Neonatal exposure to a glyphosate-based herbicide alters uterine adenogenesis in ewe lamb

ALARCÓN R; MILESI MM; RIVERA OE; INGARAMO P; MUÑOZ-DE-TORO M; LUQUE EH

Buenos Aires

Congreso; LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2017

Sociedad Argentina de Investigación Clínica (SAIC)

Abstract: Glyphosate based herbicides (GBH) are one of the most extensivelyused pesticides in agriculture all over the world. Recently, we showed that abrief exposure to a GBH during the first week of life alters uterinedevelopment and induces epithelial hyperplasia in prepubertal rats, and causespost-implantation embryo loss at adulthood. This study investigates the effects of a brief postnatal exposure to a lowdose of GBH on the differentiation of the prepubertal ewe lamb uterus. Ewelambs (Frizone breed) were sc injected from postnatal day 1 (PND1) to PND14with saline solution (vehicle) or 2 mg/Kg/day of a GBH (reference dose fromEPA, USA). On PND45 ewe lambs were hysterectomized and uterine samples wereparaffin-embedded or stored at -80°C until mRNA extraction. Cell proliferationwas assessed in all uterine compartments by quantifying the expression of Ki-67protein through immunohistochemistry (IHQ). We also determine the uterineexpression of Forkhead box A2 (Foxa2) protein by IHQ, which is involved in theuterine gland development. RT-PCR was performed to evaluate the expression of IGFfamily genes related with the cell proliferation, i.e., insulin-like growthfactor-1 (IGF-1), IGF-2 and its receptor (IGF-1R). GBH treatment decreased theproliferation rate in the subepithelial stroma (7.7±0.9% vs C:12.2±1.5%,p<0.05) and in the luminal (7.7±1.1% vs C:16.1±1.1%, p<0.005) and glandular epithelium(10.8±0.8% vs C:20.6±2.0%, p<0.005). This alteration could not be associated with a deregulation of the IGFpathway, since no changes were detected in gene expression. Foxa2 expression,which is only detected on the glandular epithelial cells, was decreased on theGBH exposed group (2.3±0.4 vs C:3.8±0.6,p<0.05). Postnatal exposureto a low dose of a GBH disrupts the uterine development of prepubertal sheep, by decreasingcell proliferation and altering the expression of Foxa2 involved in uterine adenogenesis. Thesealterations might affect female fertility at adulthood.