Research Papers: Autophagy and Cell Death:

This article has been corrected. Correction in: Oncotarget. 2018; 9:37344.

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

Lindsay F. Goodale, Soren Hayrabedyan, Krassimira Todorova, Roumen Roussev, Sivakumar Ramu, Christopher Stamatkin, Carolyn B. Coulam, Eytan R. Barnea _ and Robert O. Gilbert

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Oncotarget. 2017; 8:32419-32432. https://doi.org/10.18632/oncotarget.16028

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Lindsay F. Goodale1,6, Soren Hayrabedyan2, Krassimira Todorova2, Roumen Roussev3, Sivakumar Ramu3,8, Christopher Stamatkin3,9, Carolyn B. Coulam3, Eytan R. Barnea4,5,* and Robert O. Gilbert1,7,*

1 Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

2 Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria

3 CARI Reproductive Institute, Chicago, IL, USA

4 BioIncept, LLC, Cherry Hill, NJ, USA

5 Society for the Investigation of Early Pregnancy (SIEP), Cherry Hill, NJ, USA

6 Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA

7 Ross University School of Veterinary Medicine, Basseterre, St. Kitts, West Indies

8 Promigen Life Sciences, Downers Grove, IL, USA

9 Therapeutic Validation Core, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

* These authors have contributed equally to this work

Correspondence to:

Eytan R. Barnea, email:

Keywords: recurrent pregnancy loss, preImplantation factor (PIF), oxidative stress, PDI, embryo, Autophagy

Received: December 05, 2016 Accepted: February 22, 2017 Published: March 08, 2017


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.

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