Polychlorinated Biphenyls Suppress Thyroid Hormone Receptor-mediated Transcription through a Novel Mechanism

Polychlorinated biphenyls (PCBs) are environmental compounds that disrupt the endocrine system, and exposure to low doses causes abnormalities, particularly in the developing central nervous system. Because they are structurally similar to thyroid hormone (TH), PCBs might affect systems involving this hormone. We previously found, using reporter assays, that hydroxylated-PCB at doses as low as 10–10m suppress TH-induced transcriptional activation of TH receptor (TR). To understand the molecular mechanisms of this process, we examined whether PCBs alter coactivator or corepressor interaction with TR. Polychlorinated biphenyls suppressed steroid receptor coactivator-1 enhanced TR-mediated transcription, but did not reduce TR/steroid receptor coactivator-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. Thus, the suppression was probably not caused by coactivator dissociation. Nuclear receptor co-repressor was not recruited to TR by PCBs either in vivo or in vitro, indicating that TR corepressor binding did not induce the suppression. We then examined whether PCB influences TR binding to the thyroid hormone-response element (TRE). Electrophoretic mobility shift assays revealed that the TR/retinoid X receptor heterodimer complex was partially dissociated from TRE in the presence of PCB. These results indicate that partial dissociation of TR/retinoid X receptor heterodimer complex from the TRE is involved in the suppression of transcription induced by PCB. Polychlorinated biphenyls (PCBs) are environmental compounds that disrupt the endocrine system, and exposure to low doses causes abnormalities, particularly in the developing central nervous system. Because they are structurally similar to thyroid hormone (TH), PCBs might affect systems involving this hormone. We previously found, using reporter assays, that hydroxylated-PCB at doses as low as 10–10m suppress TH-induced transcriptional activation of TH receptor (TR). To understand the molecular mechanisms of this process, we examined whether PCBs alter coactivator or corepressor interaction with TR. Polychlorinated biphenyls suppressed steroid receptor coactivator-1 enhanced TR-mediated transcription, but did not reduce TR/steroid receptor coactivator-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. Thus, the suppression was probably not caused by coactivator dissociation. Nuclear receptor co-repressor was not recruited to TR by PCBs either in vivo or in vitro, indicating that TR corepressor binding did not induce the suppression. We then examined whether PCB influences TR binding to the thyroid hormone-response element (TRE). Electrophoretic mobility shift assays revealed that the TR/retinoid X receptor heterodimer complex was partially dissociated from TRE in the presence of PCB. These results indicate that partial dissociation of TR/retinoid X receptor heterodimer complex from the TRE is involved in the suppression of transcription induced by PCB. Polychlorinated biphenyls (PCBs) 1The abbreviations used are: PCB, polychlorinated biphenyl; TH, thyroid hormone; T4, thyroxine; T3, triiodothyronine; TR, thyroid hormone receptor; TRE, thyroid hormone response element; N-CoR, nuclear receptor co-repressor; SRC-1, steroid receptor coactivator-1; CB, chlorobiphenyl; RXR, retinoid X receptor; GR, glucocorticoid receptor; LUC, luciferase; TK, thymidine kinase; UAS, upstream activating sequence; DBD, DNA-binding domain; NBD, nuclear receptor-binding domain; LBD, ligand-binding domain; GST, glutathione S-transferase; ANOVA, analysis of variance; EMSA, electrophoretic mobility shift assay. 1The abbreviations used are: PCB, polychlorinated biphenyl; TH, thyroid hormone; T4, thyroxine; T3, triiodothyronine; TR, thyroid hormone receptor; TRE, thyroid hormone response element; N-CoR, nuclear receptor co-repressor; SRC-1, steroid receptor coactivator-1; CB, chlorobiphenyl; RXR, retinoid X receptor; GR, glucocorticoid receptor; LUC, luciferase; TK, thymidine kinase; UAS, upstream activating sequence; DBD, DNA-binding domain; NBD, nuclear receptor-binding domain; LBD, ligand-binding domain; GST, glutathione S-transferase; ANOVA, analysis of variance; EMSA, electrophoretic mobility shift assay. were produced for industrial use from the early 1930s until the beginning of the 1970s (1Tilson H.A. Kodavanti P.R. Neurotoxicology. 