Paternal fenvalerate exposure causes autism-like behavior partly by altering epigenetic reprogramming of the imprinted gene IGF2 in fetal brain and paternal sperm

Fenvalerate, a representative type II pyrethroid insecticide, is well established in the literature. Fenvalerate exerts developmental and neurological toxicity. We assessed whether paternal fenvalerate exposure induces autism-like behavioral alterations in offspring using a mouse model. Behavioral tests, including the three-chamber social interaction, self-grooming, and marble-burying tests, showed altered social and repetitive behaviors in offspring from fenvalerate-exposed fathers. NeuN, a mature neuronal marker, was reduced in the medial prefrontal cortex (mPFC) of weaning offspring from paternal fenvalerate-exposed groups. Nissl staining showed that the number of surviving neurons is reduced in the mPFC of weaning pups with paternal exposure to fenvalerate. Nestin, a marker for neural stem cells, was decreased in the fetal forebrain from paternal fenvalerate-exposed groups. Transcriptome analysis and RT-PCR showed that insulin-like growth factor 2 (IGF2), a neurotrophic factor, was downregulated in the paternal fenvalerate-exposed group. IGF2 protein was reduced in the fetal forebrain from paternal fenvalerate-exposed group. In addition, paternal fenvalerate exposure reduced methylation of the IGF2 imprinted control region (ICR) in fetal forebrain and paternal sperm. In conclusion, autism-like behaviors appear in offspring after paternal exposure to fenvalerate, which may partly be related to disruptions in epigenetic reprogramming of IGF2 in the developing brain and paternal sperm.