CONICET | Buscador de Institutos y Recursos Humanos

Glyphosate based herbicides (GBH) are one of the most extensively used pesticides in agriculture all over the world. Recently, we showed that in rats a brief exposure to a low dose of GBH during the first week of life alters uterine development, induces epithelial hyperplasia and causes post-implantation embryo loss. Present study investigates whether a brief postnatal exposure to a low dose of GBH using two different administration routes alters the uterine differentiation of prepubertal ewe lamb. Ewe lambs (Frisone breed) were sc or orally exposed from postnatal day 1 (PND1) to PND14 to saline solution (vehicle) or a low dose of a GBH (glyphosate at 2 mg/Kg/day). At PND45, uterine horns were collected for paraffin-embedding or stored at -80°C until mRNA extraction. Cell proliferation was assessed in all uterine compartments by quantifying the expression of Ki-67 protein using immunohistochemistry. RT-PCR was performed to evaluate the expression of genes related with uterine development and differentiation, such as: steroid receptors (ESR1, ESR2 and PR) and insulin-like growth factors (IGF-1, IGF-2 and its receptor IGF-1R). GBH treatment decreased the rate of proliferation in the luminal epithelium (scGBH 6.4±0.9**, oGBH 5.7±0.7** vs C 12.4±2.0, **p<0.01); glandular epithelium (scGBH 5.0±0.7*, oGBH 4.5±0.6* vs C 11.7±2.2, *p<0.05); the subepithelial stroma (scGBH 0.9±0.1**, oGBH 1.1±0.1** vs C 1.7±0.1, **p<0.01); and in the myometrium (scGBH 0.6±0.1*, oGBH 0.5±0.1* vs C 1.5±0.3, *p<0.05). Exposure to GBH did not alter the expression of sex steroid receptors and IGF family members, thus abnormal cell proliferation could not be ascribed to deregulation of these pathways. Postnatal exposure to an environmental relevant dose of GBH disrupts the development of prepubertal sheep uterus by decreasing cell proliferation, which could compromise future reproductive performance.