview Blvd., Toledo, OH 43606-3390, USA.
| | - Jessica A Garcia
- Department of Environmental Sciences, University of Toledo, Wolfe Hall Room 1235, 3050 West Towerview Blvd., Toledo, OH 43606-3390, USA
| | - Brittany Holliker
- Department of Environmental Sciences, University of Toledo, Wolfe Hall Room 1235, 3050 West Towerview Blvd., Toledo, OH 43606-3390, USA
| | - Austin C Hulbert
- Department of Environmental Sciences, University of Toledo, Wolfe Hall Room 1235, 3050 West Towerview Blvd., Toledo, OH 43606-3390, USA
| | - Ashley Nunez
- Department of Environmental Sciences, University of Toledo, Wolfe Hall Room 1235, 3050 West Towerview Blvd., Toledo, OH 43606-3390, USA; Department of Biology, Ursinus College, 601 East Main St., Collegeville, PA 19426-1000, USA
| | - Henry M Streby
- Department of Environmental Sciences, University of Toledo, Wolfe Hall Room 1235, 3050 West Towerview Blvd., Toledo, OH 43606-3390, USA
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18
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Zhu BB, Zhang ZC, Li J, Gao XX, Chen YH, Wang H, Gao L, Xu DX. Di-(2-ethylhexyl) phthalate induces testicular endoplasmic reticulum stress and germ cell apoptosis in adolescent mice. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:21696-21705. [PMID: 33411269 DOI: 10.1007/s11356-020-12210-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 12/22/2020] [Indexed: 06/12/2023]
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. This research is aimed at investigating the effect of pubertal DEHP exposure on testicular endoplasmic reticulum (ER) stress and germ cell apoptosis. Five-week-old male mice were orally administered with DEHP (0, 0.5, 50, or 500 mg/kg/day) for 35 days. Testis weight and sperm count were reduced in mice exposed to 500 mg/kg/day DEHP. The number of seminiferous tubules in stages VII-VIII, mature seminiferous tubules, was reduced and the number of seminiferous tubules in stages IX-XII, immature seminiferous tubules, was elevated in mice treated with 500 mg/kg/day DEHP. Numerous apoptotic germ cells were observed in mouse seminiferous tubules exposed to 50 and 500 mg/kg/day DEHP. Moreover, cleaved caspase-3 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. In addition, Bcl-2 was reduced and Bax/Bcl-2 was elevated in mouse testes exposed to 500 mg/kg/day DEHP. Additional experiment showed that GRP78, an ER molecular chaperone, was downregulated in mouse testes exposed to 500 mg/kg/day DEHP. Testicular p-IRE-1α, p-JNK, and CHOP, three markers of ER stress, were upregulated in mice exposed to 500 mg/kg/day DEHP. These results suggest that pubertal exposure to high doses of DEHP induces germ cell apoptosis partially through initiating ER stress in testes.
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Affiliation(s)
- Bin-Bin Zhu
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Zhi-Cheng Zhang
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Jian Li
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Xing-Xing Gao
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Yuan-Hua Chen
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Hua Wang
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China
| | - Lan Gao
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China.
| | - De-Xiang Xu
- Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
- Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, China.
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19
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Liu H, Tian Z, Guo Y, Liu X, Ma Y, Du X, Wang R, Zhang S, Shi L, Guo H, Zhang H. Microcystin-leucine arginine exposure contributes to apoptosis and follicular atresia in mice ovaries by endoplasmic reticulum stress-upregulated Ddit3. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 756:144070. [PMID: 33288253 DOI: 10.1016/j.scitotenv.2020.144070] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 11/22/2020] [Accepted: 11/22/2020] [Indexed: 06/12/2023]
Abstract
Microcystin-leucine arginine (MC-LR), an intracellular toxin to cause reproduction toxicity, is produced by blooming cyanobacteria and widely distributed in eutrophic waters. It is revealed that MC-LR-induced female reproductive toxicity is more severe than male reproductive toxicity. Previous studies mainly focused on male reproductive toxicity, and the molecular mechanisms of MC-LR-induced apoptosis, follicular atresia and infertility in female remain largely unclear. Here, it was found that MC-LR treatment could induce apoptosis, inflammation, follicular atresia, and decrease of gonadal index in mice ovaries. RNA-Seq data showed that the up-regulation of DNA-damage inducible transcript 3 (Ddit3) under endoplasmic reticulum (ER) stress had predominantly regulatory role in MC-LR-induced apoptotic pathway. Furthermore, MC-LR exposure promoted cleavage of activating transcription factor 6 (ATF6, 50kd), inositol-requiring enzyme 1 (Ire1) expression, phosphorylation of IRE1, mitogen-activated protein kinase 5 (Map3k5) and Ddit3 expression, which was accompanied by the upregulation of death receptor 5 (Dr5) and active-caspase-3, and a decrease in Bcl-2 expression. ER stress inhibitor 4-Phenyl butyric acid (4-PBA) ameliorated these MC-LR-induced changes in protein or mRNA level. More importantly, knockdown of Ddit3 suppressed MC-LR-induced cell apoptosis and follicular atresia by directly regulating Dr5 and Bcl-2. Additionally, it was also found that MC-LR increased Map3k5 phosphorylation by inhibiting protein phosphatase 2A (PP2A) activity, and then promoted Ddit3 expression. In short, our data suggests that Ddit3 promotes MC-LR-induced mice ovarian cells apoptosis and follicular atresia via ER stress activation, which provides a new insight into the relation between infertility in females and the emerging water pollutant MC-LR.
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Affiliation(s)
- Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Zhihui Tian
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Yaxin Guo
- School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Xiaohui Liu
- School of Basic Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan, China
| | - Ya Ma
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Rui Wang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Shiyu Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Linjia Shi
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
| | - Hongxiang Guo
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, Henan, China.
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China.
