ORIGINAL ABSTRACT

Exposure to glyphosate-based herbicides (GBH) may affect metabolism and induce endocrine alterations. This study evaluated whether environmentally relevant low doses of GBH affect glucose homeostasis during pregnancy and the metabolism of offspring later in life. Pregnant Wistar rats received daily oral doses of either 0.5 or 50 mg/kg of GBH or water (control) throughout the gestation period. No significant changes were observed in biometric and metabolic parameters during pregnancy. However, hepatic alterations were detected in GBH-treated rats, including reduced glycogen content and decreased global genome methylation. Offspring exhibited a transient delay in neurodevelopmental reflexes. Body mass and food intake remained unchanged up to postnatal day 70. After this period, animals were subjected to a metabolic challenge with dexamethasone. While dexamethasone-treated animals showed metabolic alterations typical of glucocorticoid exposure (glucose intolerance, insulin insensitivity, dyslipidemia), maternal GBH exposure during pregnancy did not exacerbate these effects in the offspring. Additionally, changes in DNA methylation-related gene expression were observed in female but not male offspring. In vitro, GBH exhibited greater cytotoxicity than glyphosate alone, significantly reducing the viability of 3T3-L1 adipocytes and HepG2 hepatocytes, whereas glyphosate alone had no significant effects, even at higher concentrations. Overall, gestational exposure to GBH under regulatory safe doses does not cause substantial metabolic disturbances in dams or their offspring. However, the existence of alterations in hepatic glucose metabolism and effects on hepatic epigenetic regulation at these low doses, along with the cytotoxic in vitro effects of GBH at high concentrations, warrants attention regarding human exposure and health impacts.