title: Rapamycin ameliorates chitosan nanoparticle-induced developmental defects of preimplantation embryos in mice.
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.
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Sangiliyandi
authors.initials: S
authors.lastname: Gurunathan
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: DaSom
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pathology, Hanyang University Medical Center, Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: Hyung Seok
authors.initials: HS
authors.lastname: Jang
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Park
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Ssang-Goo
authors.initials: SG
authors.lastname: Cho
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Chankyu
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Hyuk
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
authors.affiliation: Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Center (SRC), Konkuk University, Seoul, Republic of Korea.
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001755:Blastocyst / Q000187:drug effects* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D048271:Chitosan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D047108:Embryonic Development / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D053758:Nanoparticles; D006080:Ovarian Follicle / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D037761:Sirtuins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D017382:Reactive Oxygen Species; D048271:Chitosan; D058570:TOR Serine-Threonine Kinases; D037761:Sirtuins; D002118:Calcium; D020123:Sirolimus
keywords: ER stress; autophagy; chitosan nanoparticles; preimplantation; rapamycin