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Gavrilović BR, Petrović TG, Radovanović TB, Despotović SG, Gavrić JP, Krizmanić II, Ćirić MD, Prokić MD. Hepatic oxidative stress and neurotoxicity in Pelophylax kl. esculentus frogs: Influence of long-term exposure to a cyanobacterial bloom. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 750:141569. [PMID: 32853936 DOI: 10.1016/j.scitotenv.2020.141569] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/20/2020] [Accepted: 08/06/2020] [Indexed: 06/11/2023]
Abstract
Although the long-term exposure of aquatic organisms to cyanobacterial blooms is a regular occurrence in the environment, the prooxidant and neurotoxic effects of such conditions are still insufficiently investigated in situ. We examined the temporal dynamics of the biochemical parameters in the liver of Pelophylax kl. esculentus frogs that inhabit the northern (N) side of Lake Ludaš (Serbia) with microcystins (MCs) produced in a cyanobacterial bloom over three summer months. The obtained data were compared with data on frogs that live on the southern (S), MC-free side of the same lake. Our results showed that the MC-producing bloom induced oxidative damage to proteins and lipids, observed as a decrease in the concentration of protein -SH groups and increased lipid peroxidation (LPO) in the liver of N frogs in comparison to S frogs. Glutathione (GSH) played a key role in the transient defense against the MC-induced development of LPO. The low glutathione peroxidase (GPx) activity detected in all groups of frogs from the N site was crucial for the observed prooxidant consequences. The bloom impaired cholinergic homeostasis as a result of a decrease in ChE activity. A delayed neurotoxic effect in relation to the prooxidant outcomes was observed. Our results also showed that even though the integrated biomarker response (IBR) of the antioxidant biomarkers increased during exposure, the individual biochemical parameters did not exhibit a well-defined time-dependent pattern because of specific adaptation dynamics and/or additional effects of the physicochemical parameters of the water. This comprehensive environmental ecotoxicological evaluation of the cyanobacterial bloom-induced biochemical alterations in the liver of frogs provides a new basis for further investigations of the prolonged, real-life ecotoxicity of the blooms.
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Affiliation(s)
- Branka R Gavrilović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia.
| | - Tamara G Petrović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Tijana B Radovanović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Svetlana G Despotović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Jelena P Gavrić
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Imre I Krizmanić
- Institute of Zoology, Faculty of Biology, University of Belgrade, Studentski trg 16, 11000 Belgrade, Serbia
| | - Miloš D Ćirić
- Scientific Institution Institute of Chemistry, Technology and Metallurgy - National Institute, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia
| | - Marko D Prokić
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
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21
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Preparation and properties of hollow fibre nanofiltration membrane with continuous coffee-ring structure. Front Chem Sci Eng 2020. [DOI: 10.1007/s11705-020-1943-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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22
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Su RC, Meyers CM, Warner EA, Garcia JA, Refsnider JM, Lad A, Breidenbach JD, Modyanov N, Malhotra D, Haller ST, Kennedy DJ. Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles. Toxins (Basel) 2020; 12:toxins12060378. [PMID: 32521650 PMCID: PMC7354472 DOI: 10.3390/toxins12060378] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/23/2020] [Accepted: 06/03/2020] [Indexed: 11/16/2022] Open
Abstract
Harmful algal blooms (HAB) have become a major health concern worldwide, not just to humans that consume and recreate on contaminated waters, but also to the fauna that inhabit the environments surrounding affected areas. HABs contain heterotrophic bacteria, cyanobacterial lipopolysaccharide, and cyanobacterial toxins such as microcystins, that can cause severe toxicity in many aquatic species as well as bioaccumulation within various organs. Thus, the possibility of trophic transference of this toxin through the food chain has potentially important health implications for other organisms in the related food web. While some species have developed adaptions to attenuate the toxic effects of HAB toxins, there are still numerous species that remain vulnerable, including Lithobates catesbeiana (American bullfrog) tadpoles. In the current study we demonstrate that acute, short-term exposure of tadpoles to HAB toxins containing 1 µg/L (1 nmol/L) of total microcystins for only 7 days results in significant liver and intestinal toxicity within tadpoles. Exposed tadpoles had increased intestinal diameter, decreased intestinal fold heights, and a constant number of intestinal folds, indicating pathological intestinal distension, similar to what is seen in various disease processes, such as toxic megacolon. HAB-toxin-exposed tadpoles also demonstrated hepatocyte hypertrophy with increased hepatocyte binucleation consistent with carcinogenic and oxidative processes within the liver. Both livers and intestines of HAB-toxin-exposed tadpoles demonstrated significant increases in protein carbonylation consistent with oxidative stress and damage. These findings demonstrate that short-term exposure to HAB toxins, including microcystins, can have significant adverse effects in amphibian populations. This acute, short-term toxicity highlights the need to evaluate the influence HAB toxins may have on other vulnerable species within the food web and how those may ultimately also impact human health.
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Affiliation(s)
- Robin C. Su
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Casey M. Meyers
- Department of Biology, Wittenberg University, Springfield, OH 45504, USA;
| | - Emily A. Warner
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Jessica A. Garcia
- Department of Environmental Sciences, The University of Toledo, Toledo, OH 43606, USA; (J.A.G.); (J.M.R.)
| | - Jeanine M. Refsnider
- Department of Environmental Sciences, The University of Toledo, Toledo, OH 43606, USA; (J.A.G.); (J.M.R.)
| | - Apurva Lad
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Joshua D. Breidenbach
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Nikolai Modyanov
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA;
| | - Deepak Malhotra
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
| | - Steven T. Haller
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
- Correspondence: (S.T.H.); (D.J.K.); Tel.: +1-419-383-6822 (D.J.K. & S.T.H.)
| | - David J. Kennedy
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, 3000 Arlington Avenue, Toledo, OH 43614, USA; (R.C.S.); (E.A.W.); (A.L.); (J.D.B.); (D.M.)
- Department of Medical Microbiology and Immunology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
- Correspondence: (S.T.H.); (D.J.K.); Tel.: +1-419-383-6822 (D.J.K. & S.T.H.)
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Gavrilović BR, Prokić MD, Petrović TG, Despotović SG, Radovanović TB, Krizmanić II, Ćirić MD, Gavrić JP. Biochemical parameters in skin and muscle of Pelophylax kl. esculentus frogs: Influence of a cyanobacterial bloom in situ. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2020; 220:105399. [PMID: 31896464 DOI: 10.1016/j.aquatox.2019.105399] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/26/2019] [Accepted: 12/26/2019] [Indexed: 06/10/2023]
Abstract
There is little information in scientific literature as to how conditions created by a microcystin (MC) producing cyanobacterial bloom affect the oxidant/antioxidant, biotransformation and neurotoxicity parameters in adult frogs in situ. We investigated biochemical parameters in the skin and muscle of Pelophylax kl. esculentus from Lake Ludaš (Serbia) by comparing frogs that live on the northern bloom side (BS) of the lake with those that inhabit the southern no-bloom side (NBS). A higher protein carbonylation level and lower antioxidant defense system capability in the skin of frogs living in conditions of the cyanobacterial bloom were observed. Inhibition of glutathione-dependent machinery was the major mechanism responsible for the induction of cyanobacterial bloom-mediated oxidative stress in frog skin. On the other hand, the detected higher ability of muscle to overcome bloom prooxidant toxicity was linked to a higher efficiency of the biotransformation system through glutathione-S-transferase activity and/or was the consequence of indirect exposure of the tissue to the bloom. Our results have also revealed that the cyanobacterial bloom conditions induced the cholinergic neurotransmitter system in both tissues. This study provides a better understanding of the ecotoxicological impact of the MC producing cyanobacterial bloom on frogs in situ. However, further investigations of the complex mechanism involved in cyanobacterial bloom toxicity in real environmental conditions are required.
