Maternal Exposure To Deltamethrin During Pregnancy And Lactation Damages Cerebellar Purkinje Cells Through The BDNF/TrkB Signaling Pathway

Objective: Deltamethrin(DM)is a highly effective and widely used pyrethroid pesticide.As a neurotoxic agent,the toxicity symptoms of DM include cramps,salivation and hind limb muscle weakness.With increasing exposure to DM,people concern about its potential health risks.Currently,there are few studies on the cerebellar function effects of maternal exposure to DM during pregnancy and lactation.The potential harmful effects and mechanisms remain to be explored.The complex dendritic branching of the purkinje cells is important for the function of cerebellum.In this study,we constructed a rat model of DM exposure during pregnancy and lactation and a model of DM exposure in PC12 cells to investigate the effects of DM exposure on motor function,purkinje cell dendrites growth and development and the associated regulatory mechanisms of signaling pathways.Methods: Pregnant Wistar rats were ingavaged with DM(0,1,4 and 10 mg/kg/d)from the day of pregnancy until postnatal day 21(PN21)to construct an animal model of maternal DM exposure.At PN14 and PN21,the pups were tested for motor function using relevant behavioral assays.At PN21,the cerebellum of pups were taken for Immunofluorescence,Golgi-Cox Staining and Western-Blot to detect the expression levels of BDNF/TrkB signaling pathway-related proteins,the morphological characteristics of purkinje cells dendritic and related proteins.In vitro,the PC12 cells(rat adrenal pheochromocytoma cell line)was chosen as the experimental object.A DM exposure model was established and the overexpression model of BDNF was constructed by plasmid.Western Blot was used to determine the expression of stathmin protein regulated by BDNF/TrkB signaling pathway.Results: The results of animal experiments showed that in wire grip test at PN14,balance beam test and rotarod test at PN21,the motor function of male pups in the 4 mg/kg/d DM group and 10 mg/kg/d DM group was significantly impaired(P<0.05).Golgi-Cox staining revealed compared with the control group,the total dendritic length of cerebellar purkinje cells was reduced in all dose groups and the difference between the 4 mg/kg/d DM group and 10 mg/kg/d DM group was statistically significant(P<0.05);the number of cerebellar purkinje dendritic intersections and branching complexity were significantly reduced in all dose groups(P<0.05).The expression of BDNF,p-TrkB and p-stathmin in the 4 and 10 mg/kg/d DM groups were significantly reduced(P<0.05)and there was no significant change in the expression of total TrkB and stathmin between the groups(P<0.05).The in-vitro experimental results showed the expression of BDNF,p-TrkB and p-stathmin were significantly lower in the Vector+DM group(P<0.05)and the expression levels of BDNF,p-TrkB and p-stathmin were significantly higher in the LV-BDNF group compared with the Vector group(P<0.05).Compared with the Vector+DM group,the expression of BDNF,p-TrkB and p-stathmin were significantly higher in the LV-BDNF group and LV-BDNF+DM group(P<0.05).There was no significant change in total TrkB and stathmin expression between the groups(P>0.05).Conclusion: 1.Maternal DM exposure during pregnancy and lactation damages offspring cerebellar motor function.2.Maternal exposure to DM during pregnancy and lactation impairs the dendritic growth and development of purkinje cells in male offspring.3.DM exposure inhibits the BDNF/TrkB signaling pathway,thereby reducing p-stathmin and impairing cerebellar purkinje cell dendrite growth and development.