Rapamycin ameliorates chitosan nanoparticle-induced developmental defects of preimplantation embryos in mice

// Yun-Jung Choi 1 , Sangiliyandi Gurunathan 1 , DaSom Kim 1 , Hyung Seok Jang 2 , Woo-Jin Park 1 , Ssang-Goo Cho 1 , Chankyu Park 1 , Hyuk Song 1 , Han Geuk Seo 1 and Jin-Hoi Kim 1 1 Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic Korea 2 Department of Pathology, Hanyang University Medical Center, Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea Correspondence to: Jin-Hoi Kim, email: // Keywords : chitosan nanoparticles, Rapamycin, preimplantation, autophagy, ER stress Received : June 13, 2016 Accepted : July 14, 2016 Published : July 24, 2016 Abstract Chitosan nanoparticles (CSNPs) are used as drug or gene delivery vehicles. However, a detailed understanding of the effects of CSNPs on embryonic development remains obscure. Here, we show that CSNPs can be internalized into mouse blastocysts, such as the zona pellucida, the perivitelline space, and the cytoplasm. Consequently, CSNPs-induced endoplasmic reticulum (ER) stress increases both of Bip/Grp78, Chop, Atf4, Perk, and Ire1a mRNAs expression levels, and reactive oxygen species. Moreover, CSNPs show double- and multi-membraned autophagic vesicles, and lead to cell death of blastocoels. Conversely, treatment with rapamycin, which plays an important role as a central regulator of cellular proliferation and stress responses, decreased CSNPs-induced mitochondrial Ca +2 overloading, apoptosis, oxidative stress, ER stress, and autophagy. In vivo studies demonstrated that CSNPs injection has significant toxic effect on primordial and developing follicles. Notably, rapamycin rescued oxidative stress-induced embryonic defects via modulating gene expression of sirtuin and mammalian target of rapamycin. Interestingly, CSNPs treatment alters epigenetic reprogramming in mouse embryos. Overall , these observations suggest that rapamycin treatment could ameliorate CSNPs-induced developmental defects in preimplantation embryos. The data from this study would facilitate to understand the toxicity of these CSNPs, and enable the engineering of safer nanomaterials for therapeutic applications.