Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160-7140
Received March 18, 2004; accepted June 4, 2004
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ABSTRACT |
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Key Words: thyroid; pregnenolone-16-carbonitrile (PCN); polychlorinated biphenyl (PCB); thyrotropin (TSH); tumor promotion; glucuronidation; rat.
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INTRODUCTION |
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Alteration of the enzymes involved in thyroid hormone metabolism has been described as a mechanism for reducing the concentrations of available thyroid hormone in the circulation (Curran and DeGroot, 1991). Some chemicals that increase the activity of hepatic microsomal enzymes are believed to alter thyroid homeostasis by increasing the glucuronidation and biliary excretion of thyroid hormones (McClain et al., 1989
; Semler et al., 1989
). This causes a reduction in serum thyroid hormones, which in turn leads to reduced negative feedback at the pituitary, resulting in elevated TSH secretion. The microsomal enzyme inducer phenobarbital has been shown to increase thyroid gland weight, follicular cell hypertrophy, and hyperplasia (Japundzic, 1969
). It has also been found to promote thyroid follicular tumors in a rat two-stage carcinogenesis model (Hiasa et al., 1982a
; McClain et al., 1988
). The promotion of thyroid tumors by phenobarbital was prevented when rats were supplemented with exogenous T4. Phenobarbital-induced hyperplasia was also prevented by exogenous T4, and prevented by hypophysectomy as well (Japundzic, 1969
). It was subsequently determined that the effect of PB on thyroid function was primarily due to the increased hepatic clearance of T4, likely to be secondary to induction of glucuronidation.
The nature of this mechanism has been further investigated by examining the effects of other microsomal enzyme inducers on TSH secretion, thyroid growth, and thyroid follicular cell proliferation in rats (Hood et al., 1999a,b
). While there is a direct relationship between the changes in TSH and changes in thyroid cell proliferation, the effects on T4 glucuronidation are not consistent with either parameter (Hood et al., 1999b
; Hood and Klaassen, 2000a
). Certain inducers, namely phenobarbital and pregnenolone-16
-carbonitrile (PCN), increase T4 glucuronidation as well as increase serum TSH and thyroid cell proliferation. Two other inducers, 3-methylcholanthrene (3MC) and the polychlorinated biphenyl mixture Aroclor 1254 (PCB), increase T4 glucuronidation as well, but do not remarkably increase serum TSH or thyroid cell proliferation in rats. Recently, it was reported that the effects of these four inducers on T3 glucuronidation are consistent with the effects on TSH (Hood and Klaassen, 2000a
; Vansell and Klaassen, 2002
). Based on these findings, it was hypothesized that the ability to increase T3 glucuronidationrather than T4 glucuronidationmight be a better predictor of the effects of these inducers on TSH secretion.
Presently, it is unknown whether any of the aforementioned inducers, besides phenobarbital, are promoters of thyroid tumors in rats. Therefore, the purpose of this study was to determine whether chemicals that induce the glucuronidation of T3 produce elevations in serum TSH levels and promote thyroid follicular tumors. A 20-week initiation-promotion model of carcinogenesis similar to that utilized by Hiasa et al. (1987) and McClain et al. (1988)
was used. It was expected that PCN, by increasing T3 glucuronidation, would increase serum TSH, resulting in thyroid tumors, whereas PCB, which has no effect on T3 glucuronidation and on serum TSH, would not.
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MATERIALS AND METHODS |
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Animals and treatments. Male, Sprague-Dawley rats (Sasco, Wilmington, MA) weighing 150200 g were divided into three groups of 24 and one group of eight based on matched body weights. Animals were housed individually in wire-bottom cages with ad libitum food (Purina 5002 chow containing 2.5% corn oil) and water. A 20-week initiation-promotion model was utilized as described by Hiasa et al. (1987). Following a one-week acclimation period, rats were given a single injection of DIPN (2.5 g/kg body weight sc) or saline, and allowed a one-week recovery period. Saline-injected rats were then placed on control diet (n = 8), and initiated rats were placed on control diet (n = 24), diet containing 1000 ppm PCN (n = 24), or diet containing 100 ppm PCB ppm (n = 24) for 19 weeks. Diets were synthesized by DYETS, Inc. (Bethlehem, PA) from Purina 5002 chow and supplemented with 2.5% corn oil. Rats were fed and observed daily and body weights were recorded weekly through day 28, then at least biweekly thereafter. Overnight food consumption was recorded periodically throughout the study. At the end of 19 weeks, rats were decapitated and liver, thyroid, and pituitary were removed, weighed, and both thyroid lobes were fixed in 10% neutral formalin overnight for histological processing. All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee.