1997; 18: 727-743Google Scholar, 2Safe S.H. Crit. Rev. Toxicol. 1994; 24: 87-149Google Scholar, 3Tilson H.A. Jacobson J.L. Rogan W.J. Neurotoxicol. Teratol. 1990; 12: 239-248Google Scholar, 4McKinney J.D. Waller C.L. Environ. Health Perspect. 1994; 102: 290-297Google Scholar). These compounds contain 209 congeners, each of which is chlorinated to various degrees (1Tilson H.A. Kodavanti P.R. Neurotoxicology. 1997; 18: 727-743Google Scholar, 2Safe S.H. Crit. Rev. Toxicol. 1994; 24: 87-149Google Scholar, 3Tilson H.A. Jacobson J.L. Rogan W.J. Neurotoxicol. Teratol. 1990; 12: 239-248Google Scholar). These compounds are still detectable, even at the edge of the Arctic (5Dewailly E. Ryan J.J. Laliberte C. Bruneau S. Weber J.P. Gingras S. Carrier G. Environ. Health Perspect. 1994; 102: 205-209Google Scholar, 6Ayotte P. Dewailly E. Ryan J.J. Bruneau S. Lebel G. Chemosphere. 1997; 34: 1459-1468Google Scholar) and in the depths of the oceans (7Mormede S. Davies I.M. Chemosphere. 2003; 50: 563-574Google Scholar). After absorption, PCBs undergo little catalysis. They are highly lipophilic, accumulate in the liver and adipose tissue, and easily transfer to the embryo through the placenta and via breast milk (1Tilson H.A. Kodavanti P.R. Neurotoxicology. 1997; 18: 727-743Google Scholar, 2Safe S.H. Crit. Rev. Toxicol. 1994; 24: 87-149Google Scholar, 8Gladen B.C. Rogan W.J. J. Pediatr. 1991; 119: 58-63Google Scholar). Thus, PCB contamination is inheritable. At low doses, PCB might affect embryonic and neonatal development (9Jacobson J.L. Jacobson S.W. Toxicol. Ind. Health. 1996; 12: 435-445Google Scholar, 11Jacobson J.L. Jacobson S.W. Humphrey H.E. Neurotoxicol. Teratol. 1990; 12: 319-326Google Scholar, 12Jacobson S.W. Fein G.G. Jacobson J.L. Schwartz P.M. Dowler J.K. Child Dev. 1985; 56: 853-860Google Scholar, 13Chen Y.C. Guo Y.L. Hsu C.C. Rogan W.J. JAMA. 1992; 268: 3213-3218Google Scholar). Brain development seems to be particularly affected by PCB. Cognitive development among children exposed to PCBs in utero and during lactation is poor (10Jacobson J.L. Jacobson S.W. Neurotoxicology. 1997; 18: 415-424Google Scholar, 14Giesy J.P. Kannan K. Crit. Rev. Toxicol. 1998; 28: 511-569Google Scholar), and the results of studies using rodents have supported this finding (9Jacobson J.L. Jacobson S.W. Toxicol. Ind. Health. 1996; 12: 435-445Google Scholar, 10Jacobson J.L. Jacobson S.W. Neurotoxicology. 1997; 18: 415-424Google Scholar, 11Jacobson J.L. Jacobson S.W. Humphrey H.E. Neurotoxicol. Teratol. 1990; 12: 319-326Google Scholar, 12Jacobson S.W. Fein G.G. Jacobson J.L. Schwartz P.M. Dowler J.K. Child Dev. 1985; 56: 853-860Google Scholar, 13Chen Y.C. Guo Y.L. Hsu C.C. Rogan W.J. JAMA. 1992; 268: 3213-3218Google Scholar). Because perinatal hypothyroidism also induces abnormal brain development similar to that seen in PCB-affected animal models and in humans, PCB might disrupt the thyroid hormone (TH) system (15McKinney J.D. Environ. Health Perspect. 1989; 82: 323-336Google Scholar). Thyroid hormones (thyroxine (T4) and triiodothyronine (T3)) play important roles in the growth and development of many organs in embryos and neonates (16Lazar M.A. Endocr. Rev. 1993; 14: 184-193Google Scholar, 17Zhang J. Lazar M.A. Annu. Rev. Physiol. 2000; 62: 439-466Google Scholar, 18Smith J.W. Evans A.T. Costall B. Smythe J.W. Neurosci. Biobehav. Rev. 2002; 26: 45-60Google Scholar). In particular, TH is crucial to the development of the brain in human fetuses and newborns, because maternal hypothyroidism during the perinatal period causes cretinism with severe cognitive and/or mental disorders in offspring (19Koibuchi N. Chin W.W. Trends Endocrinol. Metab. 2000; 11: 123-128Google Scholar). We and others have generated experimental evidence that TH affects the brain only for a short period during its development (19Koibuchi N. Chin W.W. Trends Endocrinol. Metab. 