title: Stress-induced stimulation of choline transport in cultured choroid plexus epithelium exposed to low concentrations of cadmium.
abstract: The choroid plexus epithelium forms the blood-cerebrospinal fluid barrier and accumulates essential minerals and heavy metals. Choroid plexus is cited as being a "sink" for heavy metals and excess minerals, serving to minimize accumulation of these potentially toxic agents in the brain. An understanding of how low doses of contaminant metals might alter transport of other solutes in the choroid plexus is limited. Using primary cultures of epithelial cells isolated from neonatal rat choroid plexus, our objective was to characterize modulation of apical uptake of the model organic cation choline elicited by low concentrations of the contaminant metal cadmium (CdCl₂). At 50-1,000 nM, cadmium did not directly decrease or increase 30-min apical uptake of 10 μM [(3)H]choline. However, extended exposure to 250-500 nM cadmium increased [(3)H]choline uptake by as much as 75% without marked cytotoxicity. In addition, cadmium induced heat shock protein 70 and heme oxygenase-1 protein expression and markedly induced metallothionein gene expression. The antioxidant N-acetylcysteine attenuated stimulation of choline uptake and induction of stress proteins. Conversely, an inhibitor of glutathione synthesis l-buthionine-sulfoximine (BSO) enhanced stimulation of choline uptake and induction of stress proteins. Cadmium also activated ERK1/2 MAP kinase. The MEK1 inhibitor PD98059 diminished ERK1/2 activation and attenuated stimulation of choline uptake. Furthermore, inhibition of ERK1/2 activation abated stimulation of choline uptake in cells exposed to cadmium with BSO. These data indicate that in the choroid plexus, exposure to low concentrations of cadmium may induce oxidative stress and consequently stimulate apical choline transport through activation of ERK1/2 MAP kinase.
authors.affiliation: University of Rochester, Rochester, New York; and.
authors.forename: Robin K
authors.initials: RK
authors.lastname: Young
authors.forename: Alice R A
authors.initials: AR
authors.lastname: Villalobos
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000502:physiology; D002104:Cadmium / Q000008:administration & dosage / Q000633:toxicity*; D002794:Choline / Q000378:metabolism*; D002831:Choroid Plexus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D004848:Epithelium; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects*
chemical_list: D002104:Cadmium; D048049:Extracellular Signal-Regulated MAP Kinases; D002794:Choline
keywords: blood-cerebrospinal fluid barrier; cadmium; choline transport; choroid plexus; oxidative stress