Paternal fenvalerate exposure causes depressive-like behaviour by altering Grb10 gene DNA methylation in adolescent offspring

Fenvalerate, a typical pyrethroid pesticide, is a neurological toxicant. This study aimed to evaluate the effect of paternal exposure to fenvalerate on depressive-like behaviours in adolescent offspring. Depression-like behavior was determined by Sucrose Preference Test (SPT), Tail Suspension Test (TST) and Forced Swimming Test (FST) in adolescent offspring. The level of dopamine was reduced in the midbrain of fenvalerate-exposed adolescent offspring. Tyrosine hydroxylase (Th), a rate limiting enzyme for dopamine synthesis, was significantly reduced in the midbrain of adolescent offspring exposed to fenvalerate. And Th was decreased in the midbrain and hindbrain of fetuses exposed to fenvalerate. Transcriptome analysis revealed growth factor receptor-bound protein 10 (Grb10) was decreased in the fetal hindbrain exposed to fenvalerate. Grb10 mRNA and protein were reduced in the fetal hindbrain exposed to fenvalerate. Interestingly, in vitro experiments, Th was reduced by si-Grb10. Conversely, Th was increased by oe-Grb10. Mechanistically, the 5mC content of Grb10 gene at one CpG fragment was reduced in the fetal hindbrain exposed to fenvalerate. And the 5mC content of Grb10 gene at eighteen CpG sites was decreased in paternal sperm exposed to fenvalerate. In summary, paternal fenvalerate exposure causes depressive-like behavior by altering DNA methylation of Grb10 gene in the sperm.