2000; 11: 123-128Google Scholar, 20Porterfield S.P. Hendrich C.E. Endocr. Rev. 1993; 14: 94-106Google Scholar, 21Oppenheimer J.H. Schwartz H.L. Endocr. Rev. 1997; 18: 462-475Google Scholar). Hypothyroidism during this critical period causes diminished axonal growth and dendritic arborization in the cerebral cortex, visual and auditory cortex, hippocampus, and cerebellum (22Rabie A. Legrand J. Brain Res. 1973; 61: 267-278Google Scholar, 23Rabie A. Favre C. Clavel M.C. Legrand J. Brain Res. 1977; 120: 521-531Google Scholar). Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that are expressed in many organs, including the developing brain (16Lazar M.A. Endocr. Rev. 1993; 14: 184-193Google Scholar, 17Zhang J. Lazar M.A. Annu. Rev. Physiol. 2000; 62: 439-466Google Scholar). In the absence of a ligand, TR binds to a specific nucleotide sequence, known as the thyroid hormone response element (TRE), located at the promoter region of its target gene by forming a complex with a corepressor, such as nuclear receptor corepressor (N-CoR) and its related protein, histone deacetylase, and induces the repression of transcription. Once a ligand binds to TR, the complex dissociates, and other complexes, including coactivators such as steroid receptor coactivator-1 (SRC-1), are recruited to induce transcriptional activation (16Lazar M.A. Endocr. Rev. 1993; 14: 184-193Google Scholar, 17Zhang J. Lazar M.A. Annu. Rev. Physiol. 2000; 62: 439-466Google Scholar, 24Yen P.M. Physiol. Rev. 2001; 81: 1097-1142Google Scholar). Several postulated mechanisms might account for PCB action on the TR system. Laboratory animals perinatally exposed to PCBs have abnormal thyroid function and neurological impairment. Many investigations have shown that exposure to PCBs results in thyroid enlargement and reduced serum T4 levels with normal T3, which is the active compound of TH (25Porterfield S.P. Hendry L.B. Toxicol. Ind. Health. 1998; 14: 103-120Google Scholar, 26Brouwer A. Morse D.C. Lans M.C. Schuur A.G. Murk A.J. Klasson-Wehler E. Bergman A. Visser T.J. Toxicol. Ind. Health. 1998; 14: 59-84Google Scholar, 27Hauser P. McMillin J.M. Bhatara V.S. Toxicol. Ind. Health. 1998; 14: 85-101Google Scholar). Thus, PCB seems to affect the TH system mainly by inhibiting TH secretion in the thyroid gland, which could cause abnormal brain development. However, the general growth of animals exposed to PCBs was not significantly altered, and the T3 levels in each organ remained within the normal range (28Shimada T. Sugie A. Shindo M. Nakajima T. Azuma E. Hashimoto M. Inoue K. Toxicol. Appl. Pharmacol. 2003; 187: 1-10Google Scholar). On the other hand, several PCB congeners, particularly hydroxylated forms, can cross the blood-brain barrier and accumulate in the brain (15McKinney J.D. Environ. Health Perspect. 1989; 82: 323-336Google Scholar, 29Darnerud P.O. Morse D. Klasson-Wehler E. Brouwer A. Toxicology. 1996; 106: 105-114Google Scholar, 30Brouwer A. van den Berg K.J. Toxicol. Appl. Pharmacol. 1986; 85: 301-312Google Scholar, 31Cheek A.O. Kow K. Chen J. McLachlan J.A. Environ. Health Perspect. 1999; 107: 273-278Google Scholar). Thus, abnormal brain development might be induced by the direct action of PCBs. Because the molecular structure of PCBs (especially hydroxylated PCB, an in vivo metabolite of PCB found in the blood) is similar to that of TH, PCB might act through TR (15McKinney J.D. Environ. Health Perspect. 1989; 82: 323-336Google Scholar). However, binding studies have shown that the affinity of TRβ1 for hydroxylated PCB is less than 1/10,000 that of T4 (15McKinney J.D. Environ. Health Perspect. 1989; 82: 323-336Google Scholar). We previously examined whether PCB directly acts on TR, and reported that 10–10m hydroxylated PCB (4(OH)-2′,3,3′,4′,5′-penta CB) suppressed TR-mediated transcription in the presence of T3. The suppression induced by PCB was cell-specific, because clonal TE671 cells, which are derived from cerebellar granule cells, were particularly susceptible. After transfection with SRC-1, PCB suppressed TR-mediated transcription in the presence of T3. We also found that the suppression of TR-mediated transcription by PCBs was probably not caused by competition between PCB and T3 for TR binding (32Iwasaki T. Miyazaki W. Takeshita A. Kuroda Y. Koibuchi N. Biochem. Biophys. Res. Commun. 