Perinatal Exposure To BDE-47 Exacerbated Autistic-like Behaviors And Impairments Of Dendritic Development In A Valproic Acid-induced Rat Model Of Autism

Objective: Polybrominated diphenyl ethers(PBDEs)as flame retardants are extensively used in a wide array of products such as furnishings,and plastics,and classified as persistent organic pollutants(POPs).Autism spectrum disorders(ASD)is a complex neuro-developmental disorder typically characterized by barriers on communication and social interaction,and abnormally restricted and repetitive stereotype behaviors.There has been an increasing concern that perinatal exposure to polybrominated diphenyl ethers(PBDEs)may be a potential risk factor for autism spectrum disorders(ASD)in children.2,2’,4,4’-Tetrabromodiphenyl Ether(BDE-47)is one of the most common PBDEs and poses serious health hazards on the central nervous system(CNS).Abnormal dendritic development is known to be deeply associated with autistic-like behaviors.Thus,we aimed to investigate whether BDE-47 exposure during gestation and lactation led to autistic-like behaviors in offspring rats in the present study.valproic acid(VPA)– induced-rats model was employed as animal model of autistic-like behaviors.Besides,our study also provided the evidence that the inhibition of BDNF-CREB signaling,a key regulator of dendritic development,may be involved in the dendritic impairments induced by perinatal exposure to BDE-47 and the consequent autistic-like behaviors.Methods: Pregnant rats were randomly divided into four treatment groups: Control,BDE-47,VPA,or BDE-47+VPA.Each group consisted of 15 pregnant rats.Dams in the control,BDE-47,VPA,and BDE-47+VPA groups were intragastrically administered BDE-47 at a dose of 0,50,0,50 mg/kg/day,respectively,from E0.5 to PND21.They were also injected with either 600 mg/kg VPA(VPA group and BDE-47+VPA group)or saline solution 0.9%(control group and BDE-47 group)on E12.5. Dams were allowed to raise their own offspring until weaning at PND21.Self-grooming test,marble burying test,and T-maze test were performed at PND26,PND28,PND32 to assess the repetitive behaviors in rats.The three-chamber social interaction test,which is widely adopted to analyze the sociability and social preference,was conducted at PND36.The open field test was performed at PND40 to investigate anxiety-like behaviors in rodents.Dendrites are critical structures involved in information processing and transmission in nervous system,and alteration in dendrites has dramatic effects on neurobehaviors.In order to observe the effects of BDE-47 or VPA treatment on the dendritic structure in the prefrontal cortex of pups,the Golgi-staining was carried out.Western blotting was used to detect the expression of dendritic developmentrelated proteins in BDNF-CREB signaling pathway.The changes of BDNF,Trk B and CREB on dendrites were observed by immunofluorescence staining.Results: In the three-chamber social interaction test,perinatal exposure to BDE-47 resulted in mild social behavior changes in offspring,which were similar but less severe to those observed in pups maternally exposed to VPA.In addition,perinatal exposure to BDE-47 aggravated the changes in offspring’s society and social preference in pups maternally exposed to VPA.In three tests to detect whether offspring have repetitive stereotypical behaviors,it was shown that exposure to BDE-47 during pregnancy and lactation would lead pups spend more time grooming themselves,buried more marbles,entered same arm more,so as to determine that offspring have mild repetitive stereotypical behaviors,which were similar but less severe to those observed in pups maternally exposed to VPA.In addition,exposure to BDE-47 during pregnancy and lactation can aggravate the repetitive stereotypical behaviors in offspring maternally exposed to VPA.Exposure to BDE-47 during pregnancy and lactation led to mild anxiety like behaviors in offspring in open field test,which were similar but less severe to those observed in pups maternally exposed to VPA.In addition,maternal exposure to BDE-47 aggravated the anxiety like behaviors in offspring maternally exposed to VPA.Thus,we found that perinatal exposure to BDE-47 caused mild autistic-like behaviors in offspring,which were similar but less severe to those observed in pups maternally exposed to VPA.Moreover,perinatal exposure to BDE-47 aggravated the autistic-like behaviors in pups maternally exposed to VPA.The morphological study of dendrites showed that we also observed perinatal exposure to BDE-47 reduced dendritic length and complexity of branching pattern,and spine density in the offspring prefrontal cortex,which may contribute to autistic-like behaviors observed in the present study.Perinatal exposure to BDE-47 also exacerbated the damage of dendritic development in pups maternally exposed to VPA.Besides,perinatal exposure to BDE-47 or VPA caused the inhibition of BDNF / Trk B / AKT / CREB signaling in offspring.Perinatal exposure to BDE-47 also exacerbated the inhibition of BDNF / Trk B / AKT / CREB signaling in rats exposed to VPA.Conclusion: 1.Perinatal exposure to BDE-47 caused mild autistic-like behaviors and aggravated the autistic-like behaviors in pups maternally exposed to VPA.2.Perinatal exposure to BDE-47 caused the impairments of dendritic development in pups prefrontal cortex and also exacerbated the impairments of dendritic development in pups maternally exposed to VPA.3.The inhibition of BDNF-CREB signaling,a key regulator of dendritic development,may be involved in the dendritic impairments induced by perinatal exposure to BDE-47 and/or VPA,and the consequent autistic like behaviors.