* Division of Environmental Health Sciences, School of Public Health,
Departments of Pharmacology and
§ Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032; and
Department of Neurosurgery, Hangzhou First Hospital, Hangzhou, Zhejiang 310006, People's Republic of China
Received July 31, 2000; accepted December 18, 2000
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ABSTRACT |
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Key Words: transthyretin; thyroxine; retinol-binding protein; lead; cerebrospinal fluid; choroid plexus.
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INTRODUCTION |
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Research in both humans and animals has established that the choroid plexus accumulates lead (Pb) to an extraordinary degree following Pb exposure. Thus, the choroid plexus appears to function as a "sink" for Pb and other toxic metals (Friedheim et al., 1983; Manton et al., 1984
; Zheng et al., 1991
, 1996
). Accumulation of Pb in the choroid plexus in a low-dose, long-term Pb exposure model in rats results in a significant reduction in the concentration of transthyretin (TTR, previously named prealbumin) in the cerebrospinal fluid (Zheng et al., 1996
). Our in vitro studies of newly synthesized TTR molecules further reveal that Pb treatment inhibits the production and secretion of TTR by the choroidal epithelial cells in culture, leading to a diminished thyroxine transport at the bloodCSF barrier (Zheng et al., 1998
, 1999
).
TTR is a 55,000-Dalton protein consisting of four identical subunits in a tetrahedral symmetry (Ingenbleek and Young, 1994). Whereas plasma TTR originates primarily from the liver, brain TTR is exclusively produced, secreted, and regulated by the choroid plexus (Aldred et al., 1995
; Herbert et al., 1986
; Wade et al., 1988
). On a tissue weight basis, the choroid plexus contains 11 times more TTR mRNA than liver, and synthesizes TTR at a rate 13 times faster than the liver (Schreiber et al., 1990
). CSF TTR makes up 25% of total CSF protein (Aldred et al., 1995
). The importance of TTR in CNS development is evidenced by the fact that it is present in very high concentration during prenatal and early postnatal life (Larsen and DeLallo, 1989
). One of the possible functions of TTR in the brain is to transport thyroid hormones mainly in the form of thyroxine (3,5,3',5'-tetraiodothyronine, T4). In humans, TTR conveys about 6080% of CSF thyroxine (Hagen and Elliott, 1973
; Herbert et al., 1986
; Larsen and DeLallo, 1989
). Evidence has also suggested that thyroxine may enter the brain across the bloodbrain barrier and/or bloodCSF barrier (Blay et al., 1993
; Chanoine et al., 1992
; Dratman et al., 1991
; Schreiber et al., 1990
), and the choroid plexus might facilitate the transport of thyroid hormones from blood to CSF via TTR synthesis in the choroidal epithelia (Schreiber et al., 1990
; Southwell et al., 1993
).
The thyroid hormones have striking effects on the CNS, particularly during the developmental period (Dussault and Ruel, 1987; Legrand, 1984
). Thompson (1996) has identified several thyroid hormone-responsive genes in rat brain and further suggests a unique effect of thyroid hormone in initiating a finely tuned program of gene expression for neural development. Deficiency of thyroid hormones during early brain development produces multiple morphological alterations, including disturbance in the establishment of the normal wiring pattern in the brain that results in permanent impairment of neuronal connectivity (Legrand, 1984
; Ruiz-Marcos et al., 1979
). Deficiency of thyroid hormones during development also leads to biochemical and electrophysiological alterations, such as delayed electrical activity in the peripheral auditory system (Hebert et al., 1985
) and diminished gene expression of myelin protein (Farsetti et al., 1991
). In children, the end point of the deprivation of thyroid hormones is irreversible mental retardation (Glorieux et al., 1983
; Legrand, 1984
; Smith et al., 1957
).
In addition to the manufacture of TTR, the choroid plexus produces and secretes retinol-binding protein (RBP) to the CSF (Aldred et al., 1995; MacDonald et al., 1990
; Zetterstrom et al., 1994
). RBP, in coordination with TTR, interacts with retinol to form a trimolecular complex in a close equimolar stoichiometry over wide concentration ranges. About 9095% retinol in human blood circulates by this complex (Vogel et al., 1999
). Evidence indicates that retinol is transported by RBP across the bloodbrain barrier and bloodCSF barrier to the CNS (MacDonald et al., 1990
; Ruberte et al., 1993
; Zetterstrom et al., 1994
), and that local TTR cooperates in the transport of retinol (Martone et al., 1988
). Many studies have established that retinoids are essential to brain development (Esfandiari et al., 1994
; Maden et al., 1990
; Ruberte et al., 1993
; Sharma and Misra, 1990
; Zetterstrom et al., 1994
).