2002; 299: 384-388Google Scholar). The present study further examines the molecular mechanism of the suppressive action of PCB on TR-mediated transcription. We used the hydroxylated mono-ortho form of PCB because this type is produced from highly toxic parent PCBs, and it could be a key factor in abnormal brain development (33Kuroda Y. Environ. Sci. 2003; 10: 23-33Google Scholar, 34Sandau C.D. Ayotte P. Dewailly E. Duffe J. Norstrom R.J. Environ. Health Perspect. 2000; 108: 611-616Google Scholar, 35Sandau C.D. Ayotte P. Dewailly E. Duffe J. Norstrom R.J. Environ. Health Perspect. 2002; 110: 411-417Google Scholar). Polychlorinated Biphenyls—Aroclor 1254 was purchased from Sigma. 4(OH)-2′,3,3′,4′,5′-penta CB, 4(OH)-2′,3,3′,4′,5,5′-hexa CB, and 2,3,3′,4,4′,5′-hexa CB were purchased from AccuStandard Chemicals (New Haven, CT). Their chemical structures are shown in Fig. 1A. Plasmids—Expression vectors of TRβ1, retinoid X receptor (RXR)β (36Takeshita A. Yen P.M. Ikeda M. Cardona Y. Koibuchi N. Chin W.W. J. 1998; Scholar), and glucocorticoid receptor T. Chin W.W. J. 2001; Scholar), have The reporter the direct TRE, N. Y. Takeshita A. Yen P.M. Chin W.W. 1999; Scholar), and upstream activating (36Takeshita A. Yen P.M. Ikeda M. Cardona Y. Koibuchi N. Chin W.W. J. 1998; Scholar) in the were glucocorticoid response reporter in previously T. Chin W.W. J. 2001; Scholar). of human previously (36Takeshita A. Yen P.M. Ikeda M. Cardona Y. Koibuchi N. Chin W.W. J. 1998; Scholar). of receptor binding nuclear was previously A. M. Koibuchi N. Y. J. 2002; Scholar). binding was by of the activation in The and were a from T. K. T. T. T. M. N. Y. A. K. J. Endocrinol. Metab. 2002; Scholar). was previously (36Takeshita A. Yen P.M. Ikeda M. Cardona Y. Koibuchi N. Chin W.W. J. 1998; Scholar). was previously (36Takeshita A. Yen P.M. Ikeda M. Cardona Y. Koibuchi N. Chin W.W. J. 1998; Scholar). was by of from M. G. of the D. 1992; Scholar). were in with serum at were in or was using the (32Iwasaki T. Miyazaki W. Takeshita A. Kuroda Y. Koibuchi N. Biochem. Biophys. Res. Commun. 2002; 299: 384-388Google Scholar) or by was used as an to were with the of specific ligand and/or PCBs. After were to as previously (32Iwasaki T. Miyazaki W. Takeshita A. Kuroda Y. Koibuchi N. Biochem. Biophys. Res. Commun. 2002; 299: 384-388Google Scholar). of for each were by The were to and then as transfection studies were at in shown of in The were by was previously D. J.H. J. 2001; Scholar). were in PCB. was in the presence or absence of 4(OH)-2′,3,3′,4′,5′-penta were for in a of in In each and were The were by In and were produced in and by In binding assays were by and in that were produced by to the of to the were as by were at for in the binding in the presence or absence of T3 and/or 4(OH)-2′,3,3′,4′,5′-penta CB were with binding in the presence or absence of T3 and to and Electrophoretic for were previously T. M. T. M. J. 1996; Scholar). In or were using with In and TRβ1, and/or SRC-1, N-CoR, and of were in binding serum and and in the presence or absence of T3 and/or 4(OH)-2′,3,3′,4′,5′-penta CB for on of were to that the of the was After were to and with the use of The of TR-mediated a of PCB including a of and hydroxylated PCBs, because the of S.H. Crit. Rev. Toxicol. 1994; 24: 87-149Google Scholar). used suppressed TR-mediated transcription on the at various degrees of These also suppressed transcription was However, the of PCB was not that binding between PCB and T3 probably not cause the suppression. that the suppression by PCBs did not from not We similar results of PCB action on and On the other hand, the PCBs did not transcription in the presence of or transcription in the presence of with or and T. Miyazaki W. Takeshita A. Kuroda Y. Koibuchi N. Biochem. Biophys. Res. Commun. 