Oxidative Stress Mediated Changes In Prefrontal Cortex DNA Methylation And Anxiety-like Behavior Of Offspring Adult Mice Induced By Pregnancy Exposure To Fenvalerate

ObjectivesExposure during pregnancy can be transmitted to offspring through epigenetic pathways and cause neuropsychiatric diseases,but the role of epigenetics in the neurobehavioral impairment caused by fenvalerate exposure has not been explored.In this study,an animal model of fenvalerate exposure during pregnancy and NAC intervention was established to investigate the effects of fenvalerate exposure during pregnancy and NAC intervention on anxiety-like behaviors of offspring adult mice.MethodsTo construct the animal model of intrauterine fenvalerate exposure and NAC supplement.ICR mice aged 7 weeks were purchased,including 30 males and 60 females.After one week of adaptive feeding,the cage was cooped in a 2:1 ratio of male to female for five days.Then the pregnant mice were divided into four groups according to their body weight,12 in each group.The control group was intragastrically fed with pure corn oil emulsion,the FEN group was intragastrically fed with 20mg/kg fenvalrethrin blended with corn oil emulsion,and the NAC group was intragastrically fed with 100mg/kg N-acetylcysteine dissolved in water.FEN+NAC group was given20mg/kg fenvalerate and 100mg/kg N-acetylcysteine intragastric administration.Gavage continues throughout pregnancy until delivery.The offspring mice were raised to adulthood,and some of them were subjected to behavioral tests to detect anxiety-like behavior,while others were dissected from the prefrontal cortex for molecular tests.Molecular experiments mainly included LC-MS/MS assay to measure the content of5 m C and 5hm C in the prefrontal cortex,RT-PCR assay to measure the m RNA expression level of Dnmts,and GSH assay in the prefrontal cortex and serum using kits.ResultsIn the open field experiment,the number of standing times and fecal particles of offspring males in FEN group were significantly higher than those in control group,and the number of standing times and fecal particles of offspring males in FEN+NAC group were significantly lower than those in FEN group,with statistical significance.LC-MS/MS results showed that the content of 5m C in the prefrontal cortex of FEN+NAC group was significantly higher than that of the control group,and significantly lower than that of FEN+NAC group.There was no significant difference in the content of5 m C and 5hm C in the prefrontal cortex of female offspring.The results of RT-PCR,the m RNA expression level of Dnmt3 a in the prefrontal cortex of FEN group was significantly up-regulated.Compared with FEN group,the m RNA expression level of Dnmt3 a in FEN+NAC group was significantly down-regulated.The m RNA expression levels of Dnmt1 and Dnmt3 b in the four groups showed no significant difference.In the prefrontal cortex of offspring mice,the GSH content of FEN+NAC group decreased compared with that of the control group,and increased compared with that of FEN+NAC group.In serum,the serum GSH content of FEN group and the serum GSH-Px activity of FEN+NAC group were significantly decreased,while the serum GSH content of FEN+NAC group and the serum GSH-Px activity of FEN+NAC group were increased.ConclusionPregnancy fenvalerate exposure increased anxiety-like behavior in offspring adult mice in a sex-dependent manner,and NAC supplementation reduced anxiety-like behavior in adult mice.Intrauterine fenvalerate exposure resulted in up-regulation of DNA hypermethylation and Dnmt3 a m RNA expression in male prefrontal cortex,while NAC supplementation partially inhibited DNA hypermethylation and Dnmt3 a m RNA expression in male prefrontal cortex.Intrauterine fenvalerate exposure induced oxidative stress in mice,and NAC supplementation partially inhibited oxidative stress effect.