Abstract:

Introduction: Roundup© (RU), a glyphosate-based herbicide (GBH) is widely used for agriculture, forestry, and residential weed control. While GBHs are considered to have low toxicity in mammals, new evidence suggests that exposure to GBHs may cause reproductive deficits by disrupting placental function and altering arachidonic acid (AA) metabolism. AA is the precursor for prostaglandin (PG) synthesis; PGs are important for regulating angiogenesis in the placenta. Disruptions in PG synthesis have the potential to cause altered placental vascularization; an effect which could underlie poor pregnancy outcomes. Therefore, this study explores the impact of RU exposure on placental PG biosynthesis and angiogenesis. Methods: Htr-8/SVneo human trophoblast cells were exposed to 0.0001%, 0.001%, and 0.01% RU for 48h. We assessed the mRNA expression of proangiogenic targets (vascular endothelial growth factor (VEGFa), VEGF receptor (VEGFR1), endocrine gland-derived VEGF (PROK1), angiopoietin-like factor 4 (ANGPTL4), placental growth factor (PGF) and enzymes involved in PG biosynthesis (PTGS1, PTGS2, PTGIS, PGES, PTGDS). Prostaglandin E2 (PGE2) was measured using ELISA. Results: RU treatment significantly reduced the expression of PROK1, ANGPTL4, PLGF at all doses. VEGFa expression was not affected by RU exposure, but expression of its receptor was significantly decreased at 0.01% and 0.0001%. Expression of PTGIS and PTGDS decreased significantly across all doses, while PTGS2 and PTGES were inhibited at 0.01% and 0.0001% RU. Consistent with these changes there was a trend towards decreased PGE2 output (p=0.09). Conclusions: Exposure to RU significantly downregulates genes involved in PG biosynthesis, alongside inhibiting pro-angiogenic factors. As placental angiogenesis is critical for establishing the materno-fetal blood supply, these data suggest that altered PG synthesis may impair angiogenesis, potentially resulting in adverse pregnancy outcomes associated with GBH exposure