Developmental pyrethroid exposure and age influence phenotypes in a Chd8 haploinsufficient autism mouse model

Hundreds of genes have been associated with autism spectrum disorder (ASD), including loss-of-function mutations in chromodomain helicase DNA binding protein 8 (Chd8). Environmental factors also are implicated in autism risk and have the potential to exacerbate phenotypes in genetically sensitized backgrounds. Here we investigate transcriptional and behavioral phenotypes in a Chd8 haploinsufficient (Chd8(V986*/+)) mouse line exposed to the pesticide deltamethrin (DM) from conception to postnatal day 22. Vehicle-exposed Chd8(V986*/+) mice displayed ASD-associated phenotypes, including anxiety-like behavior and altered sociability, replicating a previous study with this mouse line. A core set of genes was altered in Chd8(V986*/+) mice at multiple ages, including Usp11, Wars2, Crlf2, and Eglf6, and proximity ligation data indicated direct binding of CHD8 to the 5’ region of these genes. Moreover, oligodendrocyte and neurodegenerative transcriptional phenotypes were apparent in 12 and 18 month old Chd8(V986*/+) mice. Following DM exposure, the mutant mice displayed an exacerbated phenotype in the elevated plus maze, and genes associated with vascular endothelial cells were downregulated in the cerebral cortex of older Chd8(V986*/+) animals. Our study reveals a gene x environment interaction with a Chd8 haploinsufficient mouse line and points to the importance of investigating phenotypes in ASD animal models across the lifespan.