Perinatal exposure to pesticides alters synaptic plasticity signaling and induces behavioral deficits associated with neurodevelopmental disorders

María I. Cuartero,Esperanza López-Merino,Víctor Briz,José A. Esteban

doi:10.1007/s10565-022-09697-2

Abstract

Increasing evidence from animal and epidemiological studies indicates that perinatal exposure to pesticides cause developmental neurotoxicity and may increase the risk for psychiatric disorders such as autism and intellectual disability. However, the underlying pathogenic mechanisms remain largely elusive. This work was aimed at testing the hypothesis that developmental exposure to different classes of pesticides hijacks intracellular neuronal signaling contributing to synaptic and behavioral alterations associated with neurodevelopmental disorders (NDD). Low concentrations of organochlorine (dieldrin, endosulfan, and chlordane) and organophosphate (chlorpyrifos and its oxon metabolite) pesticides were chronically dosed ex vivo (organotypic rat hippocampal slices) or in vivo (perinatal exposure in rats), and then biochemical, electrophysiological, behavioral, and proteomic studies were performed. All the pesticides tested caused prolonged activation of MAPK/ERK pathway in a concentration-dependent manner. Additionally, some of them impaired metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). In the case of the pesticide chlordane, the effect was attributed to chronic modulation of MAPK/ERK signaling. These synaptic alterations were reproduced following developmental in vivo exposure to chlordane and chlorpyrifos-oxon, and were also associated with prototypical behavioral phenotypes of NDD, including impaired motor development, increased anxiety, and social and memory deficits. Lastly, proteomic analysis revealed that these pesticides differentially regulate the expression of proteins in the hippocampus with pivotal roles in brain development and synaptic signaling, some of which are associated with NDD. Based on these results, we propose a novel mechanism of synaptic dysfunction, involving chronic overactivation of MAPK and impaired mGluR-LTD, shared by different pesticides which may have important implications for NDD.Graphical abstract

Highlights

Neurodevelopmental disorders include a wide range of genetic conditions that express characteristic converging phenotypes, including developmental motor delay, alterations in social and emotional behaviors, and cognitive deficits
Pesticides chronically activate mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK) signaling in hippocampal slice cultures
We found an enrichment in proteins regulating synapse development such as angiotensin-converting enzyme (ACE), actinrelated protein 2 (Arp2), Tau protein, ephrin receptor A4 (EphA4), neural cell adhesion molecule 1 (NCAM1), and plexin A4 (PlxnA4) (Chakrabarty et al 2008; Suda et al 2011; Yan et al 2016; Yang et al 2019), as revealed by functional analysis using ingenuity pathway analysis (Fig. 7c, e)

Summary

Introduction

Neurodevelopmental disorders include a wide range of genetic conditions that express characteristic converging phenotypes, including developmental motor delay, alterations in social and emotional behaviors, and cognitive deficits. Inadvertent exposure to low concentrations of environmental contaminants such as pesticides has been associated with neurodevelopmental disorders affecting millions of children worldwide, in what has been called a silent pandemic (Grandjean et al 2014; Grandjean and Landrigan 2006) In this line of evidence, an increasing number of animal and epidemiological studies indicate that prenatal and early postnatal exposure to organochlorine and organophosphate pesticides produce developmental neurotoxicity (Burke et al 2017; Grandjean and Landrigan 2006) and may increase the risk for ASD (Kalkbrenner et al 2014; Rossignol et al 2014; Shelton et al 2012) and attention deficit hyperactivity disorder (ADHD) (Polańska et al 2013; Roberts et al 2019). Human populations are still exposed to many of these contaminants, as they bioaccumulate in fatty tissues leading to escalating dietary exposure along the trophic chain (GonzálezAlzaga et al 2018; Hertz-Picciotto et al 2018; Junqué et al 2017)

Objectives

Methods

Results

Conclusion