Perinatal exposure to high concentration glyphosate-based herbicides induces intestinal apoptosis by activating endoplasmic reticulum stress in offspring

Glyphosate-based herbicides (GBHs), the most widely used pesticide worldwide, have been reported to impair organ function in humans and animals. However, research on the effect of maternal GBHs exposure on the intestinal health of offspring has received little attention. Based on the glyphosate limits defined by Codex Alimentarius Commission and European Food Safety Authority, this study established pregnant sow exposure models to investigate the influence of low (L-GBHs, 20 mg/kg) and high concentration GBHs (H-GBHs, 100 mg/kg) on the intestinal health of offspring and proposed the protective mechanism mediated by betaine. The results showed that the intestinal morphology and bar-rier function of suckling piglets were damaged in the H-GBHs group. H-GBHs increased the activity of glutathione per-oxidase (GPX) and levels of methane dicarboxylic aldehyde (MDA), hydrogen peroxide (H2O2) and inflammatory factors (tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-10 (IL-10)) in suck-ling piglets and activated Nrf2-mediated antioxidant signaling pathway. Subsequently, we found that exposure to H-GBHs triggered endoplasmic reticulum stress (ERS) and further induced apoptosis by upregulating the expression of Bcl-2-associated X protein (Bax), Caspase3, Caspase9 and Caspase12. Moreover, H-GBHs exposure perturbed mitochondrial membrane fusion and electron transport in mitochondrial respiratory chains by increasing the mRNA expression of mitofusin-2 (MFN2) and succinate dehydrogenase subunit A (SDHA), causing mitochondrial dysfunction. Dietary supplementation with betaine provided modest protection against GBHs-induced intestinal damage in suck-ling piglets. These findings reveal the mechanism of GBHs-induced intestinal damage in offspring, improving our un-derstanding of the risk of GBHs exposure in pregnant women and suggesting the potential protective effects of betaine against GBHs poisoning.

Automated summary

This study investigated the effect of maternal exposure to low and high concentration glyphosate-based herbicides (GBHs) on the intestinal health of offspring, and proposed the protective mechanism mediated by betaine. The results showed that high concentration GBHs damaged the intestinal morphology and barrier function of suckling piglets. Additionally, GBHs exposure activated antioxidant signaling pathway and induced endoplasmic reticulum stress and mitochondrial dysfunction, while betaine supplementation provided some protection against GBHs-induced intestinal damage.