Study On The Toxic Effects Of Cylindrospermopsin(CYN)

The frequency,intensity and duration of cyanobacteria blooms in freshwater and coastal waters are increasing due to climate change and nutrient enrichment,resulting in the production of toxic metabolites that have serious negative impacts on ecosystems and public health.Cylindrospermopsin(CYN)is a potent cyanobacterial toxin found in water bodies across the world.Many genes and metabolic systems of zebrafish are highly similar to human's.Using zebrafish as a vertebrate model,the toxicity and mechanism of zebrafish embryonic development were studied to advance our understanding of CYN toxicity,and environmental problems and health hazards caused by climate changes and eutrophication.The vascular system is an important channel for the transportation of substances in the body and physiological regulation of organisms.The abnormal changes in blood vessels often result in serious consequences.The impairment of vascular development may induce birth defects,diseases or even embryo lethality.Vascular endothelial cells and smooth muscle cells are the main cellular components of the vessel tissue and play important roles in maintenance of normal structure and physiological functions of vessel wall,as well as in vascular diseases.However,the impact of CYN exposure on vascular development is still poorly understood,especially its toxicological mechanism.Therefore,it is fundamental to study the potential effects of CYN exposure on vascular cells and the underlying molecular mechanism.In summary,this study explored the toxic effect of CYN on embryonic development and vascular cells and related mechanisms through in vivo and in vitro exposure experiments with model biological zebrafish and vascular cells.The main research contents and results of this article are as follows:(1)Adverse effect of CYN on embryonic development in zebrafishCYN exposure decreased embryos survival rate,hatching rate,body length and eye size in a concentration-dependent manner and induced abnormalities in embryo morphology.High concentrations(200 and 2000 n M CYN)induced yolk sac hemorrhage,abnormal heart shape,and reduced heart rate.CYN induced abnormal vascular development and led to an increase in the growth of common cardinal vein(CCV),in which CCV remodeling was delayed as reflected by the larger CCV area and wider ventral diameter.(2)The developmental toxicity mechanism of CYN on zebrafish embryosCYN could induce cell apoptosis,oxidative stress and promote the expression of oxidative stress-related genes(SOD1,CAT and GPx1)and induce changes in transcriptional levels of apoptotic-related genes(p53,Bax and Bcl-2).The adverse effects on zebrafish embryos development induced by CYN may be related to apoptosis and oxidative stress.CYN may cause oxidative stress by breaking the imbalance between ROS production and antioxidant defenses,leading to cellular apoptosis and finally affecting zebrafish embryos development.(3)The toxic effects of CYN on vascular endothelial cells and its related mechanismCYN inhibited human umbilical vein endothelial cells(HUVECs)viability,migration,promoted HUVECs apoptosis,damaged the cytoskeleton,and increased intracellular ROS levels.CYN exposure significantly affected the expression of upstream and downstream genes(ITGB,Rho,ROCK,and MLC-1)in the Rho / ROCK signaling pathway.Taken together,CYN may induce cytoskeleton damage and promote vascular endothelial cell apoptosis by Rho/ROCK signaling pathway,leading to abnormal vascular development.(4)The toxic effects of CYN on vascular smooth muscle cells and its related mechanismCYN resulted in decreased viability and migration inhibition of smooth muscle cells(SMCs),destroyed the SMCs cytoskeleton and decreased the SMCs cell area,perimeter and diameter.CYN also induced an increase in ROS levels and significantly changes the expression level of oxidative stress-related genes,causing intracellular oxidative stress,which led to cellular DNA damage,activation of p53 network,up-regulation of Bax gene expression and down-regulation of Bcl-2 gene expression,thus resulting in apoptosis of SMCs cells.In conclusion,CYN can induce oxidative stress and DNA damage of SMCs,leading to a p53-dependent apoptotic pathway.