Interactions of Persistent Environmental Organohalogens With the Thyroid Hormone System: Mechanisms and Possible Consequences for Animal and Human Health
Restricted accessResearch articleFirst published online January, 1998
Interactions of Persistent Environmental Organohalogens With the Thyroid Hormone System: Mechanisms and Possible Consequences for Animal and Human Health
Several classes of environmental contaminants have been claimed or suggested to possess endocrine-disrupting potency, which may result in reproductive problems and developmental disorders. In this paper the focus is on the multiple and interactive mechanisms of interference of persistent polyhalogenated aromatic hydrocarbons (PHAHs) and their metabolites with the thyroid hormone system. Evidence suggests that pure congeners or mixtures of PHAHs directly interfere with the thyroid gland; with thyroid hormone metabolizing enzymes, such as uridine-diphosphate-glucuronyl transferases (UGTs), iodothyronine deiodinases (IDs), and sulfotransferases (SULTs) in liver and brain; and with the plasma transport system of thyroid hormones in experimentalanimals and their offspring. Changes in thyroid hormone levels in conjunction with high PHAH exposure was also observed in captive as well as free ranging wildlife species and in humans. Maternal exposure to PHAHs during pregnancy resulted in a considerable fetal transfer of hydroxylated PHAHs, which are known to compete with thyroxine (T4) for plasma transthyretin (TTR) binding sites, and thus may be transported to the fetus with those carrier proteins that normally mediate the delivery of T4 to the fetus. Concomitant changes in thyroid hormone concentrations in plasma and in brain tissue were observed in fetal and neonatal stages of development, when sufficient thyroid hormone levels are essential for normal brain development. Alterations in structural and functional neurochemical parameters, such as glial fibrillary acidic protein (GFAP), synaptophysin, calcineurin, and serotonergic neurotransmitters, were observed in the same offspring up to postnatal day 90. In addition, some changes in locomotor and cognitive indices of behavior were observed in rat offspring, following in utero and lactational exposure to PHAHs. Alterations in thyroid hormone levels and subtle changes in neurobehavioral performance were also observed in human infants exposed in utero and through lactation to relatively high levels of PHAHs. Overall these studies indicate that persistent PHAHs can disrupt the thyroid hormone system at a multitude of interaction sites, which may have a profound impact on normal brain development in experimental animals, wildlife species, and human infants.
Adams, C., Lans, M.C., Klasson-Wehler, E., Van Engelen, J.G.M., Visser, T.J., and Brouwer, A. (1990). "Hepatic thyroid hormone 5'-deiodinase, another target-protein for monohydroxy metabolites of 3,3',4,4'-tetrachlorobiphenyl ." Organohalogen Compounds1:51-54.
2.
Bahn, A.K., Mills, J.L., Snyder, P.J., Gann, P.H., Houten, L., Bialik, O., Hollman, L., and Utiger, R.D. (1980). "Hypothyroidism in workers exposed to polybrominated biphenyls." New Engl. J. Med.302:31-33.
3.
Barter, R.A. and Klaassen, C.D. (1992). "UDP-glucuronosyltransferase inducers reduce thyroid hormone levels in rats by an extrathyroidal mechanism." Toxicol. Appl. Pharmacol.113:36-42.
4.
Barter, R.A. and Klaassen, C.D. (1994). "Reduction of thyroid hormone levels and alteration of thyroid function of four representative UDP-glucuronyltransferase inducers in rats." Toxicol. Appl. Pharmacol.128:9-17.
5.
Bastomsky, C.H. (1975). "Effect of a polychlorinated biphenyl mixture (Aroclor 1254) and DDT on biliary thyroxine excretion in rats." Endocrinology101:1150-1155.
6.
Bastomsky, C.H. (1977). "Enhanced thyroxine metabolism and high uptake goiters after a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin." Endocrinology101:292-296.
7.
Bastomsky, C.H. and Murthy, P.V.N. (1976). "Enhanced in vitro hepatic glucuronidation of thyroxine in rats following cutaneous application or ingestion of polychlorinated biphenyls." Can. J. Physiol. Pharmacol.54:23-26.
8.
Baumgartner, A. and Campos-Barros, A. (1993). "Thyroid hormones and depressive disorders— clinical overview and perspectives. Part 2: Thyroid hormones and the central nervous system—basic research." Nervenartz.64(1):11-20.
