Perinatal exposure to a glyphosate-based herbicide causes dysregulation of dynorphins and an increase of neural precursor cells in the brain of adult male rats

Daiane Cattani,Nona Struyf,Vivien Steffensen,Jonas Bergquist,Ariane Zamoner,Eva Brittebo,Malin Andersson

doi:10.1016/j.tox.2021.152922

Daiane Cattani, Nona Struyf + Show 5 more

Open Access

https://doi.org/10.1016/j.tox.2021.152922

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Abstract

Glyphosate, the most used herbicide worldwide, has been suggested to induce neurotoxicity and behavioral changes in rats after developmental exposure. Studies of human glyphosate intoxication have reported adverse effects on the nervous system, particularly in substantia nigra (SN). Here we used matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) to study persistent changes in peptide expression in the SN of 90-day-old adult male Wistar rats. The animals were perinatally exposed to 3 % GBH (glyphosate-based herbicide) in drinking water (corresponding to 0.36 % of glyphosate) starting at gestational day 5 and continued up to postnatal day 15 (PND15). Peptides are present in the central nervous system before birth and play a critical role in the development and survival of neurons, therefore, observed neuropeptide changes could provide better understanding of the GBH-induced long term effects on SN. The results revealed 188 significantly altered mass peaks in SN of animals perinatally exposed to GBH. A significant reduction of the peak intensity (P < 0.05) of several peptides from the opioid-related dynorphin family such as dynorphin B (57 %), alpha-neoendorphin (50 %), and its endogenous metabolite des-tyrosine alpha-neoendorphin (39 %) was detected in the GBH group. Immunohistochemical analysis confirmed a decreased dynorphin expression and showed a reduction of the total area of dynorphin immunoreactive fibers in the SN of the GBH group. In addition, a small reduction of dynorphin immunoreactivity associated with non-neuronal cells was seen in the hilus of the hippocampal dentate gyrus. Perinatal exposure to GBH also induced an increase in the number of nestin-positive cells in the subgranular zone of the dentate gyrus. In conclusion, the results demonstrate long-term changes in the adult male rat SN and hippocampus following a perinatal GBH exposure suggesting that this glyphosate-based formulation may perturb critical neurodevelopmental processes.

Highlights

The development of the central nervous system (CNS) from conception to adulthood is extremely complex and depends on in teractions between genetics, epigenetics, and environmental factors (Dubois et al, 2014)
Since developmental exposure to GBH has been reported to promote cognitive impairments, we focused on GBH-induced significant changes in dynorphin-related peptides expression, a family of endogenous opioids that have been previously identified by matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) and that are known to be involved in the modulation of cognitive processes (Bilkei-Gorzo et al, 2014; Ukai et al, 1997)
Since recent studies have shown that exposure to GBH during pre- and postnatal periods can promote cognitive impairments (Ait-Bali et al, 2020; Pu et al, 2020), our results suggest a potential association between GBH-induced low levels of dynorphin and cognitive deficits later in life

Summary

Introduction

The development of the central nervous system (CNS) from conception to adulthood is extremely complex and depends on in teractions between genetics, epigenetics, and environmental factors (Dubois et al, 2014). Other neurodevelopmental disabil ities, including autism spectrum disorders and cognitive impairments, affect a significant number of children (Grandjean and Landrigan, 2014). The driving factors behind these disabilities and dis orders are likely to be multifactorial, the rapid increase in incidence indicates that exposure to environmental factors may be involved (Rock and Patisaul, 2018). Pre- and post-natal exposures to environmental pollutants have been associated with neurodegenerative diseases (Antonelli et al, 2017). Agrochemicals are one of the main environmental pollutants that living organisms are continuously exposed to and epidemiological studies have suggested an association between occupational exposure to agrochem icals and increased risk for neurological disorders (Bjorling-Poulsen et al, 2008; Freire and Koifman, 2013; Jett, 2011; London et al, 2012). Traces of glyphosate have been detected in drinking water (Noori et al, 2018; Rendon-von Osten and Dzul-Caamal, 2017) and food sources (Bai and Ogbourne, 2016; Thompson et al, 2019), including a soy-based infant formula (Rodrigues and de Souza, 2018)

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