Histopathology. Following 24 h fixation in 10% neutral formalin, thyroids were processed using routine histological techniques. Paraffin-embedded thyroids (five thyroids per block in fixed orientation) were sectioned serially at 5 microns and stained with hemotoxylin and eosin by HistoTechNology, Inc. (Cleona, PA), with every third section excluded. For the eight thyroids from saline-injected control animals, all sections were examined for the presentation of pathology. Five serial sections were selected at random and blinded for analysis of the thyroids from the remaining groups (initiated control, PCN, and PCB). This is because each block contained five thyroids of varying size in each block, and therefore a given serial section did not represent the same depth of penetration for each thyroid. Of these five sections, the section with the most severe histopathology was used in the scoring for each rat.
Determination of serum T3, T4, and TSH. Blood was sampled from the retro-orbital sinus on days 1, 7, 14, 21, 42, 91 relative to the start of diet treatment, and trunk blood was collected at necropsy on day 133. After clotting at 4°C, blood samples were centrifuged for 5 min to collect serum, which was stored at 80°C until further analysis. The concentrations of total (free and protein-bound) T3 and T4, as well as TSH, were determined by radioimmunoassay. Limits of detection for these kits were 7 ng/dl, 0.25 µg/dl, and 0.50 ng/ml, respectively. When adequate quantities of serum could not be obtained from all rats, samples were distributed to ensure that at least 10 samples/group/timepoint were analyzed for each parameter.
Data analysis. Body and organ weights, food consumption, and serum hormone concentrations are expressed as the mean ± SE. Means were compared by one-way ANOVA followed by Duncan's multiple range test. Statistical significance is reported for the p < 0.05 level. For histopathology incidence, lesions were scored as either present or absent, and results are expressed as the number of thyroids with each lesion present out of the total number of thyroids examined for each group. Incidences were compared by Fisher's exact p two-tailed test, and significance is reported at the p < 0.05 level.
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RESULTS |
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Mean body weights of initiated rats fed either control diet or diet containing PCN or PCB for 19 weeks (133 days) are given in Figure 1. At day 8, the day prior to initiation with DIPN, mean body weights for all groups were not different (194 g), and there were no differences in mean body weight among the three initiated groups from day 1 to day 27 of treatment. Whereas there were no differences between control and PCN-treated rat body weights throughout the course of the study, a reduction in mean body weight gain in PCB rats was apparent by day 42 and was sustained for the duration of the study. On day 42, the mean body weight of PCB rats was 7% less than that of controls, and was 21% less than mean control group weight by day 133.
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Serum thyroid hormone concentrations were also monitored throughout the course of the experiment, and are shown in Figure 2. Within seven days of diet treatment, serum total T4 concentrations, in the top panel, were significantly reduced after PCN and PCB treatments. These reductions were sustained in both PCN and PCB-treated rats through day 21, decreasing to only 40% of controls in PCN-treated rats. These values returned to control levels between days 21 and 42 in PCN-treated rats, but were significantly lower than control rat T4 concentrations again at day 133. Serum T4 reductions in PCB-treated rats were much more dramatic. On day 21 of treatment, T4 concentrations were below the limits of detection, and remained drastically reduced through day 133, when T4 levels were only 10% that of control animals.
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Serum TSH concentrations, like those of T4, were increased after seven days of PCN and PCB dietary administration (Fig. 3, bottom panel). PCN treatment produced the largest elevations in TSH concentrations, peaking at three times control on day 14. TSH concentrations then returned to control levels on day 42, but were again higher than control on days 92 (significantly) and 133. PCB treatment induced a more sustained elevation in serum TSH between days 7 and 133; however, the increase was not as dramatic as that initially produced by PCN treatment. The average increase in TSH serum concentrations in PCB-treated animals between days 7 and 133 was 69%.
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Thyroids were evaluated histologically for the presence of follicular cell pathologies. Thyroids from eight saline-injected rats maintained on control diet were first examined to obtain a reference for normal histological appearance of the gland. Figure 4, panel A depicts the normal thyroid architecture from a saline-injected control animal. Fairly uniform follicle size and even staining are apparent. Follicles are lined with cuboidal to low-columnar epithelium. Generally, there were no dramatic differences between saline-injected control thyroids and initiated control thyroids. Follicles consisted primarily of cuboidal to low columnar epithelium with evidence of mild diffuse hyperplasia. The epithelium of some larger follicles was flattened cuboidal to squamous. Large follicles were located only on the outer edge of some glands, while other thyroids contained large follicles within the center of the gland. There was also evidence of vacuolization of the colloid and cytoplasm in a number of thyroid glands.
