Abstract
Polymorphisms of the apolipoprotein E (APOE) gene differentially affect neurobiological functions and cognitive performance and confer different vulnerabilities to subclinical exposures to chlorpyrifos (CPF), a pesticide used worldwide. The data reported on this topic suggest a complex interaction between cholinergic signaling and the APOE genotype. To gain greater functional insight into this interaction, we evaluated spatial learning and memory and hippocampal cholinergic expression in young apoE3 and apoE4 transgenic mice exposed to CPF. Male and female mice were exposed to CPF at 0 or 1 mg/kg on postnatal days 10–15 and then, exposed to CPF at 0 or 2 mg/kg for 60 days at 5 months of age. At 6 months of age, mice were tested for spatial skills in a Barnes maze. At the end of the task, animals were killed and gene expression of cholinergic components was assessed in the hippocampus. Our results show that apoE4 female mice performed worse in the spatial task, while postnatal CPF impaired escape strategies and spatial memory in apoE3 mice. In turn, CPF in adulthood improved spatial abilities in apoE4 female mice. Regarding gene expression, choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) expression were increased in apoE4 mice. Postnatal exposure to CPF increased ChAT mRNA levels in apoE4 mice, whereas adult exposure to CPF induced changes in acetylcholinesterase-S, α7- and α4-subunit nicotinic receptor expression in apoE4 females. The current findings provide new insights into APOE-dependent cholinergic signaling, which directly affects the response to CPF cholinergic insult, especially in APOE4 subjects.
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Acknowledgements
The authors would like to thank Ylenia Heinrich and Cristian Pérez Fernandez for their helpful assistance with the Barnes maze task. We also acknowledge Dr. Celeste di Paolo, Esperanza Chernichero and Juan València for their technical support with animal care. We also thank Dr. Jordi Blanco as well as Dr. Helena Torrell Galceran and Lorena García Alcalde of the Genomics facilities of the Center for Omic Sciences (COS) of the Rovira i Virgili University for their contributions to gene expression analysis.
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This research was supported by the Ministry of Economy and Competitiveness (MINECO, Spain) (Grant Number PSI2014-55785-C2-2-R and PSI2014-55785-C2-1-R), the Commission for Universities and Research of the Department of Innovation, Universities and Enterprise of the Generalitat de Catalunya (Grant Number 2014 FI_B 00075), and the European Social Fund.
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Basaure, P., Guardia-Escote, L., Cabré, M. et al. Learning, memory and the expression of cholinergic components in mice are modulated by the pesticide chlorpyrifos depending upon age at exposure and apolipoprotein E (APOE) genotype. Arch Toxicol 93, 693–707 (2019). https://doi.org/10.1007/s00204-019-02387-9
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DOI: https://doi.org/10.1007/s00204-019-02387-9