title: Prolonged endoplasmic reticulum stress alters placental morphology and causes low birth weight.
abstract: The role of endoplasmic reticulum (ER) stress in pregnancy remains largely unknown. Pregnant mice were subcutaneously administered tunicamycin (Tun), an ER stressor, as a single dose [0, 50, and 100 μg Tun/kg/body weight (BW)] on gestation days (GDs) 8.5, 12.5, and 15.5. A high incidence (75%) of preterm delivery was observed only in the group treated with Tun 100 μg/kg BW at GD 15.5, indicating that pregnant mice during late gestation are more susceptible to ER stress on preterm delivery. We further examined whether prolonged in utero exposure to ER stress affects fetal development. Pregnant mice were subcutaneously administered a dose of 0, 20, 40, and 60 μg Tun/kg from GD 12.5 to 16.5. Tun treatment decreased the placental and fetal weights in a dose-dependent manner. Histological evaluation showed the formation of a cluster of spongiotrophoblast cells in the labyrinth zone of the placenta of Tun-treated mice. The glycogen content of the fetal liver and placenta from Tun-treated mice was lower than that from control mice. Tun treatment decreased mRNA expression of Slc2a1/glucose transporter 1 (GLUT1), which is a major transporter for glucose, but increased placental mRNA levels of Slc2a3/GLUT3. Moreover, maternal exposure to Tun resulted in a decrease in vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, and placental growth factor. These results suggest that excessive and exogenous ER stress may induce functional abnormalities in the placenta, at least in part, with altered GLUT and vascular-related gene expression, resulting in low infant birth weight.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima City 770-8514, Japan. Electronic address: tkawakami@ph.bunri-u.ac.jp.
authors.forename: Takashige
authors.initials: T
authors.lastname: Kawakami
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima City 770-8514, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yoshimi
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima City 770-8514, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kadota
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima City 770-8514, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima City 770-8514, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Sato
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima City 770-8514, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D011247:Pregnancy; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000503:physiopathology; D020567:Fetal Weight / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D018811:Maternal Exposure; D008813:Mice, Inbred ICR; D010920:Placenta / Q000187:drug effects / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000008:administration & dosage / Q000009:adverse effects; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D000831:Animals, Newborn
chemical_list: C497250:Ddit3 protein, mouse; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495689:Slc2a3 protein, mouse; D051742:Transcription Factor CHOP; D014415:Tunicamycin; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Endoplasmic reticulum stress; Glucose transporter; IUGR; Placenta; Preterm birth; Tunicamycin