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Affiliation(s)
- Branka R Gavrilović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia.
| | - Marko D Prokić
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Tamara G Petrović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Svetlana G Despotović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Tijana B Radovanović
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
| | - Imre I Krizmanić
- Institute of Zoology, Faculty of Biology, University of Belgrade, Studentski trg 16, 11000 Belgrade, Serbia
| | - Miloš D Ćirić
- Scientific Institution Institute of Chemistry, Technology and Metallurgy - National Institute, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia
| | - Jelena P Gavrić
- Department of Physiology, Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
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Zhang B, Wei P, Men J, Zhang S, Shao H, Zhang Z. Crotonaldehyde-induced alterations in testicular enzyme function and hormone levels, and apoptosis in the testes of male Wistar rats are associated with oxidative damage. Toxicol Mech Methods 2019; 30:19-32. [DOI: 10.1080/15376516.2019.1646369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Biao Zhang
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Ping Wei
- Department of Gynecologic Oncology, Shandong Tumor Hospital and Institute, Jinan, Shandong, PR China
| | - Jinlong Men
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Shuman Zhang
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Hua Shao
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Zhihu Zhang
- Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
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25
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Scaia MF, Volonteri MC, Czuchlej SC, Ceballos NR. Estradiol and reproduction in the South American toad Rhinella arenarum (Amphibian, Anura). Gen Comp Endocrinol 2019; 273:20-31. [PMID: 29555118 DOI: 10.1016/j.ygcen.2018.03.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/24/2018] [Accepted: 03/14/2018] [Indexed: 12/28/2022]
Abstract
Rhinella arenarum is a South American toad with wide geographic distribution. Testes of this toad produce high amount of androgens during the non reproductive season and shift steroid synthesis from androgens to 5α-pregnanedione during the breeding. In addition, plasma estradiol (E2) in males of this species shows seasonal variations but, since testes of R. arenarum do not express aromatase, the source of plasma E2 remained unknown for several years. However, the Bidder's organ (BO), a structure located at one pole of each testis, is proposed to be the main source of E2 in male's toads since it expresses several steroidogenic enzymes and is able to produce E2 from endogenous substrates throughout the year. In addition, there were significant correlations between plasma E2 and total activity of BO aromatase, and between plasma E2 and the amount of hormone produced by the BO in vitro. In the toad, apoptosis induced by in vitro treatment with E2 was mostly detected in spermatocytes during the breeding and in spermatids during the post-reproductive season, suggesting that this steroid has an important role in controlling spermatogenesis. However, in vitro treatment with E2 had no effect on proliferation. This evidence suggests that the mechanism of action of E2 on amphibian spermatogenesis is complex and more studies are necessary to fully understand the role of estrogens regulating the balance between cellular proliferation and apoptosis. In addition, in R. arenarum in vitro studies suggested that E2 has no effect on CypP450c17 protein levels or enzymatic activity, while it reduces 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD/I) activity during the post reproductive season. As well, E2 regulates FSHβ mRNA expression all over the year suggesting a down regulation process carried out by this steroid. The effect on LHβ mRNA is dual, since during the reproductive season estradiol increases the expression of LHβ mRNA while in the non-reproductive season it has no effect. In conclusion, the effect of E2 on gonadotropins and testicular function is complex, not clearly understood and probably varies depending on the species. The aim of the current article is to review evidence on reproductive endocrinology and on the role of estradiol regulating reproduction in amphibians, with emphasis on the South American species Rhinella arenarum.
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Affiliation(s)
- María Florencia Scaia
- Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Biodiversidad y Biología Experimental, Buenos Aires, Argentina; Instituto de Biodiversidad y Biología Experimental y Aplicada (IBBEA - CONICET), Buenos Aires, Argentina.
| | - María Clara Volonteri
- Instituto de Diversidad y Evolución Austral (IDEAus - CONICET), Puerto Madryn, Chubut, Argentina
| | - Silvia Cristina Czuchlej
- Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Biodiversidad y Biología Experimental, Buenos Aires, Argentina.
| | - Nora Raquel Ceballos
- Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Biodiversidad y Biología Experimental, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
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26
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He C, Jiang S, Yao H, Zhang L, Yang C, Zhan D, Lin G, Zeng Y, Xia Y, Lin Z, Liu G, Lin Y. Endoplasmic reticulum stress mediates inflammatory response triggered by ultra-small superparamagnetic iron oxide nanoparticles in hepatocytes. Nanotoxicology 2018; 12:1198-1214. [PMID: 30422028 DOI: 10.1080/17435390.2018.1530388] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ultra-small superparamagnetic iron oxide nanoparticles (USPIO-NPs) are widely used as clinical magnetic resonance imaging contrast agents for hepatic diseases diagnosis. USPIO-NPs often damage the hepatocytes and affect the function of liver but its mechanism of action remains unclear. In the present study, USPIO-NPs caused higher cytotoxicity and lactate dehydrogenase (LDH) leakage in hepatic L02 cells than SPIO-NPs. Subsequently, USPIO-NPs affected more genes' expression than SPIO-NPs analyzed through microarray and bioinformatics analysis. The affected genes were involved in several biological processes, including calcium ion homeostasis, inflammatory response-related leukocyte chemotaxis, and migration. In addition, the level of endoplasmic reticulum (ER) calcium ion was increased by USPIO-NPs. USPIO-NPs also upregulated the genes related to acute-phase inflammation, including IL1B, IL6, IL18, TNFSF12, TNFRSF12, SAA1, SAA2, JAK1, STAT5B, and CXCL14. Furthermore, interleukin-6 (IL-6) secretion was elevated by USPIO-NPs as detected using ELISA. On the other hand, USPIO-NPs changed the morphology of ER and triggered the ER stress and unfolded protein response PERK/ATF4 pathway. Furthermore, blocking ER stress with inhibitor or ATF4 small interfering RNA counteracted IL-6-related acute-phase inflammation and cytotoxicity caused by USPIO-NPs. Taken together, we found that the USPIO-NPs could trigger stronger IL-6-related acute-phase inflammation than SPIO-NPs in hepatocytes. We demonstrated, for the first time, that IL-6-related acute-phase inflammation caused by NPs was regulated by PERK/ATF4 signaling. The PERK/ATF4 pathway explored in this study could be a candidate for diagnostic and therapeutic target against NPs-induced liver injury and cytotoxicity, which would be helpful for USPIO-NPs medical application.
