In utero and lactational exposure to low-doses of the pyrethroid insecticide cypermethrin leads to neurodevelopmental defects in male mice-An ethological and transcriptomic study.

Anthony Laugeray,Arnaud Menuet,Olivier Richard,Ameziane Herzine,Bernard Jegou,Séverine Mazaud-Guittot,Céline Montecot-Dubourg,Stéphane Mortaud,Olivier Perche,Laurianne Lesné

doi:10.1371/journal.pone.0184475

Abstract

Accumulating evidence suggests that developmental exposure to environmental chemicals may modify the course of brain development, ultimately leading to neuropsychiatric / neurodegenerative disorders later in life. In the present study, we assessed the impact of one of the most frequently used pesticides in both residential and agricultural applications − the synthetic pyrethroid cypermethrin (CYP) − on developmental neurotoxicity (DNT). Female mice were perinatally exposed to low doses of CYP (5 and 20 mg/kg body weight) from gestation to postnatal day 15. Behavioral analyses were performed during the offspring’s early life and during adulthood. Postnatal analyses revealed that perinatal exposure to CYP disturbed motor development without modifying sensory and communicative skills. We found that later in life, CYP-exposed offspring expressed maladaptive behaviors in response to highly challenging tasks and abnormal sociability. Transcriptomic analyses performed in the offspring’s brain at the end of the exposure, highlighted mitochondrial dysfunction as a relevant pathomechanism underlying CYP-induced DNT. Interestingly, several genes involved in proteostasis maintenance were also shown to be dysregulated suggesting that alterations in biogenesis, folding, trafficking and degradation of proteins may significantly contribute to CYP-related DNT. From a regulatory perspective, this study highlights that behavioral and transcriptomic analyses are complementary tools providing useful direction for better DNT characterization, and as such, should be used together more systematically.

Highlights

Pre and postnatal periods are vital time spans for brain development
We recently demonstrated that when the herbicide, glufosinate ammonium was perinatally administered through the intranasal route, the neurodevelopmental outcomes were strikingly reminiscent of ASD-like symptoms in exposed offspring, even at doses largely below the current No Observable Adverse Effect Level (NOAEL) in mice [12, 13]
The present study reports that perinatal exposure to low dose CYP through the inhalation route led to abnormal brain development during the offspring’s early life with behavioral

Summary

Introduction

Pre and postnatal periods are vital time spans for brain development This is when the production, migration and proliferation of neurons are achieved, and the elementary structure of the brain is built. Disturbances of these tightly regulated processes may negatively impact the establishment of basic neuronal circuits, weakening the fundamental structure of the brain Such modifications may be responsible for permanent impairments, thereby leading to a wide range of enduring adverse impacts on emotional cognition later in life. These core principles are the basis for the Barker’s hypothesis, which is better known as the DOHaD approach, i.e. the Developmental Origins of Health and Diseases [1]. Some of these chemicals are produced in our bodies while others enter through contaminants in the air we breathe, the water we drink and the food we eat

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