Life-long dietary pesticides cocktail induces astrogliosis along with behavioral adaptations and activates p450 metabolic pathways

Abstract Exposure to environmental contaminants is a public health concern. However, pre-clinical studies examining the impact of pesticides at low-dose and their long-term consequences are uncommon. Here, C57BL6/j male and female mice were daily fed from weaning and up to 12 months, corresponding to early-childhood into middle-age in humans, using chow pellets containing a cocktail of pesticides and exposing them to the tolerable daily intake level for each pesticide. We found that 12 months of dietary exposure to pesticides was associated with a moderate astrogliosis in the hippocampus. The expression of platelet-derived growth factor receptor beta (PDGFRβ), an indicator of pro-fibrotic tissue changes, was modified at the perivascular level. Examination of Iba1+ microglial cells did not reveal sizeable changes. Concomitantly to astrogliosis, spontaneous spatial memory and sociability were impaired in males at 12 months of dietary exposure to pesticides. Telemetry electrocorticograhic explorations ruled out the presence of epileptiform activity or theta-gamma wave modifications in these conditions. Long-term pesticides impacted the periphery where the hepatic P450 metabolic cytochromes Cyp4a14 and Cyp4a10 were significantly upregulated in male and female mice during the 12 months of exposure. The expression of β-oxidation genes, such as Acox1, Cpt1a and Eci, was also significantly increased in male and female mice in response to pesticides. Collectively, our results indicate that long-term exposure to pesticides cocktail elicits spatio-temporally restricted brain modifications and significant activation of P450 pathways in the periphery. These brain-peripheral adjustments are discussed as time-dependent vulnerability elements.