2002; 299: 384-388Google Scholar), that this suppression is to be in by examined whether PCB affects transcription. In the absence of T3, we the promoter with TRβ1 or in the presence or absence of TR was not affected by PCB with the results shown in and that PCB did not affect transcription experimental PCB TR-mediated in the of PCB might to TR as a of we further examined whether PCB TR-mediated transcription in the absence of T3. TR reduced transcription in the absence of T3. was not affected by PCB in the absence of T3 with further transcription in the absence of T3 PCB did not affect transcription, that PCB did not affect suppression from TR by the of PCB on binding between TR and a mammalian two-hybrid in cells, we between and in the presence of T3 and PCB. The of was to the binding and the of TRβ1 was to the of by and in the presence of T3, but not in the absence of the and T3 not transcription induced by and binding with T3 was not significantly reduced by hydroxylated PCB PCB significantly transcription. These results that PCB did not affect the binding of and in the presence of T3. We further this using pull-down studies did not from TRβ1 in the presence of T3 and PCB. These results that the suppressive of PCB on TR-mediated transcription is not caused by in TR and did not binding to TRβ1 in of was with in TRβ1 with or T3 and/or 4(OH)-2′,3,3′,4′,5′-penta were by and by was is of used in other PCB to K. T. T. T. M. N. Y. A. K. J. Endocrinol. Metab. 2002; Scholar) have shown that TR-mediated transcription by as an and to TR in the presence of T3. We mammalian two-hybrid assays to whether PCB to TR. We with and was not by the of PCBs that PCB did not to TRβ1 in the presence of T3 in We interaction between and TRβ1 using studies. to TR in the absence of T3, dissociated from TR and PCB did not to TR in the presence of T3 These results that PCB did not the corepressor complex to did not to TR in the presence of T3 in of was with in TRβ1 with or T3 and/or 4(OH)-2′,3,3′,4′,5′-penta were by and by was is of used in other of TR from TRE in the of whether PCB induced suppression of TR-mediated transcription is with we mammalian assays in In to with of PCB to transcription in the presence of T3 that the of PCB on TRβ1 probably not through we postulated that PCB affects TR-mediated transcription by with the binding of TR to we the of PCB on the binding of TRβ1 to TRE using In the presence of T3, complex was partially dissociated from the TRE, by PCB that TR-mediated suppression of transcription induced by PCB is at caused by dissociation of from the In the absence of T3, were also partially dissociated Fig. The results were similar using not In of TRβ1 of the TRβ1 was dissociated from the TRE by PCB in the absence of T3 In the presence of T3, TRβ1 was dissociated from TRE and the of PCB did not affect the binding We further examined the dissociation was to or TRβ1 complex using and In the presence of RXR, to the complex in the presence of T3. of PCB caused the partial dissociation of the complex from the TRE TRβ1 to TRE in the absence of T3 In the presence of T3, the TRβ1 dissociated from TRE as The of in complex The of PCB caused partial dissociation of the complex to a than in the complex Fig. dissociation of TR from TRE by PCB. in TRβ1 and/or were with with or T3 and/or 4(OH)-2′,3,3′,4′,5′-penta CB and then by are of results from was used to by dissociation of TR from TRE in the presence of by PCB. In TRβ1 and/or and/or were with with or T3 and/or 4(OH)-2′,3,3′,4′,5′-penta and CB then by results heterodimer and of the similar We also examined binding with In the absence of T3, to the TR PCB did not affect the binding which was with the In the presence of T3, did not to the TR The of PCB did not the which is with the results of the mammalian two-hybrid the TR was with the did not to the heterodimer even T3 not S. B. M. Endocrinol. 2001; Scholar) reported similar results with In PCB did not to complex in the presence of T3. We that the suppression of TR-mediated transcription by PCB is probably induced through the partial dissociation of TR from TRE in the presence of T3. was with the that of transcription in is suppressed by PCB. We also that the of suppression to Polychlorinated compounds might to TR because of to Thus, we previously examined the of the of mono-ortho hydroxylated PCB (4(OH)-2′,3,3′,4′,5′-penta CB) on TR-mediated transcription. However, the of transcriptional suppression between 10–10m and PCB was not (32Iwasaki T. Miyazaki W. Takeshita A. Kuroda Y. Koibuchi N. Biochem. Biophys. Res. Commun. 