Zebrafish Model Reveals Potentialhealth Risk Of Deltamethrin

Deltamethrin(DTM)is one of the pyrethroid pesticides with the highest insecticidal activity.In current research,we developed a series of models for toxicity identification and systematic evaluation of pesticide target organs,determined the direct and indirect toxic target organs of DTM to zebrafish,and preliminarily explored the molecular mechanism of direct toxic target organs induced by DTM.The main research results are as follows:(1)The main toxic target organs of DTM to zebrafish include nervous system,notochord,immune system,cardiovascular system,liver,kidney and swim bladder.The nervous system,notochord and immune system were the direct target organs,and the others were the indirect target organs.(2)DTM-induced neurotoxicity to zebrafish is the primary target organ toxicity.The main characteristics of neurotoxicity are as follows: the spontaneous movement times of zebrafish first increased and then decreased.The response and escape ability of zebrafish to external mechanical stimulation significantly decreased or even disappeared,and zebrafish also showed muscle twitch/spasm and “epileptiform” transient rapid and abnormal behavior.Zebrafish showed increased total motion distance and rapid motion caused by nerve excitation.Besides,Zebrafish's response capacity to light were also significantly decreased.DTM induced mild apoptosis of body axis central nerve cells and brain nerve cells in zebrafish.The above toxicity effects all showed obvious concentration dependence effect.DTM-induced near death and dying zebrafish showed histological changes such as fewer granulosa cells,looser arrangement,and even local loss in zebrafish brain.(3)DTM also directly caused different degrees of "serrated" or "wavy" distortion of zebrafish notochord with concentration dependent effect which was further confirmed.It was worth highlighting that our further studies have proved that notochord injury aggravated the neurotoxicity of DTM to zebrafish,which may be the reason why DTM is highly toxic to fish,low toxic to humans and mammals.We also found that nervous system is more sensitive than notochord when zebrafish exposed to the same concentration of DTM.(4)DTM-induced immune system abnormalities are characterized by immune activation(protection)induced by low concentration(maximum concentration of nontoxic effects)and immunosuppression(damage)induced by high concentration.Through morphological and functional changes and histopathological study,the author found that DTM-induced immunosuppression is mainly presented as the inhibition of the formation of immune cells(neutrophils,macrophages,T cells and B cells)and immune function(phagocytosis of macrophages,respiratory burst of white blood cells,and the resistance of zebrafish to cancer cells),as well as ROS production and pathological changes of intestinal mucosa in zebrafish,which may be the main pathological mechanism of immune system damage induced by DTM.(5)The cardiovascular toxicity,liver and kidney toxicity,and bladder injury induced by DTM mainly occurred at near-death and lethal concentrations,and occurred after neurotoxicity,indicating that they are secondary toxicity.The main manifestations of cardiovascular toxicity are bradycardia,pericardial edema,increased SV-BA distance,hemodynamic changes,decreased erythrocytes in the body,and cardiac histological changes.The liver toxicity was characterized by mild degeneration and atrophy of the liver and delayed absorption of the yolk sac.Kidney toxicity is characterized by renal edema and glomerular filtration inhibition.The bladder injury is mainly manifested as developmental failures or incomplete development.(6)Transcriptome results showed that the NOAEL concentration of DTM induced the expression of 913 differentially expressed genes(DEGs),which were mainly involved in activating the immune protection response and protein processing in zebrafish.Functional localization analysis of the top 20 DEGs showed that 15 genes were involved in activating the immune system to play a protective role in the zebrafish.4 genes were involved in nerve injury(nxph1)and neuroprotective effects(mmp-9,shsp and slc16a9a),respectively.One gene was involved in elastin synthesis(mfap4),and one gene was involved in renal hematopoiesis(hbaa1).The results showed that in addition to inducing nervous system and notochord injury in zebrafish,the NOAEL concentration of DTM mainly activated the compensatory protection,including the immune protection,neuroprotection,lactic acid energy supply and oxygen supply.(7)The molecular mechanism of DTM-induced notochord injury in zebrafish indicate that up-regulation of sec23/24 involved in transport/secretion of collagen ? and down-regulation of lox involved in crosslinking process of collagen ? interfere with transport/secretion and crosslinking process of collagen ?,leading to accumulation of collagen ? in non-crosslinked state at notochord of zebrafish.In summary,this study developed a series of models for identification and evaluation of toxicity of pesticide target organs based on zebrafish in vivo,and preliminarily confirmed the feasibility of zebrafish application in pesticide human health risk assessment,providing a new approach and method for pesticide human health risk assessment.