Implantation failures and exposure to glyphosate or a commercial formulation: hormonal and uterine dysfunction during the pre-implantation period as possible mechanisms.

LORENZ V; LUQUE EH; CADAVIZ FERNÁNDEZ DB; VARAYOUD J.; PACINI G; GASTIAZORO MP; MILESI MM

Simposio; International Federation of Placenta Associations 2019 (IFPA2019) - 8th Latin American Symposium on Maternal-Fetal Interaction and Placenta (VIII SLIMP).; 2019

Glyphosate is the active ingredient of broad-spectrum glyphosate-based herbicides (GBHs). Evidence regarding the toxicity of GBHs vs. glyphosate alone (Gly) is conflicted. Previously, we have showed that perinatal exposure to either Gly or a GBH caused subfertility in female rats associated with a decrease in the number of implanted embryos. In the present work, we investigated whether alterations in the hormonal milieu and/or in the uterine functional differentiation during the pre-implantation period might be related with the implantation failures detected. Pregnant rats (F0) were orally exposed to Gly or a GBH through food, in a dose of 2 mg of glyphosate/kg/day (RfD, EPA), from gestational day (GD) 9 until weaning. Sexually mature F1 females were pregnant and sacrificed on GD5 (pre-implantation period) to assess: i) the serum levels of steroid hormones, 17β-estradiol (E2) by RIA and progesterone (P4) by ELISA; and ii) in uterine biopsies, the morphological features (luminal epithelial height, number of glands, and thickness of myometrium and subephitelial stroma), the protein expression of steroid receptors (estrogen receptor alpha (ERα) and progesterone receptor (PR)) by IHQ, and the expression of implantation-associated genes (MUC1, LIF, Hoxa10, Cox-2, Areg) by RT-qPCR. Exposure to GBH and Gly increased the serum levels of E2 (Control: 21.4 ± 2.6 pg/ml; Gly: 30.4 ± 0.6 pg/ml; GBH: 30.4 ± 0.9 pg/ml) at the pre-implantation period. Regarding morphological features, lower numbers of uterine glands were detected in Gly- and GBH-exposed rats. ERα expression was increased in the stromal and glandular compartment by GBH and Gly, respectively, without changes in PR expression. A downregulation of LIF, Hoxa10 and Cox-2 genes was found in both Gly- and GBH groups. In conclusion, perinatal exposure to Gly or GBH induced hormonal and uterine morphological and molecular alterations during the pre-implantation period, which might explain, at least in part, the implantation failures triggered by Gly and GBH exposure.