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Affiliation(s)
- Chengyong He
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Shengwei Jiang
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Huan Yao
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Liyin Zhang
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Chuanli Yang
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Denglin Zhan
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Gan Lin
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Yun Zeng
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Yankai Xia
- b State Key Laboratory of Cellular Stress Biology, School of Life Sciences , Xiamen University , Xiamen , China
| | - Zhongning Lin
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
| | - Gang Liu
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China.,c State Key Laboratory of Reproductive Medicine, Institute of Applied Toxicology, School of Public Health , Nanjing Medical University , Nanjing , China
| | - Yuchun Lin
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen , China
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27
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Wu JX, Huang H, Yang L, Zhang XF, Zhang SS, Liu HH, Wang YQ, Yuan L, Cheng XM, Zhuang DG, Zhang HZ. Gastrointestinal toxicity induced by microcystins. World J Clin Cases 2018; 6:344-354. [PMID: 30283797 PMCID: PMC6163130 DOI: 10.12998/wjcc.v6.i10.344] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 06/08/2018] [Accepted: 06/28/2018] [Indexed: 02/05/2023] Open
Abstract
Microcystins (MCs) are produced by certain bloom-forming cyanobacteria that can induce toxicity in various organs, including renal toxicity, reproductive toxicity, cardiotoxicity, and immunosuppressive effects. It has been a significant global environmental issue due to its harm to the aquatic environment and human health. Numerous investigators have demonstrated that MC exposure can induce a widespread epidemic of enterogastritis with symptoms similar to food poisoning in areas close to lakes. Both in vivo and in vitro studies have provided evidence of positive associations between MC exposure and gastrointestinal toxicity. The toxicity of MCs on the gastrointestinal tract is multidimensional. MCs can affect gastrointestinal barrier function and shift the structure of gut microbiota in different gut regions. Furthermore, MCs can inhibit the secretion of gastrointestinal digestive enzymes and the release of inflammatory cytokines, which affects the expression of immune-related genes in the intestine. The damage of the intestine is closely correlated to MC exposure because the intestine is the main site for the digestion and absorption of nutrients. The damage to the gastrointestinal tract due to MCs was summarized from different aspects, which can be used as a foundation for further exploration of molecular damage mechanisms.
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Affiliation(s)
- Jin-Xia Wu
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Hui Huang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Lei Yang
- Department of Nutriology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Xiao-Feng Zhang
- Department of Nutriology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Shen-Shen Zhang
- Department of Nutriology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Hao-Hao Liu
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Yue-Qin Wang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Le Yuan
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Xue-Min Cheng
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Dong-Gang Zhuang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Hui-Zhen Zhang
- Department of Environmental Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Liu H, Zhang X, Zhang S, Huang H, Wu J, Wang Y, Yuan L, Liu C, Zeng X, Cheng X, Zhuang D, Zhang H. Oxidative Stress Mediates Microcystin-LR-Induced Endoplasmic Reticulum Stress and Autophagy in KK-1 Cells and C57BL/6 Mice Ovaries. Front Physiol 2018; 9:1058. [PMID: 30131715 PMCID: PMC6090159 DOI: 10.3389/fphys.2018.01058] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/16/2018] [Indexed: 01/28/2023] Open
Abstract
Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide intracellular toxin released by cyanobacteria that exhibits strong reproductive toxicity. However, little is known about its biotoxicity to the female reproductive system. The present study investigates unexplored molecular pathways by which oxidative stress acts on MC-LR-induced endoplasmic reticulum stress (ERs) and autophagy. In the present study, immortalized murine ovarian granular cells (KK-1 cells) were exposed to 8.5, 17, and 34 μg/mL (IC50) of MC-LR with or without N-acetyl-l-cysteine (NAC, 10 mM) for 24 h, and C57BL/6 mice were treated with 12.5, 25.0, and 40.0 μg/kg⋅bw of MC-LR with or without NAC (200 mg/kg⋅bw) for 14 days. The results revealed that MC-LR could induce cells apoptosis and morphologic changes in ovarian tissues, induce oxidative stress by stimulating the generation of reactive oxygen species (ROS), destroying antioxidant capacity, and subsequently trigger ERs and autophagy by inducing the hyper-expression of ATG12, ATG5, ATG16, EIF2α (phosphorylated at S51), CHOP, XBP1, GRP78, Beclin1, and PERK (Thr980). Furthermore, NAC pretreatment partly inhibited MC-LR-induced ERs and autophagy via the PERK/ATG12 and XBP1/Beclin1 pathways. These results suggest that oxidative stress mediated MC-LR-induced ERs and autophagy in KK-1 cells and C57BL/6 mice ovaries. Therefore, oxidative stress plays an important role in female toxicity induced by MC-LR.
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Affiliation(s)
- Haohao Liu
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xiaofeng Zhang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Shenshen Zhang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Hui Huang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Jinxia Wu
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Yueqin Wang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Le Yuan
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Chuanrui Liu
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xin Zeng
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xuemin Cheng
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Donggang Zhuang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Huizhen Zhang
- Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, China
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Zhao S, Liu Y, Wang F, Xu D, Xie P. N-acetylcysteine protects against microcystin-LR-induced endoplasmic reticulum stress and germ cell apoptosis in zebrafish testes. CHEMOSPHERE 2018; 204:463-473. [PMID: 29679867 DOI: 10.1016/j.chemosphere.2018.04.020] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 04/03/2018] [Accepted: 04/04/2018] [Indexed: 06/08/2023]
Abstract
Previous studies have shown that microcystin-LR (MCLR) is a reproductive toxicant that induces germ cell apoptosis in the testes, but the underlying mechanisms have not been well understood. In this study, we investigated that MCLR induces germ cell apoptosis is through activation of endoplasmic reticulum (ER) stress and N-acetylcysteine (NAC), an antioxidant could protect against germ cell apoptosis by inhibiting the ER stress. Healthy male zebrafish were intraperitoneally injected with NAC (500 nM), beginning at 2 h before different doses of MCLR (0, 50, 100, 200 μg/kg). As expected, acute MCLR exposure resulted in oxidative stress and germ cell apoptosis in zebrafish testes. Further analysis showed that NAC significantly alleviated MCLR-induced testicular germ cell apoptosis and inhibited the caspase-dependent apoptotic proteins. Meanwhile H&E staining showed that NAC could rescue testicular damage induced by MCLR. Moreover, MCLR induced activation of ER stress which consequently triggered apoptosis in zebrafish testes. Interestingly, NAC was effective in improving the total antioxidant capacity (T-AOC) level and activity of antioxidant enzymes in NAC pretreated groups. NAC significantly attenuated MCLR-induced upregulation of GRP78 in testes. In addition, NAC significantly attenuated MCLR-triggered testicular eIF2s1 and MAPK8 activation, indicating that NAC counteracts MCLR-induced unfolded protein response (UPR) in testes. Taken together, the results observed in this study suggested that ER stress plays a critical role in germ cell apoptosis exposed to MCLR and NAC could protect against apoptosis via inhibiting ER stress in zebrafish testes.
