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Cited by 44Pesticide Exposure and ToxicityAnesthesia and Neurotoxicity ResearchNeuroscience and Neuropharmacology Research

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

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López-Merino, Esperanza, Cuartero, María I., Esteban, José A., Briz, Víctor·2023·Cell Biology and Toxicology
DOI 10.1007/s10565-022-09697-2PMC PMC10547633
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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

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  • Dieldrin reduces both GABA-A and NMDA receptor function in cerebellar granule cells, while CPO increases the ratio of GABA-A receptor-mediated to AMPA receptor-mediated currents in CA1 pyramidal neurons, shifting network activity toward inhibition.

    “Dieldrin reduces both GABA-A and NMDA receptor function in cerebellar granule cells, while CPO increases the ratio of GABA-A receptor-mediated to AMPA receptor-mediated currents in CA1 pyramidal neurons, shifting network activity toward inhibition (Babot et al., 2007; López-Merino et al., 2022).”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as López-Merino et al., 2022

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Organochlorines such as chlordane, dieldrin, and endosulfan, as well as organophosphates such as chlorpyrifos and chlorpyrifos oxon, induce sustained ERK activation and disrupt mGluR-dependent LTD; for chlordane, pharmacological inhibition of ERK signaling rescues this plasticity deficit, supporting a causal relationship between receptor-linked ERK dysregulation and synaptic dysfunction.

    “Organochlorines such as chlordane, dieldrin, and endosulfan, as well as organophosphates such as chlorpyrifos and chlorpyrifos oxon, induce sustained ERK activation and disrupt mGluR-dependent LTD; for chlordane, pharmacological inhibition of ERK signaling rescues this plasticity deficit, supporting a causal relationship between receptor-linked ERK dysregulation and synaptic dysfunction (López-Mer”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as López-Merino et al., 2022

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Epigenetically mediated alterations converge directly on key intracellular pathways involved in synaptic plasticity and neuronal survival.

    “These epigenetically mediated alterations converge directly on key intracellular pathways involved in synaptic plasticity and neuronal survival (López-Merino et al., 2022; Qiu et al., 2023).”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as López-Merino et al., 2022

    The Introduction identifies Akt/mTOR and MAPK/ERK as intracellular pathways regulating synaptic plasticity, and the Results report increased ERK phosphorylation after chronic pesticide exposure. The Discussion mentions epigenetic defects only as a potential mechanism for disrupting brain development; it does not establish that epigenetic alterations directly affect those pathways or pathways involved in neuronal survival. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • CPO increased pupillary weight and prolonged the latency of the pupillary reflex, indicating delayed motor maturation.

    “CPO increased pupillary weight and prolonged the latency of the pupillary reflex, indicating delayed motor maturation.”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as López-Merino et al., 2022

    The Results section ('Perinatal pesticide exposure causes motor and cognitive deficits'; Fig. 5a–b) reports slightly increased pup weight at the highest CPO dose and a dose-dependent increase in righting-reflex latency, consistent with delayed motor development. It does not report pupillary weight or a pupillary reflex; those terms misidentify the measures. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The attenuation of mGluR-LTD induced by CPO and chlordane persisted into adulthood despite preserved basal synaptic transmission.

    “Notably, the attenuation of mGluR-LTD induced by CPO and chlordane persisted into adulthood despite preserved basal synaptic transmission.”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as López-Merino et al., 2022

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Cited by

Sorted by citations

Authors
López-Merino, E., Cuartero, M. I., Esteban, J. A., & Briz, V.
Affiliations
  • Consejo Superior de Investigaciones Científicas (ES)
  • Spanish National Centre for Cardiovascular Research (ES)
Corresponding author
Briz, Víctor
ORCID
Venue
Cell Biology and Toxicology
Publisher
Springer Science and Business Media LLC
Published
2022-02-08
Volume
39
Issue
5
Pages
2089-2111
ISSN
  • 0742-2091 (ISSN-L)
  • 1573-6822
DOI
10.1007/s10565-022-09697-2
PMC
PMC10547633
OpenAlex
W4210868823
Cited by
44
References
5
Citations by year
2026: 16 · 2025: 8 · 2024: 11 · 2023: 6 · 2022: 3
FWCI
3.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Biology and Toxicology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders
  • H2020 Marie Skłodowska-Curie Actions (713366)
  • Ministerio de Economía, Industria y Competitividad, Gobierno de España (PCIN-2016-095, IJCI-2015-25507)
  • Ministerio de Ciencia, Innovación y Universidades (SAF2017-86983-R, PID2020-117651RB, FPU18/02838)
  • Fundación Francisco Cobos (Eduardo Gallego postdoctoral fellowship)
  • Centro de Biología Molecular Severo Ochoa
Topics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
  • Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
neurodevelopmental disorders, developmental neurotoxicity, organochlorine pesticides, organophosphorus pesticides, chlordane, chlorpyrifos oxon, dieldrin, endosulfan, ERK signaling, metabotropic glutamate receptors, long-term depression, synaptic plasticity, hippocampus, anxiety, social dysfunction, memory impairment, motor development, proteomic profiling
MeSH terms
Animals, Chlordan, Chlorpyrifos, Female, Hippocampus, Humans, Neuronal Plasticity, Pesticides, Pregnancy, Proteomics, Rats, Neurodevelopmental Disorders

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