A Multiomics Study To Unravel the Effects of Developmental Exposure to Endosulfan in Rats: Molecular Explanation for Sex-Dependent Effects

Sonia Tarazona, Elena Bernabeu, Héctor Carmona, Belén Gómez-Giménez, Javier García-Planells, Pim E.G. Leonards, Stephan Jung, Ana Conesa, Vicente Felipo, Marta Llansola

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Exposure to low levels of environmental contaminants, including pesticides, induces neurodevelopmental toxicity. Environmental and food contaminants can reach the brain of the fetus, affecting brain development and leading to neurological dysfunction. The pesticide endosulfan is a persistent pollutant, and significant levels still remain detectable in the environment although its use is banned in some countries. In rats, endosulfan exposure during brain development alters motor activity, coordination, learning, and memory, even several months after uptake, and does so in a sex-dependent way. However, the molecular mechanisms driving these effects have not been studied in detail. In this work, we performed a multiomics study in cerebellum from rats exposed to endosulfan during embryonic development. Pregnant rats were orally exposed to a low dose (0.5 mg/kg) of endosulfan, daily, from gestational day 7 to postnatal day 21. The progeny was evaluated for cognitive and motor functions at adulthood. Expression of messenger RNA and microRNA genes, as well as protein and metabolite levels, were measured on cerebellar samples from males and females. An integrative analysis was conducted to identify altered processes under endosulfan effect. Effects between males and females were compared. Pathways significantly altered by endosulfan exposure included the phosphatidylinositol signaling system, calcium signaling, the cGMP-PKG pathway, the inflammatory and immune system, protein processing in the endoplasmic reticulum, and GABA and taurine metabolism. Sex-dependent effects of endosulfan in the omics results that matched sex differences in cognitive and motor tests were found. These results shed light on the molecular basis of impaired neurodevelopment and contribute to the identification of new biomarkers of neurotoxicity.

Original languageEnglish
Pages (from-to)4264-4279
Number of pages16
JournalACS Chemical Neuroscience
Issue number10
Early online date29 Aug 2019
Publication statusPublished - 16 Oct 2019


This work was part of the European DENAMIC project and financially supported by the European Commission (no. 282957). This work was partially supported by MINECO project grant number BIO205-71658-R. We want to acknowledge Rianne van Dijk and Sara Tufi for the metabolomics analysis.

FundersFunder number
European Commission282957
Ministerio de Economía y CompetitividadBIO205-71658-R


    • cerebellum
    • development
    • multiomics
    • neurotoxicity
    • pesticide
    • signaling pathways


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