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

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

Toxicology. 2021 Sep:461:152922. doi: 10.1016/j.tox.2021.152922. Epub 2021 Aug 30.

Authors

Daiane Cattani¹, Nona Struyf², Vivien Steffensen², Jonas Bergquist³, Ariane Zamoner⁴, Eva Brittebo², Malin Andersson²

Affiliations

¹ Department of Pharmaceutical Biosciences - BMC, Uppsala University, Box 591, 75124, Uppsala, Sweden; Department of Biochemistry, Federal University of Santa Catarina, Florianopolis, 88040-970, Brazil. Electronic address: daiane.cattani@aces.su.se.
² Department of Pharmaceutical Biosciences - BMC, Uppsala University, Box 591, 75124, Uppsala, Sweden.
³ Department of Chemistry - BMC, Analytical Chemistry and Neurochemistry, Uppsala University, Box 559, 75124, Uppsala, Sweden.
⁴ Department of Biochemistry, Federal University of Santa Catarina, Florianopolis, 88040-970, Brazil.

PMID: 34474092
DOI: 10.1016/j.tox.2021.152922

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.

Keywords: Dynorphin; Glyphosate-based herbicide; Hippocampus; MALDI IMS; Nestin; Substantia nigra.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / drug effects
Brain / pathology
Dynorphins / metabolism*
Female
Glycine / administration & dosage
Glycine / analogs & derivatives*
Glycine / toxicity
Glyphosate
Herbicides / administration & dosage
Herbicides / toxicity*
Hippocampus / drug effects
Hippocampus / pathology
Male
Neurotoxicity Syndromes / etiology*
Neurotoxicity Syndromes / pathology
Pregnancy
Prenatal Exposure Delayed Effects / pathology
Rats
Rats, Wistar
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

Herbicides
Dynorphins
Glycine