Excessive estrogenic environment during preimplantation disrupts embryo transport and development and differentially alters the transcriptomes of mouse oviduct and uterus

Objective: Exposure to estrogenic endocrine-disrupting chemicals (EEDCs) has been associated with oviductal embryo retention, also called the tube-locking effect, which heightens the risk of infertility and ectopic pregnancy. Here we used preimplantation 17β-estradiol (E 2 ) exposure as a model to investigate the mechanisms underlying the EEDC-induced tube-locking effect. Methods: Pregnant mice were subcutaneously treated with 0, 0.1, 1, or 10 µg/kg E 2 daily from day 0.5 post-coitum (D0.5) to D2.5. Their oviducts and uteri were analyzed on D3.5 using embryo flushing, histology, microarray, and real-time PCR. Results: Preimplantation E 2 treatment caused dose-dependent oviductal embryo retention and developmental delay. Transcriptomic profiling identified 33 upregulated and 24 downregulated oviductal differentially expressed genes (DEGs)/probesets and 1115 upregulated and 1004 downregulated uterine DEGs/probesets following treatment with 10 µg/kg/day E 2 (fold change >1.5 and q-value <5%). Gene Ontology (GO) analysis revealed E 2 -induced upregulation of the immune response in the oviduct and uterus, whereas ion transport was downregulated in the oviduct but upregulated in the uterus. E 2 -downregulated oviductal DEGs were also found to be involved in metabolism, nutrient transport, and muscle-related functions. Selected oviductal and uterine co-DEGs were confirmed by real-time PCR. Their dose-response patterns following preimplantation E 2 treatment were opposite to their temporal expression patterns in the uterus during preimplantation, but such opposing patterns were less consistent in the oviduct. Conclusions: The oviduct shows limited transcriptional responsiveness but marked functional susceptibility to an excessively estrogenic environment during early pregnancy. E 2 -responsive oviductal DEGs implicate dysregulation of immune homeostasis, fluid and nutrient transport, and muscle-related functions as potential contributors to the tube-locking effect associated with excessive EEDC exposure and the related risks of infertility and ectopic pregnancy.