ALTERED UTERINE MECHANISTIC PATHWAYS IN RATS ASSOCIATED WITH IMPLANTATION FAILURE AF- TER PERINATAL EXPOSURE TO GLYPHOSATE OR A COMMERCIAL FORMULATION

ALMIRÓN, A; LORENZ, V; VARAYOUD, J; DURANDO, M.; MILESI, MM

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAL 2023; 2023

Embryo implantation requires close communication between the blastocyst and a receptive uterus. The uterus is a target organ for sex steroid hormones and is consequently vulnerable to chemicals with endocrine-disrupting properties, such as glyphosate herbi-cide. In female rats, we showed that perinatal exposure to a gly-phosate-based herbicide (GBH) or its active ingredient, glyphosate (Gly), causes subfertility by increasing the rate of preimplantation embryo losses. This study aims to explore the mechanisms of action of GBH and Gly, analyzing key endocrine pathways for endometrial receptivity. Pregnant Wistar rats (F0) were treated orally with GBH or Gly (2 mg of Gly/kg/day) from gestational day (GD) 9 until weaning. Sexually mature F1 females became pregnant and uterine samples were collected on GD5 (preimplantation period). Hematoxylin-eosin uterine sections were assessed for morphological parameters: lu-minal epithelial height, glandular density, and subepithelial stroma (SS) and myometrial thickness. Moreover, protein expression levels of Ki-67, a proliferation marker, the cell cycle regulators PTEN, cy-clin G1, p27, and IGF1Rα, and estrogen receptors (ERα and ERβ) involved in controlling proliferation, were evaluated by immunohis-tochemistry. Glandular differentiation markers, such as FOXA2, β-catenin, and Wnt5a, were also assessed. GBH and Gly reduced uterine glandular density, associated with decreased expression of FOXA2, Wnt5a, and β-catenin in glands. Both GBH and Gly groups showed increased proliferation in the SS. In this compartment, GBH rats showed an increase in ERα and ERβ expression, while Gly rats exhibited an increase in PTEN and cyclin G1 expression. In conclu-sion, perinatal exposure to GBH and Gly disrupts SS proliferation and glandular differentiation, which are crucial processes for proper endometrial receptivity. These alterations might explain the implan-tation failures observed in GBH- and Gly-exposed rats.