Given that accumulation of Pb in the choroid plexus diminishes CSF TTR concentrations in animals, we postulated that environmental Pb exposure in humans may alter CSF TTR levels. As the choroid plexus also provides RBP to the CSF, we further postulated that accumulation of Pb in this tissue may interfere with RBP concentrations in CSF. Thus, the purpose of this study was to investigate a) whether TTR, total T4 (TT4), and/or RBP in human CSF were altered in a manner that correlated to CSF Pb concentrations; b) whether the status of TTR in the CSF correlated to that of TT4; and c) whether the variations of TTR, TT4, RBP, and/or Pb in the CSF were associated with serum concentrations of these parameters or with age.
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MATERIALS AND METHODS |
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Atomic absorption spectrophotometry analysis of Pb.
All samples were thawed at room temperature. Pb concentrations in the CSF and whole blood were determined by graphite furnace atomic absorption spectrometry. CSF samples were thoroughly mixed and then diluted with 1% Ultrex HNO3 containing 0.2% ammonium phosphate in a 1:5 ratio. If necessary, the samples were further diluted after the initial analysis. Standards for all determinations were prepared freshly daily from a Pb nitrate AA working stock solution in 0.5% Ultrex HNO3 (Zheng et al., 1996, 1999
). For blood Pb (BPb) concentrations, the procedure of Fernandez and Hilligoss (1982) was used. Reference materials for BPb (#SRM-2670) from the New York State Department of Health were used as internal quality control standards. A Perkin-Elmer Model 3030 Zeeman atomic absorption spectrophotometer, equipped with an HGA-600 graphite furnace, was used for quantification. The detection limit of CSF-Pb and BPb was 0.1 ng/ml and 1 ng/ml, respectively.
Radioimmunoassay (RIA) of TTR and RBP.
RIA procedures for determining serum and CSF concentrations of TTR and RBP are well established and previously described in detail (Blaner, 1990). The RIA for TTR employs purified human plasma TTR (both as standard and for use as [125I]-TTR) and a monospecific rabbit antihuman polyclonal TTR antibody. A standard displacement curve was established by plotting the percentage of maximal binding of [125I]-TTR with known amounts of homogeneously purified human plasma TTR for a standard dilution of anti-TTR. The purified human TTR was iodinated by the lactoperoxidase procedure as described by Blaner (1990). TTR concentrations in CSF and serum were quantitated using this procedure. The procedures for iodination and RIA of RBP were essentially the same as the above described for TTR, except that a rabbit antihuman polyclonal RBP antibody was used. The methods used for both TTR and RBP radioimmunoassay have proven to be sensitive, specific, and reproducible (Blaner, 1990
). As little as 25 µl CSF was usually sufficient for the assay of CSF TTR or RBP by this method. Within- and between-assay coefficients of correlation for these RIAs were 4.8 and 6.2%, respectively.
Radioimmunoassay of total thyroxine (TT4).
The method of Black et al. (1975) was used for determination of TT4 in serum and CSF. In brief, the T4 standards were prepared in hormone-free serum, which was obtained by treatment of serum with activated charcoal followed by centrifugation and then filtration. Human serum samples were incubated with known amount of T4 standard and mouse antihuman monoclonal T4 antibody (1:3000) in an RIA buffer consisting of 0.025% 8-anilino-1-napthalene sulphonic acid and 50 mM barbital. The antigen/antibody complex was precipitated by addition of 1 ml of 30% polyethylene glycol and 100 µl of 10 mg/ml gamma globulin. After centrifugation, the radioactivity in pellet was determined and converted to concentrations from a standard displacement curve.
TT4 in CSF was assayed using the same procedure, except that the standard curve was established in the RIA buffer containing 1% bovine serum albumin. The method was repeatable and reliable. The intraday precision at 50 pg/tube was 4% (n = 12) and interday precision 5% (n = 8). The detection limit of TT4 in serum and CSF was 15 pg/tube, which corresponded to 0.4 ng/ml serum and 0.075 ng/ml CSF.
Determination of protein contents.
Total protein concentrations in CSF and serum were determined using a Bio-Rad Protein Assay Kit (Bio-Rad Lab, Richmond, CA) with bovine serum albumin as the standard.
Statistical analyses.
Hospital records and other clinical reports were reviewed and abstracted for demographic data, clinical diagnoses, and neuropathological diagnoses. Data are expressed as the mean ± SD unless otherwise stated. Associations between Pb, TTR, and TT4 in the CSF and serum were analyzed by a linear regression or by multiple linear regressions when the multiple factors were considered, following the data transformation to logarithm. This transformation is valid with regard to the symmetric distribution and the linearity of variables following the logarithm transformation. The differences between two means were analyzed by a standard, parametric ANOVA.