9.
Becker, J.B. and Beer, M.E. (1986). "The influence of estrogen on nigrostriatal dopamine activity: Behavioral and neurochemical evidence for both pre- and postsynaptic components." Behav. Brain Res.19:27-33.
10.
Beetstra, J.B., Van Engelen, J.G.M., Karels, P., Van Der Hoek, H.J., De Jong, M., Docter, R., Krenning, E.P., Henneman, G., Brouwer, A., and Visser, T.J. (1991). "Thyroxine and 3,3',5-triiodothyronine are glucuronidated in rat liver by different uridine diphosphateglucuronyltransferases." Endocrinology128:741-746.
11.
Bergman, Å., Klasson-Wehler, E., and Kuroki, H. (1994). "Selective retention of hydroxylated PCB metabolites in blood." Environ. Health Perspect.102(5):464-469.
12.
Bertazzi, P.A., Zochetti, C., Pesatori, A.C., Guercilena, S., Sanarico, M., and Radice, L. (1989). "Ten year mortality study of the population in the Seveso incident in 1976." Am. J. Epidem.129:1187-1200.
13.
Boissier, J.R., Euvrard, C., and Labrie, F. (1982). "Interaction of estrogens and the dopaminergic system" Acta Physiol. Pharmacol. Bulg.8(1-2):50-57.
14.
Brewster, D.W., Elwell, M.R., and Birnbaum, L.S. (1988). "Toxicity and disposition of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) in the rhesus monkey (Macaca mulatta)." Toxicol. Appl. Pharmacol.93:231-246.
15.
Brouwer, A. (1989). "Inhibition of thyroid hormone transport in plasma of rats by polychlorinated biphenyls." Arch. Toxicol. Suppl.13:440-445.
16.
Brouwer, A. and VAN Den Berg, K.J. (1986). "Binding of a metabolite of 3,4,3',4'-tetrachlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein complex carrying both retinol and thyroxin." Toxicol. Appl. Pharmacol.85:301-312.
17.
Brouwer, A., Van Den Berg, K.J., Blaner, W.S., and Goodman, D.S. (1986). "Transthyretin (prealbumin) binding of PCBs. A model for the mechanism of interference with vitamin A and thyroid hormone metabolism." Chemosphere15(9-12):1699-1706.
18.
Brouwer, A., Blaner, W.S., Kukler, A., and Van Den Berg, K.J. (1988). "Study on the mechanism of interference of 3,4,3',4'-tetrachlorobiphenyl with the plasma retinol-binding proteins in rodents." Chem-Biol. Interact.68:203-217.
19.
Brouwer, A., Reijnders, P.J.H., and Koeman, J.H. (1989). "Polychlorinated biphenyl (PCB)-contaminated fish induces vitamin A and thyroid hormone deficiency in the common seal (Phoca vitulina). AquaticToxicol.15:99-106.
20.
Brouwer, A., Lans, M.C., De Haan, L.H.J., Murk, A.J., and Morse, D.C. (1994). "Formation and toxicological aspects of phenolic metabolites of polychlorobiphenyls (PCBs) and related compounds." Organohalogen Compounds20:465-469.
21.
Brouwer, A., Ahlborg, U.G., Van Den Berg, M., Birnbaum, L.S., Boersma, E.R., Bosveld, A.T.C., Denison, M.S., Hagmar, L., Holene, E., Huisman, M., Jacobson, S.W., Jacobson, J.J., Koopman-Esseboom, C., Koppe, J.G., Kulig, B.M., Morse, D.C., Muckle, G., Peterson, R.E., Sauer, P.J.J., Seegal, R., Smits-Van Prooije, A.E., Touwen, B.C.L., Weisglas-Kuperus, N., and Winneke, G. (1995). "Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants." Eur. J. Pharmacol. [Environ. Toxicol. Pharmacol. section]293:1-40.
22.
Byrne, J.J., Carbone, J.P., and Hanson, E.A. (1987). "Hypothyroidism and abnormalities in the kinetics of thyroid hormone metabolism in rats treated chronically with polychlorinated biphenyl and polybrominated biphenyl." Endocrinology121:520-527.
23.
Calvo, R., Obregon, M.J., RUIZ DE Ona, C., ESCOBAR Del Rey, F., and MORREALE DE Escobar, G. (1990). "Congenital hypothyroidism, as studied in rats: The crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain." J. Clin. Invest.86:889-899.
