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

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

Mar del Plata

Congreso; LXVIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2023

SAIC

Embryo implantation requires close communication between the blastocyst anda receptive uterus. The uterus is a target organ for sex steroid hormones and isconsequently vulnerable to chemicals with endocrine-disrupting properties, suchas glyphosate herbicide. In female rats, we showed that perinatal exposure to aglyphosate-based herbicide (GBH) or its active ingredient, glyphosate (Gly),causes subfertility by increasing the rate of preimplantation embryo losses. Thisstudy aims to explore the mechanisms of action of GBH and Gly, analyzing keyendocrine pathways for endometrial receptivity. Pregnant Wistar rats (F0) weretreated orally with GBH or Gly (2 mg of Gly/kg/day) from gestational day (GD) 9until weaning. Sexually mature F1 females became pregnant and uterinesamples were collected on GD5 (preimplantation period). Hematoxylin-eosinuterine sections were assessed for morphological parameters: luminal epithelialheight, glandular density, and subepithelial stroma (SS) and myometrialthickness. Moreover, protein expression levels of Ki-67, a proliferation marker,the cell cycle regulators PTEN, cyclin G1, p27, and IGF1Rα, and estrogenreceptors (ERα and ERβ) involved in controlling proliferation, were evaluated byimmunohistochemistry. Glandular differentiation markers, such as FOXA2, β-catenin, and Wnt5a, were also assessed. GBH and Gly reduced uterine glandulardensity, associated with decreased expression of FOXA2, Wnt5a, and β-cateninin glands. Both GBH and Gly groups showed increased proliferation in the SS. Inthis compartment, GBH rats showed an increase in ERα and ERβ expression,while Gly rats exhibited an increase in PTEN and cyclin G1 expression. Inconclusion, perinatal exposure to GBH and Gly disrupts SS proliferation andglandular differentiation, which are crucial processes for proper endometrialreceptivity. These alterations might explain the implantation failures observed inGBH- and Gly-exposed rats.