Assessing the Role of ortho-Substitution on Polychlorinated Biphenyl Binding to Transthyretin, a Thyroxine Transport Protein

Abstract

.ortho-Substituted polychlorinated biphenyls (PCBs) make up a large part of the PCB residue found in the environment and human tissues. Our laboratory as well as others have demonstrated that ortho-substituted congeners exhibit important biological activities by aryl hydrocarbon (Ah) receptor-independent mechanisms, including changes in second messenger systems necessary for normal cell function and growth. Previous structure-activity relationship (SAR) studies on second messengers and transthyretin (TTR; prealbumin) binding focused little attention on the ortho-substituted PCBs. Disruption of thyroid hormone (TH) transport is one potentially important mechanism by which PCBs can alter TH homeostasis. A more systematic study of PCB binding to TTR, a major TH transport protein, was undertaken, in which the role of ortho-substitution was more thoroughly investigated. Results from this study indicated that the ortho-only substituted series showed significant binding activity and the relative affinities were 2,2,6 > 2,2 ‫؍‬ 2,6 Ͼ Ͼ 2 ‫؍‬ 2,2,6,6. As anticipated on the basis of steric considerations, bromine was shown to be more active as an ortho-substituent where the relative affinity of 2,2-Br was equivalent to 2,2,6-Cl. The congener patterns (dimeta-substitution in one or both rings) most closely resembling the diiodophenolic ring of thyroxine (T 4 ) showed the highest binding activity. Multiple ortho-substituents were shown to decrease binding activity in such patterns. Congener patterns (single metasubstitution in one or both rings) more closely resembling the monoiodophenolic ring of T 3 showed significantly lower binding activity, consistent with the relatively low binding activity of T 3 and smaller size of chlorine compared to iodine. The addition of ortho-substitution to such patterns gave variable results depending on the substituent relationship (adjacency or nonadjacency) to the pattern. Some patterns such as 2,2,4,4,5,5 showed good binding activity and represent common congeners in the commercial Aroclor mixtures and in the environment. The binding potencies of ortho-PCBs to TTR may represent a signature SAR that predicts specific biologic/toxic effects. In this regard, the binding potencies were consistent with measured biological activities of these PCBs, including effects on cell dopamine content, Ca 2؉ homeostasis, and protein kinase C translocation in neuronal cells and brain homogenate preparations.

Blood dendritic cells in cattle infected with bovine leukemia virus (BLV): isolation and phenotyping

“…It has been suggested that binding of PCB with transthyretin in blood plasma protects against their rapid removal from circulation. PCB153 binds with transthyretin more effectively than PCB104 (IC50, 90 vs. >1000) (Chauhan et al 2000). In our study, the mean concentration of PCB153 in blood plasma was about 1.4 ng/ml.…”

“…This could result from feeding ewes with hay containing PCB153 since the concentrations of PCB153 congener in hay is among the highest compared to other congeners (Chauhan et al 2000). Costera et al (2006) showed that amounts of PCB153 in hay may reach 460 ng/kg/DM.…”

The effects of prenatal PCBs on adult female paced mating reproductive behaviors in rats

“…PCBs and their metabolites can act at multiple nodes of the neuroendocrine axis: they may serve as hormone mimics (Connor et al, 1997), alter circulating hormone levels (Desaulniers et al, 1999), change patterns of estrous cyclicity (Meerts et al, 2004;Buitenhuis et al, 2004), disrupt hormone metabolism Kester et al, 2000;Yamane et al, 1975), influence endocrine-related and hypothalamic gene expression (Aluru et al, 2004;Bansal et al, 2005;Colciago et al, 2005;Flouriot et al, 1995;Gore et al, 2002;Pravettoni et al, 2005;Salama et al, 2003), interfere with hormone binding proteins (Brouwer and van den Berg, 1986;Chauhan et al, 2000), alter neuronal signaling to endocrine regions of the brain (Khan and Thomas, 2001;Morse et al, 1996;Seegal et al, 1985;Seegal et al, 1990) or indirectly affect steroid receptor availability via molecular crosstalk (Brunnberg et al, 2003;Pearce et al, 2004).…”

Differential effects of two lots of aroclor 1254 on enzyme induction, thyroid hormones, and oxidative stress.

“…The decrease in T 4 is likely due to multiple mechanisms such as induction of several uridine diphosphate glucuronysyltransferases (UDPGTs) and binding to T 4 transport protein, transthyretin (TTR) (11,37). Cheek et al (11) found that hydroxylated PCBs are potent ligands for TTR, having affinities in the 1 nM range, 50-fold greater than that of T 4 .…”

“…Cheek et al (11) found that hydroxylated PCBs are potent ligands for TTR, having affinities in the 1 nM range, 50-fold greater than that of T 4 . Recently, Chauhan et al (37) studied the structure-activity relationships of 49 PCB congeners and demonstrated differential binding activity on T 4 -TTR binding. When compared on the basis of TEQ, the greater mass of PCB congeners in lot 124-191 was more effective for the decrease in total T4 ( Figure 4B).…”