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

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

Buenos Aires

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

Objectives: 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 thatperinatal exposure to either Gly or a GBH caused subfertility in female ratsassociated with a decrease in the number of implanted embryos. In thepresent work, we investigated whether alterations in the hormonal milieuand/or in the uterine functional differentiation during the pre-implantation period might be related with the implantation failures detected.Methods: Pregnant rats (F0) were orally exposed to Gly or a GBH throughfood, in a dose of 2 mg of glyphosate/kg/day (RfD, EPA), from gestationalday (GD) 9 until weaning. Sexually mature F1 females were pregnant andsacrificed on GD5 (pre-implantation period) to assess: i) the serum levelsof steroid hormones, 17b-estradiol (E2) by RIA and progesterone (P4) byELISA; and ii) in uterine biopsies, the morphological features (luminalepithelial height, number of glands, and thickness of myometrium andsubephitelial stroma), the protein expression of steroid receptors (estrogenreceptor alpha (ERa) and progesterone receptor (PR)) by IHQ, and theexpression of implantation-associated genes (MUC1, LIF, Hoxa10, Cox-2,Areg) by RT-qPCR.Results: 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 thepre-implantation period. Regarding morphological features, lowernumbers of uterine glands were detected in Gly- and GBH-exposed rats.ERa expression was increased in the stromal and glandular compartmentby GBH and Gly, respectively, without changes in PR expression. Adownregulation of LIF, Hoxa10 and Cox-2 genes was found in both Gly- andGBH groups.Conclusion: In conclusion, perinatal exposure to Gly or GBH inducedhormonal and uterine morphological and molecular alterations during thepre-implantation period, which might explain, at least in part, the implantation failures triggered by Gly and GBH exposure.