2002; 299: 384-388Google Scholar). The present study further using several PCB congeners, that PCB transcription. the PCB is induced by the of T3 binding TR, then PCB action not be the affinity of several PCB is less than 1/10,000 that of T4 (15McKinney J.D. Environ. Health Perspect. 1989; 82: 323-336Google Scholar). Thus, the of PCBs on TR-mediated transcription is probably not caused by competition with TH for TR The suppressive of PCB was not induced by because that PCB did not affect not We postulated that the of PCB could be induced by dissociation of the coactivator complex from TR or by of a corepressor because which TR corepressor K. T. T. T. M. N. Y. A. K. J. Endocrinol. Metab. 2002; Scholar). However, PCB did not from TR either in vivo or in PCB also did not to TR. Thus, the mechanism of PCB action on TR-mediated transcription from that of A. On the other hand, PCB did not affect transcription in the absence of T3 in either the presence or the absence of TR, that PCB not affect transcription of the promoter in of the to which PCB J. 1993; 268: Scholar, C.C. W. Toxicol. Appl. Pharmacol. 1999; Scholar), might also be because receptor is not expressed in A. 1998; 18: Scholar). using EMSA, we found that PCB partially dissociated TR from TRE in the presence of T3. The of dissociation was which is with the of the transcriptional complex was also partially dissociated from TRE by PCB. On the other hand, the of PCB on complex was The cause of such is Because PCB was not on transcription, the of PCB action is to be within TR. The of TR in and heterodimer complex have PCB On the other hand, in EMSA, PCB also partially dissociated TR or heterodimer from TRE T3, it did not complex from is with transcriptional because PCB did not alter TR-mediated transcription T3, corepressor to TR. These results indicate that of TR in complex alter the PCB In mammalian study using and SRC-1, PCB transcription Because the cause for TR-mediated transcriptional suppression by PCB in the present study be partial dissociation of such in binding might not alter the of PCB on TR-mediated transcription. However, this that PCB might act several of TR such as and in vivo have to the that the of PCB action on the thyroid hormone system is the thyroid PCB the placenta and is which might cause the or thyroid to reduce thyroid hormone brain development might be However, the T4 is by perinatal PCB such animals which is by perinatal reduced T4, the T3 in organs is not by PCB the organs might not PCB The present study that PCB acts directly on the TR to suppress transcription. Thus, we that the of action of PCB on the TH system is TR and not the thyroid is the of PCB in the brain than in other studies are to this Many factors might alter PCB action on TR-mediated transcription. key of PCB is that at low doses, which not cause maternal PCB compounds and hydroxylated are to the embryo through the placenta and are and they might disrupt brain development or cause other (10Jacobson J.L. Jacobson S.W. Neurotoxicology. 1997; 18: 415-424Google Scholar, 14Giesy J.P. Kannan K. Crit. Rev. Toxicol. 1998; 28: 511-569Google Scholar). mainly in the developing human brain during the perinatal to the period (22Rabie A. Legrand J. Brain Res. 1973; 61: 267-278Google Scholar, 23Rabie A. Favre C. Clavel M.C. Legrand J. Brain Res. 1977; 120: 521-531Google Scholar) the blood-brain barrier is not Thus, toxic in the can easily the brain during the critical period are (33Kuroda Y. Environ. Sci. 2003; 10: 23-33Google Scholar). Kuroda and (33Kuroda Y. Environ. Sci. 2003; 10: 23-33Google Scholar, J. M. Kuroda Y. Brain Res. 2002; Scholar) of the cerebellar cortex, in which form of in the presence of similar low of hydroxylated PCB also the of of in this system (33Kuroda Y. Environ. Sci. 2003; 10: 23-33Google Scholar). with the present studies a of PCBs on In results that PCBs suppress TR-mediated transcription directly through partial dissociation of TR from the The of PCB action might not be thyroid gland, but TR, which is expressed in many organs, including the central nervous system. We that this study significantly to on PCB to the of in the We M. for the study and T. for the