Sex and APOE ε4 Allele Shape Behavioral and Epigenetic Susceptibility to Prenatal Chlorpyrifos Exposure in Mice

Pesticides are essential for modern agriculture but raise concerns about potential neurodevelopmental consequences, leading to bans in some countries. This study aimed to investigate the long-term effects of prenatal exposure to chlorpyrifos (CPF) on behavior and DNA methylation, considering genetic susceptibility via the apolipoprotein E (APOE) genotype. Pregnant mice-C57BL/6J and those carrying human APOE ε3 or ε4 alleles-were orally exposed to 0 or 1 mg/kg/day of CPF from gestational day 12 to 18. Adult offspring underwent light and dark and Morris water maze tests to assess anxiety-like behavior and spatial learning and memory. Then, hippocampal samples were collected to assess DNA methylation. Results indicated that body weight was lower in females and CPF-treated mice. C57BL/6J males spent less time in the light compartment, worsened by CPF. In contrast, within APOE genotype ε4 carriers spent more time in the light compartment, with CPF increasing male activity. Moreover, long-term retention was impaired in both male and female apoE4 mice prenatally exposed to CPF. DNA methylation analysis revealed sex-dependent differences, with hypomethylation in the CPF-treated male hippocampus. These findings highlight how pesticides and genetic factors interact, affecting neurobehavioral development, and explore the potential impact of CPF on DNA methylation.