Inhibition by lead of production and secretion of transthyretin in the choroid plexus: its relation to thyroxine transport at blood-CSF barrier.
Long-term, low-dose Pb exposure in rats is associated with a significant decrease in transthyretin (TTR) concentrations in the CSF. Since CSF TTR, a primary carrier of thyroxine in brain, is produced and secreted by the choroid plexus, in vitro studies were conducted to test whether Pb exposure interferes with TTR production and/or secretion by the choroid plexus, leading to an impaired thyroxine transport at the blood-CSF barrier. Newly synthesized TTR molecules in the cultured choroidal epithelial cells were pulse-labeled with [35S]methionine. [35S]TTR in the cell lysates and culture media was immunoprecipitated and separated by SDS-PAGE, and quantitated by autoradiography and liquid scintillation counting. Pb treatment did not significantly alter the protein concentrations in the culture, but inhibited the synthesis of total [35S]TTR (cells + media), particularly during the later chase phase. Two-way ANOVA of the chase phase revealed that Pb exposure (30 microM) significantly suppressed the rate of secretion of [35S]TTR compared to the controls (p < 0.05). Accordingly, Pb treatment caused a retention of [35S]TTR by the cells. In a two-chamber transport system with a monolayer of epithelial barrier, Pb exposure (30 microM) reduced the initial release rate constant (kr) of [125I]T4 from the cell monolayer to the culture media and impeded the transepithelial transport of [125I]T4 from the basal to apical side of epithelial cells by 27%. Taken together, these in vitro data suggest that sequestration of Pb in the choroid plexus hinders the production and secretion of TTR by this tissue. Consequently, this may alter the transport of thyroxine across this blood-CSF barrier.
School of Public Health, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. wz18@columbia.edu
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D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D011228:Prealbumin / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013974:Thyroxine / Q000134:cerebrospinal fluid / Q000378:metabolism*
D011228:Prealbumin; D007854:Lead; D013974:Thyroxine