Paternal Fenvalerate Exposure Increases The Risk Of Anxiety And Depression-like Behavior In Offspring And Its Epigenetic Mechanism

Purpose Anxiety and depression are increasingly affecting people’s daily lives,based on the parent Fen exposure mouse model established in the early stage of this class,the toxic effects of Fen exposure on anxiety and depression-like neurobehavior of offspring mice and the possible mechanism of the effects were discussed.Methods According to the intergenerational model of Fen exposure in paternal mice previously established by the research group,and the previous experiment of the research group found that oral exposure to Fen at a dose of 20 mg/kg would not cause significant toxic effects on experimental mice,so the dose used in the intergenerational model established earlier was continued in this study.Exposure to Fen at 20 mg/kg was taken as the high dose group,and exposure to Fen at 2 mg/kg was taken as the low dose group.According to the design of the project,45 ICR male mice and 45 female mice are required for the project.The purchased mice should have similar body weight between the same sex,and their weeks of age should be between 6 and 7 weeks.Before the formal experiment,the experimental mice need to adapt to the environment in the standardized mouse room for about a week before the formal experiment.Before the experiment,45 male mice were divided into 3 groups（control group,low and high dose group）according to the principle of similar body weight.15 male mice in each group were given Fen or corn oil mixed solution through oral and gastric channels at a fixed time every morning.The experiment lasted for 35 consecutive days.After the drug administration,a male mouse was mated with a female mouse,and the next day was about 6:00 to observe whether the female mouse had sperm residue from the male mouse.If so,the female mouse was identified as Gestational day 0（GD 0）.Pregnant female mice could give birth to F1 generation mice on GD18 or GD 19 days,and each female mouse could have 6 F1 generation mice,half male and half female.On the 21 st Day of birth（Postnatal Day,PND 21）,each F1 mouse could be placed in a cage alone until the adult stage of the next stage of the experiment.The adult F1 generation mice were divided into two parts.Some F1 generation mice were subjected to anxiety and depression-like behavior experiments.The anxiety type behavior experiments were open field experiment and elevated cross maze experiment,and the depression-like behavior experiments were forced swimming experiment,tail suspension experiment and sugar water preference experiment,and the other was sacrificed for molecular biological detection.HE staining was performed on the brains of F1 generation mice respectively to observe the effects of paternal Fen exposure on the structure and morphology of cerebral neurons in F1 generation mice.Real-time Polymerase chain reaction（RT-PCR）was used to detect the m RNA expression levels of Dnmts,Tet 2 and BDNF in the prefrontal cortex.Results There were no statistically significant differences in body weight and food intake among male rats in the three groups during 35 days of administration,and no statistically significant differences in body weight and food intake among female rats in different dose groups during pregnancy of F0 generation.In the anxiety and depression-like behavior experiment of F1 generation mice,in the open field test,the standing times of F1 generation female mice in each dose group were increased compared with the control group（P < 0.05）;In F1 generation male mice,there was no difference in each index between each dose group and the control group（P > 0.05）.In the elevated cross maze experiment,F1 generation female mice（P < 0.05）,Fen dose groups decreased the time at open arm and increased the time at closed arm compared with control group（P < 0.05）,but there was no statistical difference between each dose group（P > 0.05）;In all dose groups of F1 male mice,there was no statistical difference in the cumulative time of F1 generation mice at the open and closed arms in the dose group compared with the control group（P > 0.05）.In the suspended tail experiment,the immobile state time of Fen dose group increased compared with the control group（P < 0.05）;In F1 generation male mice,there was no difference in each index between each dose group and the control group（P > 0.05）.In the forced swimming experiment,the immobile state time increased in Fen dose group compared with control group（P <0.05）;In F1 generation male mice,there was no difference in each index between each dose group and the control group（P > 0.05）.The pathological results showed that there were no differences among the groups of male rats in F1 generation,compared with the dose group,the structure and morphology of cerebral cortex neurons of female rats in F1 generation were different.RT-PCR results showed that the m RNA expression levels of Dnmt 1,Dnmt 3a,Tet 2 and BDNF in the prefrontal cortex of F1 generation male rats were not significantly different,while the m RNA expression levels of Dnmt 1 and BDNF in the prefrontal cortex of F1 generation female rats were significantly changed.Conclusion Paternal Fen exposure can cause anxiety and depression-like behavior in F1 generation mice,increase the risk of anxiety and depression-like neurobehavior in F1 generation female mice.The increased anxiety and depression-like behavior in F1 generation female rats induced by paternal Fen exposure may be mediated by DNA methylation in the prefrontal cortex.