APOE genetic background and sex confer different vulnerabilities to postnatal chlorpyrifos exposure and modulate the response to cholinergic drugs

Behav Brain Res. 2019 Dec 30;376:112195. doi: 10.1016/j.bbr.2019.112195. Epub 2019 Aug 29.

Abstract

Chlorpyrifos (CPF) is an extensively used organophosphate pesticide. Exposure to CPF has been related to neurobehavioral disorders, particularly during neurodevelopment. Apolipoprotein E (apoE) is a lipid and cholesterol carrier and a susceptibility factor for cognitive impairment which can influence the response to toxic exposures. The study was aimed at assessing the effects of postnatal exposure to CPF on object recognition memory and its modulation by sex and APOE genotype. Human apoE3 and apoE4 targeted replacement mice and C57BL/6 mice were postnatally exposed to 0 or 1 mg/kg/day of CPF. Recognition memory was evaluated in an Object Recognition Test (ORT). In order to study the contribution of cholinergic and GABAergic neurotransmitter systems to recognition memory, a pharmacological challenge was included. Sex, genotype and postnatal exposure to CPF were key factors throughout the testing period. Specifically, CPF increased exploratory behavior and impaired discrimination performance. We observed that administering scopolamine, a cholinergic antagonist, was detrimental to recognition memory. However, discrimination in C57BL/6 and apoE4 males improved with the administration of the cholinergic agonist rivastigmine, but the same drug worsened retention in apoE4 females. Finally, the GABAergic agonist alprazolam altered performance in a sex- and genotype-dependent manner. Overall, these results suggest complex interactions between sex, APOE genotype and postnatal CPF exposure and indicate a different functioning of both the cholinergic and GABAergic neurotransmitter system between groups.

Keywords: APOE; Brain development; Chlorpyrifos; Cholinergic system; Pesticide; Recognition memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein E3 / genetics
  • Apolipoprotein E4 / genetics
  • Apolipoproteins E / genetics*
  • Apolipoproteins E / metabolism
  • Chlorpyrifos / adverse effects*
  • Chlorpyrifos / metabolism
  • Chlorpyrifos / pharmacology
  • Cholinergic Agents / pharmacology
  • Cholinergic Neurons / drug effects
  • Disease Susceptibility / metabolism
  • Exploratory Behavior / drug effects
  • Female
  • GABAergic Neurons / drug effects
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Male
  • Maze Learning / drug effects
  • Memory / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Reaction Time / drug effects
  • Recognition, Psychology / drug effects
  • Scopolamine
  • Sex Characteristics
  • Sex Factors

Substances

  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E
  • Cholinergic Agents
  • Scopolamine
  • Chlorpyrifos