The Replacement Herbicide, <scp>l</scp> -Glufosinate, Induces Similar Developmental Effects as Racemic-Glufosinate

The chiral herbicide glufosinate-ammonium (racemic-GLA) is banned in the European Union due to developmental toxicity. Its herbicidally active l-enantiomer (l-GLA), marketed as a potential safer alternative, lacks developmental toxicity assessment. This study investigated the reproductive/developmental toxicity of l-GLA and racemic-GLA in pregnant mice at 13 and 130 μg/kg/day, achieving serum concentrations below or comparable to those reported in humans. Prenatal exposure to l-GLA and racemic-GLA at both doses caused fetal growth restriction (FGR), an approximate 10% reduction in placental weight, and structural abnormalities, including a smaller labyrinth zone, underdeveloped junctional zone, and increased apoptosis. l-GLA or racemic-GLA exposure impaired placental putrescine metabolism by downregulating arginase 1 (<i>Arg1</i>) and upregulating amine oxidase copper containing 1 (<i>Aoc1</i>) and monoamine oxidase A (<i>Maoa</i>) gene expression, resulted in reduced putrescine concentrations. Furthermore, impaired pyruvate metabolism, likely from 4-hydroxy-2-oxoglutarate aldolase 1 (<i>Hoga1</i>) downregulation, depleted pyruvate and increased lactate in the placenta. In human placental trophoblast cells, putrescine or pyruvate supplementation rescued impaired celluar migration and invasion caused by l-GLA or racemic-GLA. These results indicate that environmentally relevant doses of l-GLA/racemic-GLA impair trophoblast function via putrescine/pyruvate-mediated metabolic reprogramming, leading to placental dysfunction and FGR. These findings challenge the presumed safety of l-GLA as a racemic-GLA alternative.