Materials.
Chemicals were obtained from the following sources: bovine lactoperoxidase, barbital, 8-anilino-1-napthalene sulphonic acid, polyethylene glycol, and thyroxine (3,5,3',5'-tetraiodothyronine, T4, M.W. = 777) in free acid from Sigma Chemical Co., St. Louis, MO; 125Iodide (specific activity: 17 mCi/µg), 125I-labeled T4 (specific activity: 1.2 mCi/µg) from Du Pont, Boston, MA; PD-10 Sephadex G-25 column from Pharmacia Biotech; and AAS standards of Pb from Alfa Products, Danvers, MA. Human TTR (M.W. = 55,000) and RBP (M.W. = 21,000) and rabbit antihuman TTR or RBP antiserum were prepared according to the procedures described earlier (Blaner, 1990). All reagents were of analytical grade, HPLC grade, or the highest available pharmaceutical grade.
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RESULTS |
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CSF TT4 concentrations were highly significantly associated with CSF TTR concentrations, having an r of 0.33 (p = 0.003; Fig. 1). The age of the population played an insignificant role in this relationship, as verified by multiple linear regression analyses. CSF TTR tended to decline with an increase in age, but this relationship did not achieve statistical significance (r = 0.21, p = 0.06; Fig. 2
). Similarly, there was no significant age-related change in the concentration of CSF TT4 (r = 0.129, p = 0.254), serum TTR (r = 0.008, p = 0.940), or serum TT4 (r = 0.085, p = 0.449). No gender-based differences were observed for TTR and TT4 concentrations in either the CSF or the serum (Table 1
).
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Pb in Human Blood and CSF
Blood Pb (BPb) varied widely among this population, ranging from 2.5 µg/dl to 40.3 µg/dl, with an average of about 15 µg/dl (Table 1). BPb concentrations were not statistically associated with age (r = 0.140, p = 0.212). The mean value of BPb observed in this study is lower than those observed among Pb-exposed Chinese workers (2533 µg/dl; Ho et al., 1998), but higher than those reported in general population in Beijing (10 µg/dl; Tang et al., 1990) and Shanghai (9.2 µg/dl; Shen et al., 1997).
The range of CSF Pb (0.05 to 3.8 µg/dl) was at least 10 times less than that observed for BPb. The average concentration of CSF Pb was 0.53 µg/dl. CSF Pb concentrations did not change with increasing age (r = 0.068, p = 0.603). Regression analysis revealed that CSF Pb concentrations did not change as the function of BPb (r = 0.102, p = 0.439).
Although CSF Pb concentrations in males was on average 23% higher than those of females, this apparent difference did not achieve statistical significance (p > 0.4). There was no significant gender difference in BPb concentrations.
Effect of CSF Pb and BPb on TTR and TT4 in the CSF
The presence of Pb in the CSF was inversely associated with CSF TTR concentrations (r = 30, p = 0.023; Fig. 3). Multiple regression analyses excluded the possible contribution of an age factor in this relationship. Serum TTR concentrations, however, did not change as a function of BPb (r = 0.11, p = 0.31).
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RBP in Human CSF and Serum and the Effect of Pb
Among this Chinese population, CSF RBP concentrations ranged from 0.03 to 1.1 µg/mg CSF proteins, a variation much less than that observed for CSF TTR. Per milligram of protein, RBP concentrations in both serum and CSF were about 10 times less than corresponding TTR concentrations (Fig. 5). In contrast to CSF TTR, RBP concentrations in the CSF were highly significantly associated with RBP in serum (r = 0.39, p = 0.0004; Fig. 6
). The levels of RBP in serum appeared to affect directly its level in the CSF. In addition, RBP concentrations in CSF showed a significant increase as a function of age (r = 0.24, p = 0.03; Fig. 7
), while RBP concentrations in serum did not change with age (r = 0.10, p = 0.36).
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Effect of BPb on TTR, TT4, and RBP in Serum
By linear regression analyses, there was no significant correlation between BPb and serum concentrations of TTR (r = 0.114, p = 0.307), TT4 (r = 0.160, p = 0.152), or RBP (r = 0.096, p = 0.393).