24.
Chen Y-C. and Hsu, C.-C. (1994). "Effects of prenatal exposure to PCBs on the neurological function of children: A neuropsychological and neurophysiological study." Develop. Med. Child. Neurol.36:312-320.
25.
Collins, W.T. and Capen, C.C. (1980a). "Biliary excretion of 125I-thyroxine and fine structural alterations in the thyroid glands of Gunn rats fed polychlorinated biphenyls (PCBs)." Lab. Invest.43(2):158-164.
26.
Collins, W.T. and Capen, C.C. (1980b). "Fine structural lesions and hormone alterations in thyroid glands of perinatal rats exposed in utero and by the milk to polychlorinated biphenyls." Am. J. Pathol.99:125-142.
27.
Collins, W.T. and Capen, C.C. (1980c). "Ultrastructural and functional alterations of the rat thyroid gland produced by polychlorinated biphenyls compared with iodide excess and deficiency, and thyrotropin and thyroxine administration ." Virchows Arch. B Cell Path.33:213-231.
28.
Collins, W.T., Capen, C.C., Kasza, L., Carter, C., and Dailey, R.E. (1977). "Effect of polychlorinated biphenyl (PCB) on the thyroid gland of rats. Ultrastructural and biochemical investigations." Am. J. Pathol.89(1):119-130.
29.
Darnerud, P.O. and Sinjari, T. (1996). "Effects of polybrominated diphenylethers (PBDEs) and polychlorobiphenyls (PCBs) on thyroxine and TSH levels in rats and mice ." Organohalogen Compounds29:316-319.
30.
Darnerud, P.O., Morse, D.C., Klasson-Wehler, E., and Brouwer, A. (1996). "Binding of a 3,3',4,4'-tetrachlorobiphenyl (CB-77) metabolite to fetal transthyretin and effects on fetal thyroid hormone levels in mice." Toxicology106:105-114.
31.
De Haan, L.H.J., Van Dijk, L., and Brouwer, A. (1994). "Effects of hydroxylated PCB metabolites on the Gap-Junctional Intercellular Communication between mouse Hepa1c1c7 cells." Organohalogen Compounds20:491-495.
32.
Den Besten, C., Vet, J.J.R.M., Besselink, H.T., Kiel, G.S., VAN Berkel, B.J.M., Beems, R., and VAN Bladeren , P.J. (1991). " The liver, kidney, and thyroid toxicity of chlorinated benzenes." Toxicol. Appl. Pharmacol.111:69-81.
33.
Den Besten, C., Bennik, M.H.J., Bruggeman, I., Schielen, P., Kuper, F., Brouwer, A., KOEMAN, J.H., VOS, J.G., and VAN BLADEREN, P.J. (1993). " The role of oxidative metabolism in hexachlorobenzene-induced porphyria and thyroid hormone homeostasis: A comparison with pentachlorobenzene in a 13-week feeding study." Toxicol. Appl. Pharmacol.119:181-194.
34.
Den Besten, C., Brouwer, A., Rietjens, I.C.M.C., and Van Bladeren, P.J. (1994). "Biotransformation and toxicity of halogenated benzenes." Hum. Experiment. Toxicol.13( 12):866-875.
35.
De Swart, R.L., Ross, P.S., Timmerman, H.H., Hijman, W.C., De Ruiter, E.M., Liem, A.K.D., Brouwer, A., Van Loveren, H., Reijnders, P.J.H., Vos, J.G., and Osterhaus, A.D.M.E. (1995). "Short term fasting does not aggravate immunosuppression in harbour seals (Phoca vitulina) with high body burdens of organochlorines." Chemosphere31(10):4289-4306.
36.
Eltom, S.E., Babish, J.G., and Ferguson, D.C. (1992). "The interaction of 1-triiodothyronine and 2,3,7,8-tetrachlorodibenzo-p-dioxin on Ah receptor mediated hepatic Phase I and Phase II enzymes and iodothyronine 5'-deiodinase in thyroidectomized rats." Toxicol. Lett.61:125-139.
37.
Emmett, E.A., Maroni, M., Jefferys, J., Schmith, J., Levin B.K., and Alvares, A. (1988). "Studies of transformer repair workers exposed to PCBs: II. Results of clinical laboratory investigations." Am. J. Ind. Med.14:47-62.