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Panel B contains a lesion of cystic hyperplasia. The colloid space is dilated with papillary projections into the cystic space; there is slight compression of the surrounding tissue due to the expanded volume of the colloid space. Panel C shows a nodule of hyperplastic follicles. There is distinct demarcation from the surrounding tissue without compression; colloid-filled follicles are irregularly shaped with cuboidal to columnar epithelium and slight papillary infolding. A second type of focal hyperplasia that was noted in these thyroids contained smaller, more hyperchromatic follicles with decreased colloid and darker nuclei than the focus shown in Panel C. Part of a cystic adenoma is shown in Panel D. It is well circumscribed with a thin capsule and formation of an irregular, complex network of projections into the cystic lumen. The follicular adenoma in panel E is characterized by an irregular but single morphological pattern of hyperchromatic follicles with nuclear crowding, partial encapsulation, and compression of surrounding tissue. Other adenomas included in this classification exhibited a more solid pattern of densely packed cells with a high nuclear to cytoplasm ratio, stained more basophilic, with some atypical nuclei and mitotic figures present. Panels F and G show two follicular carcinomas at two different magnifications. At lower power, there is evidence of a heterogeneous growth pattern, with prominent vascularity and cellular pleomorphism. At higher magnification, there is evidence of a well-differentiated neoplasm, atypical nuclei, vascularization, and mitotic figures.
A sixth classification, termed complete carcinoma, was established to describe the unique histopathology detected in some PCB-treated rats. These lesions differed dramatically from that of the localized follicular carcinomas also observed in this study. A small portion of a complete thyroid carcinoma is shown in Panel H. Extreme lymphocytic invasion and mixed cell types and patterns are visible, with no normal recognizable thyroid architecture remaining. The entire gland consisted of such architecture, extending beyond the normal thyroid capsule. The histological appearance and severity of this lesion was consistent among thyroids in which it was detected, and no pre-neoplastic lesions indicative of earlier stages of progression to such complete carcinomas were observed.
The incidence of each lesion in thyroids from (initiated) control, PCN-, and PCB-treated rats is presented in Table 1, including the mean number of lesions observed per thyroid section in parenthesis. Cystic hyperplasia, focal hyperplasia, follicular adenoma, and follicular carcinoma were present in thyroids from control rats. The incidence of all proliferative-type lesions was increased above control incidence following PCN treatment, including 100% incidence of focal hyperplasia, as well as the mean number of proliferative foci per section. PCB treatment produced only a slight, but not statistically significant, increase in the incidence and mean frequency of these lesions. However, 4 of 22 PCB thyroids were entirely transformed such that the origin of neither the tissue nor the lesion could be readily identified microscopically, termed complete carcinomas. This was the only lesion that was observed at a significantly increased incidence in thyroids from PCB-treated animals, and was completely absent from thyroids of PCN-treated animals.
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DISCUSSION |
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Because PCN increases the glucuronidation of T3, serum TSH, and cell proliferation, it was hypothesized that in this study, PCN would promote the formation of thyroid follicular tumors in rats. Data collected in this study confirmed that hypothesis. Effects of PCN on liver and thyroid gland weight, serum thyroid hormones, and TSH were consistent with previous observations. Serum TSH concentrations peaked in PCN-treated rats on day 14 of diet, but continued to be greater than those of the control group throughout the course of the study. Effects of PCN on thyroid gland morphology were consistent with those described for other stimuli that mediate increases in TSH. In PCN-treated rats, the incidence of pre-neoplastic nodules was 100% with a mean of approximately 12 hyperplastic foci per section, and the incidence of follicular adenoma was 87.5% with a mean of greater than four adenomas per thyroid section. The incidence of follicular carcinoma (42%) was also significantly increased above that induced by DIPN alone. Taken with previously published data indicating that biliary excretion of T3 metabolites, particularly T3-glucuronide, is increased by PCN in rats (Vansell and Klaassen, 2002), these data suggest that PCN acts on the thyroid via a secondary mechanism to promote the transformation of thyroid lesions from hyperplasias to carcinomas.
