Pesticides DEET, fipronil and maneb induce stress granule assembly and translation arrest in neuronal cells

Abstract

Pesticides entering our body, either directly or indirectly, are known to increase the risk of developing neurodegenerative disorders. The pesticide-induced animal models of Parkinson's disease and Alzheimer's disease recapitulates many of the pathologies seen in human patients and have become popular models for studying disease biology. However, the specific effect of pesticides at the cellular and molecular levels is yet to be fully established. Here we investigated the cellular effect of three commonly used pesticides: DEET, fipronil and maneb. Specifically, we looked at the effect of these pesticides in the formation of stress granules and the concomitant translational arrest in a neuronal cell line. Stress granules represent an ensemble of non-translating mRNAs and appear in cells under physiological stress. Growing evidence indicates that chronic stress may covert the transient stress granules into amyloids and may thus induce neurodegeneration. We demonstrate here that all three pesticides tested induce stress granules and translation arrest through the inactivation of the eukaryotic initiation factor, eIF2α. We also show that oxidative stress could be one of the major intermediary factors in the pesticide-induced stress granule formation and that it is a reversible process. Our results suggest that prolonged pesticide exposure may result in long-lived stress granules, thus compromising the neuronal stress response pathway and leading to neurodegeneration.

Genetic variability in pathways associates with pesticide-induced nervous system disease in the United States

“…Additionally, both Polymarcine (metiram) and maneb were prioritized for all three diseases. Metiram and maneb are both ethylenebisdithiocarbamate (EBDC) fungicides, and while polymarcine toxicity is understudied compared to other EBDCs, both rodent models 41 and epidemiological studies have implicated maneb in Parkinson disease, especially with co-exposure to paraquat (which was applied in all years in all states in our study) 42,43 . We also identified metiram as a high priority chemical for multiple sclerosis and, while metiram has not been linked to multiple sclerosis in the literature, it has been linked to amyotrophic lateral sclerosis (ALS), so it may also be worth investigating further 44 .…”

Data-Driven Characterization of Genetic Variability in Disease Pathways and Pesticide-Induced Nervous System Disease in the United States Population

“…Polymarcine, mancozeb, and maneb are EBDC fungicides, and while polymarcine toxicity is understudied compared to other EBDCs, both rodent models 55 and epidemiological studies have implicated maneb in Parkinson disease, especially with co-exposure to paraquat (which was applied in all years in all states in our study). 56 , 57 We also identified polymarcine as a high-priority chemical for multiple sclerosis, and while polymarcine has not been linked to multiple sclerosis in the literature, it has been linked to amyotrophic lateral sclerosis (ALS), so it may also be worth investigating further. 58 Lastly, we identified copper among the top three priority pesticides in all three diseases.…”

Current status of pesticide effects on environment, human health and it’s eco-friendly management as bioremediation: A comprehensive review

“…Several epidemiological and molecular research highlighted a close association between persistent pesticides exposure and increased risk of diseases such as neurodegenerative disorders, endocrine disruptors, respiratory complications, reproductive disorders, and birth defects ( García et al, 2017 ; Larsen et al, 2017 ; Addissie et al, 2020 ; Bast et al, 2021 ; Bhadauriya et al, 2021 ; Witczak et al, 2021 ; Gea et al, 2022 ; Iteire et al, 2022 ). In addition, the carcinogenic, teratogenic, and mutagenic nature of these compounds are also believed to be a contributing source of cancer development in the human population.…”