Neonatal exposure of ewe lambs to a glyphosate-based herbicide alters the expression of proteins involved in uterine development and differentiation

RIVERA OE; MUÑOZ-DE-TORO M; MILESI MM; BELMONTE N; ALARCÓN R; DIOGUARDI G; LUQUE EH

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica, LXIV Reunión de la Sociedad Argentina de Inmunología y XLVIII Reunión de la Sociedad Argentina de Farmacología Experimental; 2016

Sociedad Argentina de Investigación Clínica, Sociedad Argentina de Inmunología y Sociedad Argentina de Fisiología Experimental

Glyphosate-based herbicides (GBH) are one of the most employed agrochemicals around the world. Recently, we showed that, in the rat, developmental exposure to a GBH alters uterine organogenetic differentiation showing hyperplasia in prepubertal samples and inducing post-implantation embryo loss. No reports are available regarding GBH effects on the reproductive system of the ewe lamb. This study investigates the effects of a brief postnatal exposure to a GBH on the morphology and differentiation of the prepubertal sheep uterus. Ewe lambs (Frizone breed) were sc injected from postnatal day 1 (PND1) to PND14 with saline solution (vehicle) or 2 mg/Kg/day of a GBH. On PND45 ewe lambs were hysterectomized and uterine samples were paraffin-embedded. In trichrome stained sections morphological parameters were evaluated: luminal epithelial height, glandular density, thickness of the subepithelial stroma and myometrium. Immunohistochemistry was performed to quantify the uterine expression of Ki-67 (cellular proliferation marker) and proteins involved in uterine development and differentiation: estrogen receptor α (ERα), progesterone receptor (PR), Wnt7a and β-catenin. GBH treatment did not alter uterine morphology, but reduced the proliferation rate in the subepithelial stroma, and in the luminal and glandular epithelium. The decrease in cell proliferation was associated with a downregulation of ERα expression in the same compartments. PR expression was increased in the glandular epithelium and in the subepithelial stroma, and downregulated in the luminal epithelium. GBH group also showed a decrease in Wnt7a expression in the subepithelial stroma and a downregulation in β-catenin expression in the luminal and glandular epithelium. Exposure to a low dose of a GBH during early postnatal development decreased uterine proliferation and disrupted the expression of morphoregulatory proteins in prepubertal sheep. All these alterations might impair female fertility at adulthood.