Effects of the PCB mixture, Aroclor 1254, on thyroid were also evaluated in this study. Because data previously collected by this laboratory indicated this PCB mixture does not increase the glucuronidation of T3, serum TSH, or thyroid cell proliferation, the expectation was that it would fail to promote thyroid tumors. Whereas the results of this study did not indicate that PCB produces proliferative changes in thyroid follicular cells or tumors that are proliferative in nature, the results also demonstrated that the action of PCB on the thyroid gland is more complicated than presumed. In the present study, PCB increased serum TSH concentrations, albeit not to the degree produced by PCN treatment. In the majority of previously reported rat studies, the PCB mixture utilized, Aroclor 1254, did not increase serum TSH. The concentration selected for the current study was 100 ppm, a dose that has significantly decreased T4 serum concentrations, but which previously has not elicited increases in TSH. However, higher dietary concentrations of Aroclor 1254 than those used in this study have resulted in elevated serum TSH. At days 14 and 20, 250 ppm resulted in an increase in serum TSH (Barter and Klaassen, 1994), although concentrations of 200 ppm and 300 ppm in two subsequent studies did not increase serum TSH (Hood et al., 1999a
; Liu et al., 1995
). It may be the case that accumulation of PCBs over the duration of 19 weeks resulted in a larger effective dose than that for rats fed similar concentrations for shorter lengths of time, particularly considering the decrease in body weight gain observed in PCB-treated rats. This, along with the apparent systemic toxicity produced by PCB (as evidenced by two early mortalities), likely contributed to the drastic reductions of total T4 serum concentrations, and may have been a greater factor in elevating serum TSH than in previous studies. It is also important to point out, though, that Aroclor 1254 is a mixture of different structural congeners, with varying phenobarbital and TCDD-like chemical properties (Parkinson et al., 1983
). It is possible that differing contributions of individual PCB congeners or their metabolites could have contributed to the increase in TSH in this study (Kato et al., 2000
).
Despite the elevation of serum TSH produced by PCB, however, there was not a significant increase in the incidence of proliferative thyroid lesions typically associated with excessive TSH stimulation. The most striking finding was the occurrence of thyroid carcinomas in thyroids from four PCB-treated rats that did not exhibit histomorphology consistent with the thyroid tumors observed in PCN-treated rats, and which did not correlate with increased serum TSH concentrations in individual rats. Thyroids from the 18 remaining PCB-treated rats were fairly similar to those of initiated controls, and did not exhibit the full continuum of proliferative changes induced by excessive TSH secretion. Rather, in the case of PCB, there was evidence that anti-thyroid activity may have blunted the TSH responsiveness of the thyroid. In thyroids from PCB-treated rats that were not considered carcinogenic, there appeared to be an increase in the number of cystic follicles (different than cystic hyperplasia in that the follicle is lined with squamous epithelium, and there is no increase in cell number), indicative of inactivity, and increased vacuolization of the colloid and epithelial cytoplasm (data not quantified). Both PCB and polybrominated biphenyl (PBB; Firemaster) mixtures have been shown to produce changes in thyroid histology that may indicate interference with normal thyroid synthesis and secretion, such as increased vacuolization and accumulation of colloid droplets and abnormal lysozymes in follicular cells (Collins et al., 1977; Kasza et al., 1978
). PBBs appear to preferentially accumulate in thyroid, where they have been proposed to bind to thyroid macromolecules and interfere with the organification of iodide (Allen-Rowlands et al., 1981
). Byrne and colleagues (1987
; Sepkovic and Byrne, 1984
) demonstrated that disturbances in thyroid hormone synthesis and distribution might occur following long-term administration of PCB and PBB. In addition to an increase in the biological half-life and distribution space for T3 and T4, they demonstrated diminished response of serum T3 and T4 levels to exogenous TSH injections. These findings were interpreted to be evidence not of thyroid-pituitary axis suppression, but of direct thyroid damage. If PCBs do exert a direct anti-thyroid effect, this could possibly desensitize the thyroid to TSH stimulation, perhaps in a way that would prevent typical proliferative changes.