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Affiliation(s)
- Sujuan Zhao
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Ying Liu
- Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Fang Wang
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Dexiang Xu
- School of Public Health, Anhui Medical University, Hefei 230032, China.
| | - Ping Xie
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
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Zhao S, Sun H, Yan W, Xu D, Shen T. A proteomic study of the pulmonary injury induced by microcystin-LR in mice. Toxicon 2018; 150:304-314. [PMID: 29908261 DOI: 10.1016/j.toxicon.2018.06.072] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 06/09/2018] [Accepted: 06/12/2018] [Indexed: 12/28/2022]
Abstract
MCLR has been shown to act as potent hepatotoxin, and recent studies showed that MCs can accumulate in lung tissue and exert adverse effects. However, the exact mechanism still remain unclear. The present study mainly focuses on the impairments of respiratory system after MCLR exposure in mice. After intratracheal instillation with MCLR (0, 10 and 25 μg/kg bw), histological change was examined in MCLR exposure groups. Results indicated that exposure of MCLR led to serious histopathology alteration and apoptosis in lung of mice. To further our understanding of the toxic effects of MCLR on the lung, we employed a proteomic method to search the mechanisms behind MCLR-induced pulmonary injury. In total, 38 proteins were identified to be significantly altered after MCLR exposure. These proteins involved in inflammatory response, apoptosis, cytoskeleton, and energetic metabolism, suggesting MCLR exerts complex toxic effects contributing to pulmonary injury. Furthermore, MCLR also induced pulmonary inflammation, as manifested by up-regulating the protein levels of interleukin-1β (IL-1β) and p65 subunit. Our results indicated that MCLR exerts lung injury mainly by generating inflammation and apoptosis.
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Affiliation(s)
- Sujuan Zhao
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Hong Sun
- Maternal and Child Health Hospital of Hubei Province, Wuhan 430070, China.
| | - Wei Yan
- China Institute of Agricultural Quality Standards & Testing Technology, Hubei Academy of Agricultural Sciences, Wuhan 430064, China.
| | - Dexiang Xu
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Tong Shen
- School of Public Health, Anhui Medical University, Hefei 230032, China
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Jia X, Liu Z, Lu X, Tang J, Wu Y, Du Q, He J, Zhang X, Jiang J, Liu W, Zheng Y, Ding Y, Zhu W, Zhang H. Effects of MCLR exposure on sex hormone synthesis and reproduction-related genes expression of testis in male Rana nigromaculata. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 236:12-20. [PMID: 29414332 DOI: 10.1016/j.envpol.2018.01.057] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/12/2018] [Accepted: 01/17/2018] [Indexed: 06/08/2023]
Abstract
Microcystin-leucine-arginine (MCLR) is the most popular and toxic variant among microcystins, which can cause severe reproductive toxicity to animals. However, the mechanisms of reproductive toxicity induced by MCLR in amphibians are still not entirely clear. In the current study, toxicity mechanisms of MCLR on the reproductive system of male Rana nigromaculata followed by low concentration (0, 0.1, 1, and 10 μg/L) and short-term (0, 7, and 14 days) MCLR exposure were shown. It was observed that MCLR could be bioaccumulated in the testes of male frogs, and the theoretical bioaccumulation factor values were 0.24 and 0.19 exposed to 1 μg/L and 10 μg/L MCLR for 14 days, respectively. MCLR exposure significantly decreased testosterone (T) concentrations and increased estradiol (E2) concentrations exposed to 1 and 10 μg/L MCLR for 14 days. The mRNA levels of HSD17B3 were downregulated, and HSD17B1 and CYP19A1 mRNA expression levels were upregulated, respectively. Only 10 μg/L MCLR group showed significant induction of follicle-stimulating hormone (FSH) levels and cyclic adenosine monophosphate (cAMP) content. Moreover, AR and ESR1 mRNA expression levels were significantly upregulated exposed to 1 and 10 μg/L MCLR for 14 days, respectively. Our results suggested that low-concentration MCLR induced transcription changes of CYP19A1, HSD17B3, and HSD17B1 led to endocrine disorders, and caused interference of spermatogenesis by the decrease of T and abnormal gene expressions of AR and ESR1 in the testes of R. nigromaculata.
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Affiliation(s)
- Xiuying Jia
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Zhengquan Liu
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Xiangjun Lu
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Juan Tang
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Yingzhu Wu
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Qiongxia Du
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Jianbo He
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Xinyun Zhang
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Jinxiao Jiang
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Wenli Liu
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Yuqing Zheng
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China
| | - Ying Ding
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China; Key Laboratory of Hangzhou City for Ecosystem Protection and Restoration, Hangzhou Normal University, Hangzhou 310036, China
| | - Weiqin Zhu
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China; Key Laboratory of Hangzhou City for Ecosystem Protection and Restoration, Hangzhou Normal University, Hangzhou 310036, China
| | - Hangjun Zhang
- College of Life and Environmental Sciences, Hangzhou Normal University, Xuelin Road 16#, Xiasha Gaojiao Dongqu, Hangzhou, Zhejiang Province, 310036, China; Guangzhou Key Laboratory of Environmental Exposure and Health, School of Environment, Jinan University, Guangzhou 510632, China; Key Laboratory of Hangzhou City for Ecosystem Protection and Restoration, Hangzhou Normal University, Hangzhou 310036, China.
