PreImplantation factor (PIF) protects cultured embryos against oxidative stress: relevance for recurrent pregnancy loss (RPL) therapy

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.

Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response

“…As trophoblast differentiate into an endovascular phenotype a4 integrin is up-regulated [33] and up-regulation of integrins by PIF during throphoblast invasion was reported previously [15, 18]. Thus, current and previous data support the use of synthetic PIF in early recurrent pregnancy loss [20, 23, 41] and studies are in preparation.…”

Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract

“…During in vitro bovine embryo production, exposure of maturing oocytes to nitric oxide, LPS, or TNFα generally does not affect fertilization (cleavage) but either reduces development to blastocyst stage or results in increased blastocyst apoptosis (reviewed in Gilbert, 2011). Similarly, maturation of oocytes in an environment of oxidative stress did not influence cleavage but reduced development to blastocyst stage (Goodale et al, 2017). Given that these in vitro studies necessarily use rather extreme conditions, it is plausible that naturally occurring, inflammation-associated insults could result in more subtle damage evident even later in development.…”

Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity

“…In addition, PIF negated oxidative stress of cultured bovine IVF embryos induced by a protein-di-sulphide isomerase inhibitor. In presence of PIF more than two-fold increase in embryos reaching the blastocyst stage was noted [76, 77]. …”