Certainly, such an anti-thyroid effect would also contribute to the reduction in T4 serum concentrations. This idea does not appear to agree with the finding that PCB decreases serum T4 primarily by an extrathyroidal mechanism (Barter and Klaassen, 1992), presumably via increased biliary excretion of T4 (Vansell and Klaassen, 2001
). However, there is evidence that multiple processes are contributing. In studies using the homozygous Gunn rat that possesses a deficiency in T4 glucuronidation and biliary clearance, T4 serum concentrations were reduced to the same extent following PCB treatment as in heterozygous rats (Collins and Capen, 1980
). Histologically, thyroids from homozygotes had changes suggestive of impaired hormone secretion, while heterozygote thyroids appeared to be stimulated. Thus, multiple mechanisms must be involved. In the aforementioned study (Byrne et al., 1987
), a reduction in T4 production rates was noted, and the authors suggest that this, along with cell membrane damage associated with PCB and PBB intoxication may have expanded pools for T4 dilution, and therefore contributed to reductions in serum T4. It has also been suggested that the thyrotoxic effects of PCBs are related to the similarity between the structures of individual PCB congeners and thyroid hormones (McKinney, 1989
; Rickenbacher et al., 1986
). PCB congeners and/or their hydroxylated metabolites interfere with plasma, cytosolic, and nuclear T4 binding (Brouwer and van den Berg, 1986; McKinney et al., 1987
; Rickenbacher et al., 1986
). Such interference could displace T4 from serum transthyretin (Chauhan et al., 2000
; Cheek et al., 1999
; Darnerud et al., 1996
) and enhance tissue uptake, as would induction of transporter expression. It has also been proposed that PCBs may bind to thyroid hormone receptors in the pituitary to blunt TSH release (Morse and Brouwer, 1994
; Rickenbacher et al., 1986
). Whether these binding properties could also attribute to direct thyroid gland impairment is not known.
The fact that serum T4 concentrations appear to be completely ablated with virtually no consequence on serum T3 is particularly interesting, considering nearly 80% of T3 is derived from deiodination of T4 (Visser, 1990), and deiodination of T4 is generally inhibited, rather than enhanced by PCB (Hood and Klaassen, 2000b
). This suggests the involvement of mechanisms for the maintenance of serum T3 concentrations. It has been shown that during thyroid hormone imbalance, de novo synthesis and secretion of T3 by the thyroid may take place in preference to synthesis of T4 (Delange and Ermans, 1996
; Kaplan, 1980
). The role of individual PCBs in mediating such a process requires further investigation. However, free T4 serum concentrations were not determined in the present study, and therefore the physiological impact of such a large reduction in total T4 serum concentrations cannot be completely assessed.
Previously, it was reported that the effects of microsomal enzyme inducers on the glucuronidation of T4, and the subsequent reductions in serum T4 produced by inducer treatment, are inconsistent with the effects on serum TSH (Hood and Klaassen, 2000a). However, increases in T3 glucuronidation produced by microsomal enzyme inducers do correlate with elevations in serum TSH. It therefore reasons that changes in T3 glucuronidation, rather than T4 glucuronidation, may regulate increases in TSH secretion and thyroid cell proliferation. Further, inducers that increase T3 glucuronidation and serum TSH should then promote thyroid tumors (PCN), while inducers that do not increase T3 glucuronidation and serum TSH should not promote thyroid tumors. The results of this study partially support this hypothesis, in that PCN increased the number and incidence of thyroid proliferative and neoplastic lesions consistent with excessive TSH stimulation, whereas PCB did not. However, PCB produced thyroid carcinomas in four rats, an occurrence that appears to be unrelated to the elevations in serum TSH also observed. It is not completely clear as to why PCB did not promote thyroid follicular tumors in a manner similar to PCN when both treatments elevated serum TSH, although there is some indication PCB may directly impair thyroid function. When previously studied, this PCB mixture, Aroclor 1254, had no effect on serum TSH, thyroid cell proliferation, or thyroid hyperplasia (Hood et al., 1999b
). Whether TSH serum concentrations do not reliably indicate thyroid gland stimulation, or whether PCBs may act directly to inhibit the action of TSH on the thyroid, is unknown. Nonetheless, the data herein clearly indicate that (1) PCN mediates a different type of thyroid tumor than PCB and by a different mechanism, and (2) that tumorigenesis in the thyroid is more complicated than can be predicted from serum TSH in the case of chemicals that may exert other thyrotoxic effects. The mechanisms of both PCN- and PCB-induced thyroid neoplasia require further characterization. Evaluation of other inducers of T3 glucuronidation as potential thyroid tumor promoters is necessary, as well as studies to examine whether supplemental T3 alone can prevent PCN-induced thyroid tumors, as it has been demonstrated for methimizole (Jemec, 1980
). Such evidence would aid in determining the potential for a chemical to elicit thyroid disturbances secondary to excessive TSH stimulation. It is also important to begin to consider other direct actions of microsomal enzyme inducers, in particular individual PCB congeners, that may lead to thyroid tumor formation, and that are independent of TSH stimulation.
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ACKNOWLEDGMENTS |
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NOTES |
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2 To whom correspondence should be addressed. Fax: (913) 588-7501. E-mail: cklaasse{at}kumc.edu.
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