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DISCUSSION |
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Our data further demonstrate that CSF TT4 concentrations do not vary as a function of serum TT4 concentrations. Given the lipid solubility of thyroxine, one might speculate that thyroxine would be able to cross the bloodbrain barrier through a simple diffusion mechanism responsive to mass balance. However, data from human and animal studies indicate that the transport of thyroxine between serum and the CSF is highly restricted (Ingenbleek and Young, 1994; Kirkegaard and Faber, 1991
; Schreiber et al., 1990
). Alteration of thyroxine binding to TTR results in altered patterns of thyroxine distribution in the choroid plexus and other regions of the brain (Chanoine et al., 1992
). In vivo exposure to certain toxic fungicides (hexachlorobenzene and pentachlorophenol) can also cause a diminished uptake of 125I-T4 into CSF and into specific brain structures such as the occipital cortex, thalamus, and hippocampus. This phenomenon has been taken to suggest a fine control of thyroxine availability to the CSF by the brain barriers (Kirkegaard and Faber, 1991
; van Raaij et al., 1994
). Based on our results from this human study, it appears that brain TT4 economy is probably not governed by serum thyroxine concentrations, but rather by the mechanisms that control its entrance, movement, and metabolism in the CNS.
The results of our human study reveal a significant correlation between thyroxine and TTR in the CSF. The question as to whether TTR plays an essential role in transport of thyroxine to the brain remains to be a subject of controversy. Some investigators have suggested that thyroid hormones are taken up in the choroid plexus from the blood via fenestrated capillaries and the loose stroma of choroid plexus into the choroidal epithelial cells, where TTR is synthesized. Thyroxine then binds with a high affinity to TTR, which is subsequently secreted into the CSF (Chanoine et al., 1992; Schreiber et al., 1990
; Southwell et al., 1993
). Other investigators have argued that the CNS acquires thyroid hormone mainly through the bloodbrain barrier (Blay et al., 1993
; Dratman et al., 1991
). Our observation of the positive relationship between TTR and TT4 in human CSF does not necessarily prove a possible function of TTR in transport of thyroxine across the bloodbrain barrier and/or bloodCSF barrier. However, it may indicate that TTR is required to convey thyroxine within human cerebral compartment, and thus is essential in maintaining the homeostasis of thyroxine in human CSF.
Although long postulated, it is still startling that there is a significant inverse association between Pb and TTR concentrations in the CSF among this population. As the CSF and blood samples in this study were obtained primarily from patients with diverse diseases, possible interference in our results due to disease status cannot be ruled out. Nevertheless, the results of this human study appear to be consistent with our previous observations from animal experiments. Our earlier studies have shown that low-dose, long-term exposure of weanling rats to Pb in drinking water reduces TTR levels in the CSF (Zheng et al., 1996). Using a pulse-chase technique to follow the newly synthesized TTR molecules labeled with [35S]methionine in rat choroidal epithelial cells, we have also shown that Pb treatment inhibits the synthesis of total [35S]TTR by these cells and greatly suppresses the rate of polarized secretion of [35S]TTR from the cultured cells into the extracellular space (Zheng et al., 1999
). Taken together, these data and other published data suggest that the accumulation of Pb in the choroid plexus following Pb exposure alters one of the important functions of the choroid plexus in neuroendocrinal regulation, i.e., suppression of TTR production and its secretion into the CNS. As TTR carries most of thyroxine in the CSF, it seems possible that the toxic action of Pb on TTR might ultimately alter thyroid hormone status in the CSF. This may, in turn, impair brain development and functional maturation and account in part for the toxic effects of Pb on brain development and function.
In contrast to TTR in the CSF, no statistically significant association between Pb exposure and the levels of RBP in human CSF was observed. The choroid plexus produces and secretes RBP into the CSF (Aldred et al., 1995; MacDonald et al., 1990
; Zetterstrom et al., 1994
). RBP, probably along with TTR, assists in the transport of retinol across the bloodbrain barrier and bloodCSF barrier to the CNS, although at present mechanistic details of this process remain unclear (MacDonald et al., 1990
; Martone et al., 1988
; Ruberte et al., 1993
). One of the interesting observations from this study in humans was that CSF RBP concentrations were closely related to serum concentrations of RBP. In other words, RBP in the cerebral compartment, unlike TTR, may be importantly derived from the blood source. The brain barriers, while capable of synthesizing RBP, e.g., in the choroid plexus to the CNS, may be more permeable to the smaller RBP molecules than to TTR. How this would affect retinol homeostasis within the cerebral compartment is a subject worthy further investigation.
In summary, for a total of 82 randomly selected, paired human CSF/serum samples, we observed a significant correlation between TTR and TT4 concentrations in the CSF and a significant inverse association between CSF Pb and TTR concentrations. These results suggest that CSF TTR may be importantly involved in thyroxine transport in the cerebral compartment and that Pb exposure may alter this function of TTR in humans.
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ACKNOWLEDGMENTS |
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NOTES |
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