38.
Eriksson, P. (1988). "Effects of 3,3',4,4'-tetrachlorobiphenyl in the brain of the neonatal mouse." Toxicology49:43-48.
39.
Eriksson, P., Lundkvist, U., and Fredriksson, A. (1991). "Neonatal exposure to 3,3',4,4'tetrachlorobiphenyl: Changes in spontaneous behaviour and cholinergic muscarinic receptors in the adult mouse." Toxicology69:27-34.
40.
Euvrard, C., Oberlander, C., and Boissier, J.R. (1980). "Antidopaminergic effect of estrogens at the striatal level." J. Pharmacol. Exp. Ther.214:179-185.
41.
Fein, G.G., Jacobson, J.L., Jacobson, S.W., Schwartz, P.M., and Dowler, J.K. (1984). "Prenatal exposure to polychlorinated biphenyls: Effects on birth size and gestational age." J. Pediatr.105:315-320.
42.
Freeman, S. and Sohmer, H. (1995). "Effect of thyroxine on the development of somatosensory and visual evoked potentials in the rat." J. Neurol. Sci.128(2):143-150.
43.
Gierthy, J.F., Lincoln, D.W., Gillespie, M.B., Seeger, J.J., Martinez, H.L., Dickermann, H.W., and Kumar, S.A. (1987). "Suppression of estrogen-regulated extracellular tissue plasminogen activator activity in MCF-7 cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin ." Cancer Res.47:6198-6203.
44.
Gladen, B.C., Rogan, W.J., Hardy, P., Thullen, J., Tingelstad, J., and Tully, M. (1988). "Development after exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethane transplacentally and through human milk." J. Pediatr.113:991-995.
45.
Goldey, E.S., KEHN, L.S., LAU, C., REHNBERG, G.L., and CROFTON, K.M. (1995). "Developmental exposure to PCBs (Aroclor 1254) reduces circulating thyroid hormone concentrations and causes hearing deficits in rats." Toxicol. Appl. Pharmacol.135(1):77-88.
46.
Goodman, D.S. (1980). "Plasma retinol-binding protein in lipoprotein structure." Ann. N.Y. Acad. Sci.348:378-390.
47.
Gould, E., Frankfurt, M., Westlind-Danielsson, A., and McEwen, B.S. (1990). "Developing forebrain astrocytes are sensitive to thyroid hormone." Glia3(4):283-292.
48.
Grässle, B. and Biesmann, A. (1984). "Effects of DDT, polychlorinated biphenyls and thiouracil on eggshell quality in Japanese quail (Coturnix coturnix japonica). Chem.-Biol. Interact.42:371-377.
49.
Gray, L., JR., Ostby, J., Marshall, R., and Andrews, J. (1993). "Reproductive and thyroid effects of low-level polychlorinated biphenyl (Aroclor 1254) exposure." Fundam. Appl. Toxicol.20:288-294.
50.
Guo, Y.L., Yu, M.-L., Lin, L.-Y., Hsu, C.-C., and Rogan, W.J. (1996). "Chloracne, goiter, and anemia 13 years after PCB/PCDF poisoning: Follow-up of the Taiwan Yucheng cohort." Organohalogen Compounds30:223-227.
51.
Gupta, B.N., McConnell, E.E., Goldstein, J.A., Harris, M.W., and Moore, J.A. (1983). "Effects of a polybrominated biphenyl mixture in the rat and mouse. I. Six-month exposure." Toxicol. Appl. Pharmacol.68:1-18.
52.
Henry. E.C. and Gasiewicz, T.A. (1986). "Effects of thyroidectomy on the Ah-receptor and enzyme inducibility by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver ." Chem.-Biol. Interact.59:29-42.
53.
Henry, E.C. and Gasiewicz, T.A. (1987). "Changes in thyroid hormones and thyroxine glucuronidation in hamsters compared with rats following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin ." Toxicol. Appl. Pharmacol.89:165-174.
54.
Holene, E., Nafstad, I., Skaare, J.U., Bernhoft, A., Engen, P., and Sagvolden, T. (1995). "Behavioral effects of pre- and postnatal exposure to individual polychlorinated biphenyl congeners in rats." Environ. Toxicol. Chem.14(6):967-976.
55.
