title: Nrf2 signalling and autophagy are involved in diabetes mellitus-induced defects in the development of mouse placenta.
abstract: It is widely accepted that diabetes mellitus impairs placental development, but the mechanism by which the disease operates to impair development remains controversial. In this study, we demonstrated that pregestational diabetes mellitus (PGDM)-induced defects in placental development in mice are mainly characterized by the changes of morphological structure of placenta. The alteration of differentiation-related gene expressions in trophoblast cells rather than cell proliferation/apoptosis is responsible for the phenotypes found in mouse placenta. Meanwhile, excess reactive oxygen species (ROS) production and activated nuclear factor erythroid2-related factor 2 (Nrf2) signalling were observed in the placenta of mice suffering from PGDM. Using BeWo cells, we also demonstrated that excess ROS was produced and Nrf2 signalling molecules were activated in settings characterized by a high concentration of glucose. More interestingly, differentiation-related gene expressions in trophoblast cells were altered when endogenous Nrf2 expression is manipulated by transfecting Nrf2-wt or Nrf2-shRNA. In addition, PGDM interferes with autophagy in both mouse placenta and BeWo cells, implying that autophagy is also involved, directly or indirectly, in PGDM-induced placental phenotypes. Therefore, we revealed that dysfunctional oxidative stress-activated Nrf2 signalling and autophagy are probably responsible for PGDM-induced defects in the placental development of mice. The mechanism was through the interference with differentiation-related gene expression in trophoblast cells.
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: Mei-Yao
authors.identifier: 0000-0002-2168-3133
authors.initials: MY
authors.lastname: He
authors.affiliation: Division of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632, People's Republic of China Postdoctoral Research Station of Chinese and Western Integrative Medicine, Institute of Integrated Traditional Chinese and Western, Medical College, Jinan University, Guangzhou 510630, People's Republic of China.
authors.forename: Guang
authors.identifier: 0000-0001-7595-2880
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Han
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Division of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: Zheng-Lai
authors.initials: ZL
authors.lastname: Ma
authors.affiliation: Division of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Tang
authors.affiliation: Division of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou 510632, People's Republic of China yang_xuesong@126.com.
authors.forename: Xuesong
authors.identifier: 0000-0002-2537-5752
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou 510632, People's Republic of China tlgs@jnu.edu.cn.
authors.forename: Guo-Sheng
authors.identifier: 0000-0001-7899-6125
authors.initials: GS
authors.lastname: Liu
mesh_terms: D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D002460:Cell Line; D048909:Diabetes Complications / Q000196:embryology* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010920:Placenta / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology / Q000473:pathology
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species
keywords: Nrf2; ROS; autophagy; placenta; pregestational diabetes mellitus; trophoblast cell