Exposure To Nonylphenol In Early Life Induces Pro-Inflammatory Cytokines In Prefrontal Cortex: Involvement Of Gut-Brain Axis

Objective: Nonylphenol(NP),a typical persistent organic pollutant(POP),which is ubiquitously exists in various environmental media.Gestation and lactation are two critical periods of neurodevelopment in central nervous system(CNS).The damages to the CNS were largely irreversible caused by exposure to NP during early life,but the underlying mechanism remains unclear.There are growing concerns about the high levels of pro-inflammatory cytokines in the brain have been implicated in the CNS damages.Thus,we established an animal model of exposure to NP in early life.Furthermore,the VPA-exposed rats were established as positive controls.We investigated the levels of IL-1?,IL-6,and TNF-? in the prefrontal cortices.We also investigated the permeability of intestinal barrier,and BBB,which are two crucial barriers in the gut-brain axis communication.Methods: Pregnant rats were randomly divided into control,VPA,and NP treatment groups.On GD12,the pregnant rats in the VPA treatment group were intraperitoneally injected with 600 mg/kg VPA.From GD 0 till PND21,the pregnant rats in other groups were subjected to NP(dissolved in corn oil)daily by oral gavage at 0,10,or 50 mg/kg.ELISA was used to detected the IL-1?,IL-6,and TNF-? levels of prefrontal cortices,serums and intestines.BBB,BCSFB,and intestinal barrier permeability were detected using 4-kDa fluorescein isothiocyanate-dextran(FITC-dextran).Western blotting was performed to detect the production of ZO-1 and CLDN-1 in prefrontal cortex and intestine.Immunofluorescence staining was used to observe the production of ZO-1 and CLDN-1 in prefrontal cortex and intestine.Results: Exposure to NP and VPA in early life increased the IL-1? and IL-6 levels of prefrontal cortex and serum.Besides,perinatal exposure to NP significantly increased the BBB permeability and tended to increase the BCSFB permeability.The expressions of ZO-1 and CLDN-1 were significantly decreased in the prefrontal cortex of pups subjected to NP and VPA.Moreover,exposure to NP in early life significantly increased the IL-1?,IL-6,and TNF-? levels of intestine.The intestinal barrier permeability was significantly increased in NP and VPA treatment.The expressions of ZO-1 and CLDN-1 in the intestine of pups subjected to NP and VPA.Conclusion: NP exposure in early life increased the levels of pro-inflammatory cytokines in the prefrontal cortex,serum and intestine.The BBB and the intestinal barrier permeability were increased in the rats exposed to NP in early life.The decreased expressions of ZO-1 and CLDN-1 were found,which may underlie these increases in the BBB and the intestinal barrier permeability.Taken together,these results suggest that gut-brain communication of pro-inflammatory cytokines may contribute to the increase of pro-inflammatory cytokines in the prefrontal cortex caused by NP exposure in early life.