Impact of a high-fat diet on spatial learning and memory: The role of sex, APOE genotype, and postnatal chlorpyrifos exposure

Environmental factors, such as exposure to neurotoxicants and diet, play a critical role in shaping cognitive function, particularly in genetically susceptible individuals. Chlorpyrifos (CPF), an organophosphate pesticide, and high-fat diets (HFD) have been independently associated with cognitive impairment, yet their combined effects remain poorly understood. Apolipoprotein E (APOE) genotype influences vulnerability to cognitive decline, with the ε4 allele being a major risk factor for neurodegenerative diseases. This study assessed the interplay between APOE genotype, sex, early-life CPF exposure, and HFD on spatial learning and memory. Male and female C57BL/6, apoE3- and apoE4-targeted replacement (TR) mice were orally exposed to CPF during postnatal days 10–15 and subsequently subjected to a HFD for 8 weeks. At the end of the HFD challenge, body weight gain was calculated, and spatial learning and memory assessed using the Morris Water Maze test. Results indicate that HFD-driven weight gain was influenced by sex and APOE genotype. All groups acquired the spatial learning task, but postnatal CPF exposure affected performance in certain groups. Retention was more variable in females, suggesting increased susceptibility to environmental exposures. Notably, apoE4-TR females showed improved memory retention following either CPF exposure or HFD, whereas apoE4-TR males exhibited impaired long-term memory after HFD exposure. These findings highlight the complex interactions between genetic and environmental factors. Understanding these dynamics is essential for developing targeted nutritional and public health strategies to mitigate cognitive decline. Importantly, dietary recommendations should not be generalized but tailored to individual profiles to optimize cognitive health and disease prevention.