Effects of Endocrine-Disrupting Chemicals on Endometrial Receptivity and Embryo Implantation: A Systematic Review of 34 Mouse Model Studies

Abstract

Several available studies have already analyzed the systemic effects of endocrine-disrupting chemicals (EDCs) on fertile woman and neonatal outcomes, but little is still known in humans about the precise mechanisms of interference of these compounds with the endometrial receptivity. There is consistent evidence that continuous and prolonged exposure to EDCs is a risk factor for reduced fertility and fecundity in women. Preliminary studies on mammalian models provide robust evidence about this issue and could help gynecologists worldwide to prevent long term injury caused by EDCs on human fertility. In this systematic review, we aimed to systematically summarize all available data about EDC effects on blastocyst endometrial implantation. We performed a systematic review using PubMed^®/MEDLINE^® to summarize all in vivo studies, carried out on mice models, analyzing the molecular consequences of the prolonged exposure of EDC on the implantation process. 34 studies carried out on mouse models were included. Primary effects of EDC were a reduction of the number of implantation sites and pregnancy rates, particularly after BPA and phthalate exposure. Furthermore, the endometrial expression of estrogen (ER) and progesterone receptors (PR), as well as their activation pathways, is compromised after EDC exposure. Finally, the expression of the primary endometrial markers of receptivity (such as MUC1, HOXA10, Inn and E-cadherin) after EDC contact was analyzed. In conclusion EDC deeply affect blastocyst implantation in mouse model. Several players of the implantation mechanism are strongly influenced by the exposure to different categories of EDC.

Keywords: endocrine disrupting chemicals; environmental pollutants; implantation failure; infertility; phthalate; post-implantation loss.

Figure 1

Environmental distribution of endocrine-disruptor chemicals (EDCs).

Figure 2

PRISMA flow chart. 381 records were excluded after title and abstract screening because, basing on inclusion and exclusion criteria, they were not pertinent with the searched studies.

Figure 3

Association between EDC and embryo implantation. BPA: bisphenol A; PR: progesterone; E: estrogen; PRa/b: progesterone receptor; ERa/ERb: estrogen receptors: EP: epithelial cell (luminal and glandular epithelia); HOXA10: homeobox 10; Hand2: heart- and neural crest derivatives-expressed protein 2; LIF: leukemia inhibitory factor; LIFR: LIF receptor; DEHP: di-(2-ethylhexyl)-phthalate; VEGF: vascular endothelial growth factor; MUC1: mucin1; DEHP: di-(2-ethylhexyl) phthalate; PCB: 2,30,4,40,5-pentachlorobiphenyl; Cd: cadmium; ITGB3: integrin subunit beta 3; EMX-2: empty spiracles homeobox 2; OP: 4-tert-octylphenol; BaP: benzo(a)pyrene; CYP: cypermethrin; CP: β-cypermethrin; p-ERK: phosphorylation extracellular signal-related kinase NF-KB: nuclear factor-KB; NCOR1: nuclear receptor corepressor 1; ESR1: estrogen receptor 1.