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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. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the Intertalentum Postdoctoral Program (Marie Curie cofund UAM-UE, EU project 713366) for V.B. and by grants from the Spanish Ministry of Science and Innovation (SAF2017-86983-R, PID2020-117651RB) and from the Spanish Ministry of Economy and Competitiveness (PCIN-2016– 095) for J.A.E.. V.B. was also recipient of the 2019 Eduardo Gallego postdoctoral fellowship from Fundación Francisco Cobos. M.I.C. was recipient of a postdoctoral fellowship from the Spanish Ministry of Economy (IJCI-2015–25507). E.LM. was recipient of a predoctoral fellowship from the Spanish Ministry of Science and Innovation (FPU18/02838). Sí |
