Parental preconceptual α-cypermethrin exposure alters embryonic brain transcriptomics in mice: Implications for autism spectrum disorder and stress vulnerability

Abstract

Pyrethroid insecticides are widely used in agriculture and households, and their exposure can affect neurodevelopment. Few studies have evaluated how preconception parental exposure could also affect this process. To address this knowledge gap, adult C57Bl6/J mice were gavaged daily with α-cypermethrin at a human relevant low (0.3 mg/kg) or high (10 mg/kg) dose in corn oil for four weeks prior to conception. Offspring embryonic day 16 dorsal forebrain was extracted for transcriptomic analysis. In offspring forebrains of exposed compared to unexposed parents, there was increasing number of differentially expressed genes (DEGs) from paternal (least) to maternal to both parent exposure (most). A dose dependent effect was observed in offspring forebrain for paternal and maternal preconceptual exposures. Maternal and both parent exposures led to upregulated genes in offspring brain for biological processes involved in translation with predicted activation of EIF4E, a gene associated with autism. In contrast, paternal exposure upregulated cell cycle related DNA damage signaling processes. After any parent exposure, there was upregulation of biological processes involved in mitochondria function and oxidative stress and a downregulation of neuronal and synaptic processes with predicted inhibition of BDNF signaling. Weighted gene correlation network analysis identified modules associated with different parent exposures that were over-represented with DEGs and had similar functional signatures as DEG-related pathways. Importantly, DEGs in offspring forebrain after any parent exposure were over-represented with genes related to autism spectrum disorder (ASD) and stress vulnerability. The study highlights the potential contribution of preconception parental pyrethroid exposure to aberrant brain functioning.