Altered uterine mechanistic pathways in rats associated with implantation failure after perinatal exposure to glyphosate or a commercial formulation

ALMIRÓN, AILÍN; LORENZ, VIRGINIA; VARAYOUD, JORGELINA; DURANDO, MILENA; MILESI, MARÍA MERCEDES

Mar del Plata

Congreso; Reunión de Sociedades de Biociencias - LXVIII Reunión Anual de la Sociedad Argentina de Investigación en Clínica (SAIC); 2023

Sociedades SAIC, SAB, AAFE & AACYTAL

Embryo implantation requires close communication between theblastocyst and a receptive uterus. The uterus is a target organ forsex steroid hormones and is consequently vulnerable to chemicalswith endocrine-disrupting properties, such as glyphosate herbicide.In female rats, we showed that perinatal exposure to a glyphosate-based herbicide (GBH) or its active ingredient, glyphosate(Gly), causes subfertility by increasing the rate of preimplantationembryo losses. This study aims to explore the mechanisms of actionof GBH and Gly, analyzing key endocrine pathways for endometrialreceptivity. Pregnant Wistar rats (F0) were treated orally with GBH orGly (2 mg of Gly/kg/day) from gestational day (GD) 9 until weaning.Sexually mature F1 females became pregnant and uterine sampleswere collected on GD5 (preimplantation period). Hematoxylin-eosinuterine sections were assessed for morphological parameters: luminalepithelial height, glandular density, and subepithelial stroma(SS) and myometrial thickness. Moreover, protein expression levelsof Ki-67, a proliferation marker, the cell cycle regulators PTEN, cyclinG1, p27, and IGF1Rα, and estrogen receptors (ERα and ERβ)involved in controlling proliferation, were evaluated by immunohistochemistry.Glandular differentiation markers, such as FOXA2,β-catenin, and Wnt5a, were also assessed. GBH and Gly reduceduterine glandular density, associated with decreased expression ofFOXA2, Wnt5a, and β-catenin in glands. Both GBH and Gly groupsshowed increased proliferation in the SS. In this compartment, GBHrats showed an increase in ERα and ERβ expression, while Gly ratsexhibited an increase in PTEN and cyclin G1 expression. In conclusion,perinatal exposure to GBH and Gly disrupts SS proliferationand glandular differentiation, which are crucial processes for properendometrial receptivity. These alterations might explain the implantationfailures observed in GBH- and Gly-exposed rats.