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Jiang S, Lin Y, Yao H, Yang C, Zhang L, Luo B, Lei Z, Cao L, Lin N, Liu X, Lin Z, He C. The role of unfolded protein response and ER-phagy in quantum dots-induced nephrotoxicity: an in vitro and in vivo study. Arch Toxicol 2018; 92:1421-1434. [DOI: 10.1007/s00204-018-2169-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 01/25/2018] [Indexed: 12/20/2022]
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Zou L, Su L, Sun Y, Han A, Chang X, Zhu A, Liu F, Li J, Sun Y. Nickel sulfate induced apoptosis via activating ROS-dependent mitochondria and endoplasmic reticulum stress pathways in rat Leydig cells. ENVIRONMENTAL TOXICOLOGY 2017; 32:1918-1926. [PMID: 28296042 DOI: 10.1002/tox.22414] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 02/17/2017] [Accepted: 02/21/2017] [Indexed: 06/06/2023]
Abstract
Nickel can induce apoptosis of testicular Leydig cells in mice, whereas the mechanisms remain unclear. In this study, we investigated the role of nickel-induced reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum stress (ERS) mediated apoptosis pathways in rat Leydig cells. Fluorescent DCF and Annexin-V FITC/PI staining were performed to measure the production of ROS and apoptosis in Leydig cells. RT-qPCR and Western blot were conducted to analyze the key genes and proteins involved in mitochondria and ERS apoptotic pathways. The results showed that nickel sulfate induced ROS generation, consequently resulted in nucleolus deformation and apoptosis in testicular Leydig cells, which were then attenuated by ROS inhibitors of N-acetylcysteine (NAC) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). Nickel sulfate-triggered Leydig cells apoptosis via mitochondria and ERS pathways was characterized by the upregulated mRNA and proteins expression of Bak, cytochrome c, caspase 9, caspase 3, GRP78, GADD153, and caspase 12, which were inhibited by NAC and TEMPO respectively. The findings indicated that nickel-induced ROS generation was involved in apoptosis via mitochondria and ERS pathways in rat Leydig cells.
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Affiliation(s)
- Lingyue Zou
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Li Su
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Yifan Sun
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Aijie Han
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Xuhong Chang
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - An Zhu
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Fangfang Liu
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Jin Li
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
| | - Yingbiao Sun
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, 730000, China
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Zhao Y, Cao Q, He Y, Xue Q, Xie L, Yan Y. Impairment of endoplasmic reticulum is involved in β-cell dysfunction induced by microcystin-LR. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2017; 223:587-594. [PMID: 28162804 DOI: 10.1016/j.envpol.2017.01.061] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 01/02/2017] [Accepted: 01/21/2017] [Indexed: 06/06/2023]
Abstract
Microcystins (MCs) widely distributed in freshwaters have posed a significant risk to human health. Previous studies have demonstrated that exposure to MC-LR impairs pancreatic islet function, however, the underlying mechanisms still remain unclear. In the present study, we explored the role of endoplasmic reticulum (ER) impairment in β-cell dysfunction caused by MC-LR. The result showed that MC-LR modified ER morphology evidenced by increased ER amount and size at low doses (15, 30 or 60 μM) and vacuolar and dilated ER ultrastructure at high doses (100 or 200 μM). Also, insulin content showed increased at 15 or 30 μM but declined at 60, 100, or 200 μM, which was highly accordant with ER morphological alteration. Transcriptomic analysis identified a number of factors and several pathways associated with ER protein processing, ER stress, apoptosis, and diabetes mellitus in the cells treated with MC-LR compared with non-treated cells. Furthermore, MC-LR-induced ER stress significantly promoted the expression of PERK/eIF2α and their downstream targets (ATF4, CHOP, and Gadd34), which indicates that PERK-eIF2α-ATF4 pathway is involved in MC-LR-induced insulin deficiency. These results suggest that ER impairment is an important contributor to MC-LR-caused β-cell failure and provide a new insight into the association between MCs contamination and the occurrence of human diseases.
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Affiliation(s)
- Yanyan Zhao
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China
| | - Qing Cao
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China
| | - Yaojia He
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
| | - Qingju Xue
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China
| | - Liqiang Xie
- State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, 73 East Beijing Road, Nanjing 210008, PR China.
| | - Yunjun Yan
- Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China.
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Zhang S, Liu C, Li Y, Imam MU, Huang H, Liu H, Xin Y, Zhang H. Novel Role of ER Stress and Autophagy in Microcystin-LR Induced Apoptosis in Chinese Hamster Ovary Cells. Front Physiol 2016; 7:527. [PMID: 27877136 PMCID: PMC5099254 DOI: 10.3389/fphys.2016.00527] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 10/24/2016] [Indexed: 12/20/2022] Open
Abstract
Microcystin-LR (MC-LR) is a ubiquitous peptide that exhibits strong reproductive toxicity, although the mechanistic basis for such toxicity remains largely unknown. The present study was conducted to investigate the mechanisms underlying the adverse effects of exposure to MC-LR in Chinese hamster ovary (CHO) cells. The results showed that MC-LR inhibited the in vitro proliferation of CHO cells significantly, with an IC50 of 10 μM. Moreover, MC-LR-treated CHO cells revealed strong induction of cell cycle arrest and apoptosis. Additionally, exposure of CHO cells to MC-LR resulted in excess reactive oxygen species production and intracellular calcium release, with resultant endoplasmic reticulum stress (ERs). There was also extensive accumulation of autophagic vacuoles with the highest concentration of MC-LR used (10 μM). Furthermore, the expression of ERs (GRP78, ATF-6, PERK, IRE1, CHOP) and autophagy (Beclin1 and LC3II) proteins was increased, with concomitantly reduced expression of LC3I suggesting that ERs and autophagy were induced in CHO cells by MC-LR treatment. Conversely, pretreatment of CHO cells with 4-Phenyl butyric acid, the ERs inhibitor reduced the MC-LR-induced apoptotic cell death and cellular autophagy as evidenced by the reduced expression of Beclin1 and LC3II. Similarly, MC-LR treatment in combination with an autophagy inhibitor (3-methyladenine) increased apoptotic cell death compared with MC-LR alone, and induced ERs via upregulating ERs proteins. The overall results indicated that activation of ERs and autophagy are both associated with MC-LR-induced apoptosis in CHO cells. ERs may be a trigger of autophagy in this process.
