Exposure to chlorpyrifos during pregnancy differentially affects social behavior and GABA signaling elements in an APOE- and sex-dependent manner in a transgenic mouse model

Abstract

The massive use of chlorpyrifos (CPF) has been associated with an increased prevalence of neurodevelopmental disorders. Some previous studies have shown that prenatal, but not postnatal, CPF exposure causes social behavior deficits in mice depending on sex while others have found that in transgenic mice models carrying the human apolipoprotein E (APOE) ε3 and ε4 allele confer different vulnerabilities to either behavioral or metabolic disorders after CPF exposure. This study aims to evaluate, in both sexes, how prenatal CPF exposure and APOE genotype impact on social behavior and its relation to changes in GABAergic and glutamatergic systems. For this purpose, apoE3 and apoE4 transgenic mice were exposed through the diet to 0 or 1 mg/kg/day of CPF, between gestational day 12 and 18. A three-chamber test was used to assess social behavior on postnatal day (PND) 45. Then, mice were sacrificed, and hippocampal samples were analyzed to study the gene expression of GABAergic and glutamatergic elements. Results showed that prenatal exposure to CPF impaired social novelty preference and increased the expression of GABA-A α1 subunit in females of both genotypes. In addition, the expression of GAD1, the ionic cotransporter KCC2 and the GABA-A α2 and α5 subunits were increased in apoE3 mice, whereas CPF treatment only accentuated the expression of GAD1 and KCC2. Nevertheless, future research is needed to evaluate whether the influences detected in the GABAergic system are present and functionally relevant in adults and old mice.