title: The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the development and function of the blood-brain barrier.
abstract: Prenatal exposure to environmental chemicals such as dioxins is known to have adverse effects on the developing central nervous system (CNS) in mammals. Because the fetal blood-brain barrier (BBB) is immature, dioxins are thought to exert their toxic effects on the CNS by crossing the BBB and acting on neural cells directly. However, little is known whether dioxins alter the BBB. In this study, to investigate the effects of dioxins on BBB function, we exposed an in vitro BBB system comprising rat endothelial cells, astrocytes, and pericytes to the toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) either before or after BBB formation. We assessed BBB permeability and the function of tight junctions by measuring transendothelial electric resistance (TEER) values following exposure. Subsequently, total RNA and proteins were obtained from the cells for analysis. TEER values following TCDD exposure before but not after BBB formation were lower than those of the control group. We also observed that the expression of the tight junction proteins ZO-1 and claudin-5 was suppressed following TCDD exposure. To examine the cause of this reduction in protein levels, we performed a real-time quantitative polymerase chain reaction assay and observed low expression of the glial cell line-derived neurotrophic factor (GDNF) mRNA in the exposed groups. Moreover, to rescue the effects of TCDD, we applied extrinsic GDNF with TCDD. The several disruptions caused by TCDD were rescued by the GDNF addition. Our findings suggest that exposure to TCDD during BBB formation disrupts and impairs BBB function in part by the suppression of GDNF action, which may contribute to the adverse effects of TCDD on the fetal CNS.
authors.affiliation: Department of Public Health, Faculty of Life Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: miya@gunma-u.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Miyazaki
authors.affiliation: Department of Public Health, Faculty of Life Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Public Health, Faculty of Life Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Katoh
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D062507:Claudin-5 / Q000096:biosynthesis; D018920:Coculture Techniques; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics; D017097:Electric Impedance; D042783:Endothelial Cells / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D066298:In Vitro Techniques; D008954:Models, Biological; D020286:Pericytes / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis
chemical_list: D062507:Claudin-5; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D062826:Zonula Occludens-1 Protein; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1
keywords: Blood–brain barrier; Brain development; Dioxins; Glial cell line-derived neurotrophic factor