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Affiliation(s)
| | | | | | | | | | | | | | - Huizhen Zhang
- Department of Environmental Health, College of Public Health, Zhengzhou UniversityZhengzhou, China
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Woźny M, Lewczuk B, Ziółkowska N, Gomułka P, Dobosz S, Łakomiak A, Florczyk M, Brzuzan P. Intraperitoneal exposure of whitefish to microcystin-LR induces rapid liver injury followed by regeneration and resilience to subsequent exposures. Toxicol Appl Pharmacol 2016; 313:68-87. [PMID: 27765657 DOI: 10.1016/j.taap.2016.10.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 10/11/2016] [Accepted: 10/13/2016] [Indexed: 12/22/2022]
Abstract
To date, there has been no systematic approach comprehensively describing the sequence of pathological changes in fish during prolonged exposure to microcystin-LR (MC-LR). Towards this aim, juvenile whitefish individuals received an intraperitoneal injection with pure MC-LR, and the injection was repeated every week to maintain continuous exposure for 28days. During the exposure period, growth and condition of the fish were assessed based on biometric measurements. Additionally, selected biochemical markers were analysed in the fishes' blood, and their livers were carefully examined for morphological, ultrastructural, and molecular changes. The higher dose of MC-LR (100μg·kg-1) caused severe liver injury at the beginning of the exposure period, whereas the lower dose (10μg·kg-1) caused less, probably reversible injury, and its effects began to be observed later in the exposure period. These marked changes were accompanied by substantial MC-LR uptake by the liver. However, starting on the 7th day of exposure, cell debris began to be removed by phagocytes, then by 14th day, proliferation of liver cells had markedly increased, which led to reconstruction of the liver parenchyma at the end of the treatment. Surprisingly, despite weekly-repeated intraperitoneal injections, MC-LR did not accumulate over time of exposure which suggests its limited uptake in the later phase of exposure. In support, mRNA expression of the membrane transport protein oatp1d was decreased at the same time as the regenerative processes were observed. Our study shows that closing of active membrane transport may serve as one defence mechanism against further MC-LR intoxication.
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Affiliation(s)
- Maciej Woźny
- Department of Environmental Biotechnology, Faculty of Environmental Sciences, University of Warmia and Mazury in Olsztyn, ul. Słoneczna 45G, 10-709 Olsztyn, Poland.
| | - Bogdan Lewczuk
- Department of Histology and Embryology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, ul. M. Oczapowskiego 13, 10-713 Olsztyn, Poland
| | - Natalia Ziółkowska
- Department of Histology and Embryology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, ul. M. Oczapowskiego 13, 10-713 Olsztyn, Poland
| | - Piotr Gomułka
- Department of Ichthyology, Faculty of Environmental Sciences, University of Warmia and Mazury in Olsztyn, ul. M. Oczapowskiego 5, 10-719 Olsztyn, Poland
| | - Stefan Dobosz
- Department of the Salmonid Research in Rutki, Inland Fisheries Institute in Olsztyn, Rutki, 83-330 Żukowo, Poland
| | - Alicja Łakomiak
- Department of Environmental Biotechnology, Faculty of Environmental Sciences, University of Warmia and Mazury in Olsztyn, ul. Słoneczna 45G, 10-709 Olsztyn, Poland
| | - Maciej Florczyk
- Department of Environmental Biotechnology, Faculty of Environmental Sciences, University of Warmia and Mazury in Olsztyn, ul. Słoneczna 45G, 10-709 Olsztyn, Poland
| | - Paweł Brzuzan
- Department of Environmental Biotechnology, Faculty of Environmental Sciences, University of Warmia and Mazury in Olsztyn, ul. Słoneczna 45G, 10-709 Olsztyn, Poland
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Zhang Z, Zhang XX, Wu B, Yin J, Yu Y, Yang L. Comprehensive insights into microcystin-LR effects on hepatic lipid metabolism using cross-omics technologies. JOURNAL OF HAZARDOUS MATERIALS 2016; 315:126-134. [PMID: 27208774 DOI: 10.1016/j.jhazmat.2016.05.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 05/04/2016] [Accepted: 05/05/2016] [Indexed: 06/05/2023]
Abstract
Microcystin-LR (MC-LR) can induce hepatic tissue damages and molecular toxicities, but its effects on lipid metabolism remain unknown. This study investigated the effects of MC-LR exposure on mice lipid metabolism and uncovered the underlying mechanism through metabonomic, transcriptomic and metagenomic analyses after administration of mice with MC-LR by gavage for 28 d. Increased liver weight and abdominal fat weight, and evident hepatic lipid vacuoles accumulation were observed in the mice fed with 0.2mg/kg/d MC-LR. Serum nuclear magnetic resonance analysis showed that MC-LR treatment altered the levels of serum metabolites including triglyceride, unsaturated fatty acid (UFA) and very low density lipoprotein. Digital Gene Expression technology was used to reveal differential expression of hepatic transcriptomes, demonstrating that MC-LR treatment disturbed hepatic UFA biosynthesis and activated peroxisome proliferator-activated receptor (PPAR) signaling pathways via Pparγ, Fabp1 and Fabp2 over-expression. Metagenomic analyses of gut microbiota revealed that MC-LR exposure also increased abundant ratio of Firmicutes vs. Bacteroidetes in gut and altered biosynthetic pathways of various microbial metabolic and pro-inflammatory molecules. In conclusion, oral MC-LR exposure can induce hepatic lipid metabolism disorder mediated by UFA biosynthesis and PPAR activation, and gut microbial community shift may play an important role in the metabolic disturbance.
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Affiliation(s)
- Zongyao Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China; Center for Environmental Health Research, South China Institute of Environmental Sciences, The Ministry of Environmental Protection of PRC, Guangzhou 510655, China
| | - Xu-Xiang Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China.
| | - Bing Wu
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Jinbao Yin
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
| | - Yunjiang Yu
- Center for Environmental Health Research, South China Institute of Environmental Sciences, The Ministry of Environmental Protection of PRC, Guangzhou 510655, China
| | - Liuyan Yang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China.
