Impact of a high-fat diet on spatial learning and memory: the role of sex, <em>APOE</em> genotype, and postnatal chlorpyrifos exposure.

Abstract

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