In utero and lactational exposure to low-doses of the pyrethroid insecticide cypermethrin leads to neurodevelopmental defects in male mice—An ethological and transcriptomic study

Accumulating evidence suggests that developmental exposure to environmental chemicals may modify the course of brain development, ultimately leading to neuropsychiatric / neurodegenerative disorders later in life. In the present study, we assessed the impact of one of the most frequently used pesticides in both residential and agricultural applications - the synthetic pyrethroid cypermethrin (CYP) - on developmental neurotoxicity (DNT). Female mice were perinatally exposed to low doses of CYP (5 and 20 mg/kg body weight) from gestation to postnatal day 15. Behavioral analyses were performed during the offspring's early life and during adulthood. Postnatal analyses revealed that perinatal exposure to CYP disturbed motor development without modifying sensory and communicative skills. We found that later in life, CYP-exposed offspring expressed maladaptive behaviors in response to highly challenging tasks and abnormal sociability. Transcriptomic analyses performed in the offspring's brain at the end of the exposure, highlighted mitochondrial dysfunction as a relevant pathomechanism underlying CYP-induced DNT. Interestingly, several genes involved in proteostasis maintenance were also shown to be dysregulated suggesting that alterations in biogenesis, folding, trafficking and degradation of proteins may significantly contribute to CYP-related DNT. From a regulatory perspective, this study highlights that behavioral and transcriptomic analyses are complementary tools providing useful direction for better DNT characterization, and as such, should be used together more systematically.