Preimplantation factor negates embryo toxicity and promotes embryo development in culture

Abstract

Preimplantation factor (PIF) is secreted by viable mammalian embryos and promotes implantation and trophoblast invasion. Whether PIF also has a direct protective or promoting effect on the developing embryo in culture is unknown. This study examined the protective effects of synthetic PIF (sPIF) on embryos cultured with embryo toxic serum (ETS) from recurrent pregnancy loss patients ( n = 14), by morphological criteria at 72 h of culture, and determined sPIF-promoting effect on singly cultured bovine IVF embryo development. sPIF negated the ETS-induced effect by increasing mouse blastocyst rate versus other embryonic stages (odds ratio (OR) 2.01, 95% confidence intervals (CI) 1.14–3.55, chi-squared = 12.74, P = 0.002), increased blastocyst rate (39.0% versus 23.7% ETS alone) and lowered embryo demise rate (11.0% versus 28.8%, OR 0.24, 95% CI 0.11–0.54), which was not replicated by scrambled PIF or the control. sPIF added to bovine embryos for 3 days promoted development at day 7 of culture (11% versus 0%, chi-squared = 4.0, P = 0.045). In conclusion, sPIF prevented embryo demise caused by exposure to ETS and promoted development of singly cultured bovine IVF embryos following short-term exposure. sPIF-based therapy for reducing recurrent pregnancy loss and improving lagging cultured IVF embryo development should be explored. Preimplantation factor (PIF) is a novel peptide, secreted by the embryo at the 2-cell stage. It is present throughout viable pregnancy but absent in non-viable pregnancy. PIF has essential immune-modulatory, acceptance and maintenance effects on the maternal system for embryo implantation, creating the necessary environment in the uterus and helping better embedding of the placenta. Herein we investigate in two complementary models whether PIF can help embryos survive under adverse conditions, protect against recurrent pregnancy loss and promote lagging embryo development. PIF’s synthetic analogue (sPIF) is available at suitable purity for human use and its use is proposed in physiological range doses. sPIF administration strongly suggested a targeted and safe treatment regimen, successfully negating the toxicity present in the blood (serum) of patients suffering from recurrent miscarriages in the relevant pooled mouse embryo model used. sPIF showed an equally important beneficial effect to prevent suboptimally developed embryo demise and improve their development. In a (single bovine) IVF model, highly relevant for low-responder human embryos that produce low-quality but viable embryos, sPIF increased embryo survival under adverse conditions. To document sPIF’s specific effect, an inactive, same-composition (scrambled) protein was tested, which showed no effect. To evidence sPIF’s safety and unique needs-based action, high concentrations added to optimally cultured embryos equally showed no effect. We conclude that sPIF administration may specifically reduce cases of repeat miscarriage and improve viable but suboptimal embryo survival. These added observations help complete PIF’s overall crucial function in accommodating and facilitating successful pregnancy.