Abstract
Recurrent pregnancy loss (RPL) affects 2-3% of couples. Despite a detailed work-up, the etiology is frequently undefined, leading to non-targeted therapy. Viable embryos and placentae express PreImplantation Factor (PIF). Maternal circulating PIF regulates systemic immunity and reduces circulating natural killer cells cytotoxicity in RPL patients. PIF promotes singly cultured embryos’ development while anti-PIF antibody abrogates it. RPL serum induced embryo toxicity is negated by PIF. We report that PIF rescues delayed embryo development caused by <3 kDa RPL serum fraction likely by reducing reactive oxygen species (ROS). We reveal that protein disulfide isomerase/thioredoxin (PDI/TRX) is a prime PIF target in the embryo, rendering it an important ROS scavenger. The 16F16-PDI/TRX inhibitor drastically reduced blastocyst development while exogenous PIF increased >2 fold the number of embryos reaching the blastocyst stage. Mechanistically, PDI-inhibitor preferentially binds covalently to oxidized PDI over its reduced form where PIF avidly binds. PIF by targeting PDI/TRX at a distinct site limits the inhibitor’s pro-oxidative effects. The >3kDa RPL serum increased embryo demise by three-fold, an effect negated by PIF. However, embryo toxicity was not associated with the presence of putative anti-PIF antibodies. Collectively, PIF protects cultured embryos both against ROS, and higher molecular weight toxins. Using PIF for optimizing in vitro fertilization embryos development and reducing RPL is warranted.
Highlights
In order to effectively develop in culture, embryos depend on autocrine factors [1, 2]
PreImplantation Factor (PIF) acts as a rescue factor, negating embryo toxicity induced by fractioned Recurrent pregnancy loss (RPL) serum
We previously showed that PIF protects against embryo toxicity by negating the 5% unfractionated RPL sera
Summary
In order to effectively develop in culture, embryos depend on autocrine factors [1, 2]. Embryos are highly vulnerable to reactive oxygen species (ROS) and multiple attempts have been utilized to reduce such vulnerability [3, 4]. Identification of an endogenous compound that would bind specific targets within the embryo to reduce ROS or other toxicity could be of great benefit. There are ongoing concerns that culturing multiple embryos for a prolonged period can lead to epigenetic adverse effects [5-8]. Cases in point are rare imprinting disorders such as Angelman syndrome, Beckwith-Wiedemann syndrome and retinoblastoma in children who are conceived with the use of in vitro fertilization (IVF) [9]. Prolonged embryo cultures can lead to premature delivery [10]
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