Chronic exposure to chlorpyrifos triggered body weight increase and memory impairment depending on human apoE polymorphisms in a targeted replacement mouse model Fiona Peris-Sampedro a,b,c , Pia Basaure a,b,c , Ingrid Reverte a,b,c , Maria Cabré a,d , José L. Domingo c , Maria Teresa Colomina a,b,c, ⁎ a Research in Neurobehavior and Health (NEUROLAB), Universitat Rovira i Virgili, Tarragona, Spain b Department of Psychology and Research Center for Behavioral Assessment (CRAMC), Universitat Rovira i Virgili, Tarragona, Spain c Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira i Virgili, Reus, Spain d Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, Tarragona, Spain HIGHLIGHTS • Repeated adulthood exposure to CPF increased body weight only in apoE3 mice. • Learning and memory in the Barnes Maze task differed among the apoE genotypes. • Search velocity in the Barnes Maze task was increased in CPF-exposed apoE2 mice. • Repeated adulthood exposure to CPF led to a mild memory impairment in apoE3 mice. • The apoE genotype modulated the toxic effects of the pesticide CPF. abstract article info Article history: Received 19 January 2015 Received in revised form 25 February 2015 Accepted 3 March 2015 Available online 5 March 2015 Keywords: Chlorpyrifos Pesticides Mice Apolipoprotein E Obesity Learning Despite restrictions on their use, humans are still constantly exposed to organophosphates (OPs). A huge number of studies have ratified the neurotoxic effects of chlorpyrifos (CPF) and suggested its association with neurode- generative diseases, but data are still scarce. Human apolipoprotein E (apoE) plays an important role in lipid transport and distribution. In humans, the apoE4 isoform has been linked to an increased risk of Alzheimer's dis- ease (AD). ApoE3 is the most prevalent isoform worldwide, and has been often established as the healthful one. The current study, performed in targeted replacement (TR) adult male mice, aimed to inquire whether genetic variations of the human apoE respond differently to a chronic dietary challenge with CPF. At four/five months of age, mice carrying apoE2, apoE3 or apoE4 were pair-fed a diet supplemented with CPF at 0 or 2 mg/kg body weight/day for 13 weeks. Cholinergic signs were monitored daily and body weight changes weekly. In the last week of treatment, learning and memory were assessed in a Barnes maze task. Dietary CPF challenge increased body weight only in apoE3 mice. Differences in the acquisition and retention of the Barnes maze were attributed to apoE genetic differences. Our results showed that apoE4 mice performed worse than apoE2 and apoE3 carriers in the acquisition period of the spatial task, and that apoE2 mice had poorer retention than the other two genotypes. On the other hand, CPF increased the search velocity of apoE2 subjects during the acquisition period. Retention was impaired only in CPF-exposed apoE3 mice. These results underline that gene × environment interactions need to be taken into account in epidemiological studies. Given that apoE3, the most common polymorphism in humans, has proved to be the most sensitive to CPF, the potential implica- tions for human health merit serious thought. © 2015 Elsevier Inc. All rights reserved. 1. Introduction Although pesticides have generally improved agricultural productivi- ty, their widespread use has resulted in severe environmental pollution, and endangered human health. The highly-lipophilic organophosphorus (OPs) compound chlorpyrifos (CPF) is one of the most frequently used non-persistent pesticides worldwide, even though the US Environmental Physiology & Behavior 144 (2015) 37–45 ⁎ Corresponding author at: Department of Psychology and Research Center for Behavior Assessment (CRAMC), Universitat Rovira i Virgili, Sescelades Campus, 43007 Tarragona, Spain. E-mail address: mariateresa.colomina@urv.cat (M.T. Colomina). http://dx.doi.org/10.1016/j.physbeh.2015.03.006 0031-9384/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/phb