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Chen L, Chen J, Zhang X, Xie P. A review of reproductive toxicity of microcystins. JOURNAL OF HAZARDOUS MATERIALS 2016; 301:381-99. [PMID: 26521084 DOI: 10.1016/j.jhazmat.2015.08.041] [Citation(s) in RCA: 257] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 08/20/2015] [Accepted: 08/23/2015] [Indexed: 05/25/2023]
Abstract
Animal studies provide strong evidence of positive associations between microcystins (MCs) exposure and reproductive toxicity, representing a threat to human reproductive health and the biodiversity of wild life. This paper reviews current knowledge of the reproductive toxicity of MCs, with regard to mammals, fishes, amphibians, and birds, mostly in males. Toxicity of MCs is primarily governed by the inhibition of protein phosphatases 1 and 2A (PP1 and PP2A) and disturbance of cellular phosphorylation balance. MCs exposure is related to excessive production of reactive oxygen species (ROS) and oxidative stress, leading to cytoskeleton disruption, mitochondria dysfunction, endoplasmic reticulum (ER) stress, and DNA damage. MCs induce cell apoptosis mediated by the mitochondrial and ROS and ER pathways. Through PP1/2A inhibition and oxidative stress, MCs lead to differential expression/activity of transcriptional factors and proteins involved in the pathways of cellular differentiation, proliferation, and tumor promotion. MC-induced DNA damage is also involved in carcinogenicity. Apart from a direct effect on testes and ovaries, MCs indirectly affect sex hormones by damaging the hypothalamic-pituitary-gonad (HPG) axis and liver. Parental exposure to MCs may result in hepatotoxicity and neurotoxicity of offspring. We also summarize the current research gaps which should be addressed by further studies.
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Affiliation(s)
- Liang Chen
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Jun Chen
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
| | - Xuezhen Zhang
- College of Fisheries, Huazhong Agricultural University, Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Wuhan 430070, China.
| | - Ping Xie
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
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Cai F, Liu J, Li C, Wang J. Critical Role of Endoplasmic Reticulum Stress in Cognitive Impairment Induced by Microcystin-LR. Int J Mol Sci 2015; 16:28077-86. [PMID: 26602924 PMCID: PMC4691030 DOI: 10.3390/ijms161226083] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 11/16/2015] [Accepted: 11/17/2015] [Indexed: 01/11/2023] Open
Abstract
Recent studies showed that cyanobacteria-derived microcystin-leucine-arginine (MCLR) can cause hippocampal pathological damage and trigger cognitive impairment; but the underlying mechanisms have not been well understood. The objective of the present study was to investigate the mechanism of MCLR-induced cognitive deficit; with a focus on endoplasmic reticulum (ER) stress. The Morris water maze test and electrophysiological study demonstrated that MCLR caused spatial memory injury in male Wistar rats; which could be inhibited by ER stress blocker; tauroursodeoxycholic acid (TUDCA). Meanwhile; real-time polymerase chain reaction (real-time PCR) and immunohistochemistry demonstrated that the expression level of the 78-kDa glucose-regulated protein (GRP78); C/EBP homologous protein (CHOP) and caspase 12 were significantly up-regulated. These effects were rescued by co-administration of TUDCA. In agreement with this; we also observed that treatment of rats with TUDCA blocked the alterations in ER ultrastructure and apoptotic cell death in CA1 neurons from rats exposed to MCLR. Taken together; the present results suggested that ER stress plays an important role in potential memory impairments in rats treated with MCLR; and amelioration of ER stress may serve as a novel strategy to alleviate damaged cognitive function triggered by MCLR.
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Affiliation(s)
- Fei Cai
- Department of Pharmacology, Hubei University of Science and Technology, Xianning 437100, China.
| | - Jue Liu
- Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.
| | - Cairong Li
- Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning 437100, China.
| | - Jianghua Wang
- Fisheries College, Huazhong Agricultural University, Wuhan 430070, China.
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Mechanisms of microcystin-LR-induced cytoskeletal disruption in animal cells. Toxicon 2015; 101:92-100. [DOI: 10.1016/j.toxicon.2015.05.005] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 05/06/2015] [Accepted: 05/12/2015] [Indexed: 12/31/2022]
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Zhao S, Li G, Chen J. A proteomic analysis of prenatal transfer of microcystin-LR induced neurotoxicity in rat offspring. J Proteomics 2015; 114:197-213. [DOI: 10.1016/j.jprot.2014.11.015] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 11/14/2014] [Accepted: 11/23/2014] [Indexed: 01/25/2023]
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Milutinović A, Zorc-Pleskovič R, Živin M, Vovk A, Seša I, Šuput D. Magnetic resonance imaging for rapid screening for the nephrotoxic and hepatotoxic effects of microcystins. Mar Drugs 2013; 11:2785-98. [PMID: 23921723 PMCID: PMC3766865 DOI: 10.3390/md11082785] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 06/04/2013] [Accepted: 07/19/2013] [Indexed: 01/08/2023] Open
Abstract
In vivo visualization of kidney and liver damage by Magnetic Resonance Imaging (MRI) may offer an advantage when there is a need for a simple, non-invasive and rapid method for screening of the effects of potential nephrotoxic and hepatotoxic substances in chronic experiments. Here, we used MRI for monitoring chronic intoxication with microcystins (MCs) in rat. Male adult Wistar rats were treated every other day for eight months, either with MC-LR (10 μg/kg i.p.) or MC-YR (10 μg/kg i.p.). Control groups were treated with vehicle solutions. T1-weighted MR-images were acquired before and at the end of the eight months experimental period. Kidney injury induced by the MCs presented with the increased intensity of T1-weighted MR-signal of the kidneys and liver as compared to these organs from the control animals treated for eight months, either with the vehicle solution or with saline. The intensification of the T1-weighted MR-signal correlated with the increased volume density of heavily injured tubuli (R2 = 0.77), with heavily damaged glomeruli (R2 = 0.84) and with volume density of connective tissue (R2 = 0.72). The changes in the MR signal intensity probably reflect the presence of an abundant proteinaceous material within the dilated nephrons and proliferation of the connective tissue. T1-weighted MRI-is a valuable method for the in vivo screening of kidney and liver damage in rat models of intoxication with hepatotoxic and nephrotoxic agents, such as microcystins.
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Affiliation(s)
- Aleksandra Milutinović
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, Ljubljana 1000, Slovenia; E-Mails: (A.M.); (R.Z.-P.)
| | - Ruda Zorc-Pleskovič
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, Ljubljana 1000, Slovenia; E-Mails: (A.M.); (R.Z.-P.)
| | - Marko Živin
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana 1000, Slovenia; E-Mails: (M.Z.); (A.V.)
| | - Andrej Vovk
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana 1000, Slovenia; E-Mails: (M.Z.); (A.V.)
- Centre for Clinical Physiology, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana 1000, Slovenia
| | - Igor Seša
- Institute Jožef Stefan, Jamova 23, Ljubljana 1000, Slovenia; E-Mail:
| | - Dušan Šuput
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, Ljubljana 1000, Slovenia; E-Mails: (M.Z.); (A.V.)
- Centre for Clinical Physiology, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana 1000, Slovenia
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