Huisman, M., Koopman-Esseboom, C., Fidler, V., Hadders-Algra, M., Van Der Paauw, C.G., Tuinstra, L.M.G. Th, Weisglas-Kuperus, N., Sauer, P.J.J., Touwer, B.C., and Boersma, E.R. (1995). "Perinatal exposure to polychlorinated biphenyls and dioxins and its effect on neonatal neurological development." Early Hum. Develop.41(2):111-127.
56.
Jacobson, S.W., Fein, G.G., Jacobson, J.L., Schwartz, P.M., and Dowler, J.K. (1985). "The effect of intrauterine PCB exposure on visual recognition memory." Child Develop.56:853-860.
57.
Jacobson, J.L., Jacobson, S.W., and Humphrey, H.E.B. (1990). "Effects of in utero exposure to polychlorinated biphenyls and related contaminants on cognitive functioning in young children." J. Pediatr.116:38-45.
58.
Jansen, H.T., Cooke, P.S., Porcelli, J., Liu, T.-C., and Hansen, L.G. (1993). "Estrogenic and antiestrogenic actions of PCBs in the female rat: In vitro and in vivo studies." Reproductive Toxicol.7:237-248.
59.
Jeffries, D.J. and French, M.C. (1971). "Hyper- and hypothyroidism in pigeons fed DDT: An explanation for the thin eggshell phenomenon." Environ. Pollut.1:235-242.
60.
Jenssen, B.M. (1996). "An overview of exposure to, and effects of, petroleum oil and organochlorine pollution in grey seals (Halichoerus grypus)." Sci. Total Environ.186(1-2):109-118.
61.
Jones, M.K., Weisenburger, W.P., Sipes, I.G., and Haddock Russel, D. (1987). "Circadian alterations in prolactin, corticosterone, and thyroid hormone levels and down-regulation of prolactin receptor activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin." Toxicol. Appl. Pharmacol.87:337-350.
62.
Kaplan, M.M., Visser, T.J., Yaskoski, K.A., and Leonard, J.L. (1983). "Characteristics of iodothyronine tyrosyl ring deiodination by rat cerebral cortical microsomes." Endocrinology112:35-42.
63.
Kasza, L., Collins, W.T., Capen, C.C., Garthoff, L.H., and Friedman, L. (1978). "Comparative toxicity of polychlorinated biphenyl and polybrominated biphenyl in the rat thyroid gland: Light and electron microscopic alterations after subacute dietary exposure." J. Environ. Pathol. Toxicol.1:587-599.
64.
Kohn, M.C., Sewall, C.H., Lucier, G.W., and Portier, C.J. (1996). "A mechanistic model of effects of dioxin on thyroid hormones in the rat." Toxicol. Appl. Pharmacol.165:29-48.
65.
Koopman-Esseboom, C., Morse, D.C., Weisglas-Kuperus, N., Lutke-Schipholt, I., Van Der Paauw, C.G., Tuinstra, L.G.M.T., Brouwer, A., and Sauer, P.J.J. (1994). "Effects of dioxins and polychlorinated biphenyls on thyroid hormone status of pregnant women and their infants." Pediatr. Res.36(4):468-473.
66.
Korach, K.S., Sarver, P., Chae, K., McLachlan, J.A., and McKinney, J.D. (1988). "Estrogen receptor binding activity of polychlorinated hydroxybiphenyls: Conformationally restricted structural probes." Mol. Pharmacol.33:120-126.
67.
Kreis, K., Roberts, C., and Humphrey, H.E.B. (1982). "Serial PBB levels, PCB levels and clinical chemistries in Michigan's PBB cohort." Arch. Environ. Health37(3):141-146.
68.
Lans, M.C. (1995). "Thyroid hormone binding proteins as novel targets for hydroxylated polyhalogenated aromatic hydrocarbons (PHAHs): Possible implications for toxicity." Thesis Agricultural UniversityWageningen ISBN 90-5485-430-8.
69.
Lans, M.C., Brouwer, A., Koppe, J.G., and Van Den Berg, M. (1990a). "Enzyme induction and alterations in thyroid hormone, vitamin A and K levels by TCDD in neonatal and maternal rats." Chemosphere20(7-9): 1129-1134.
70.
Lans, M.C., Kubiczak, G., Douwes, J., and Brouwer, A. (1990b). "In vitro effects of 3,4,3',4'tetrachlorobiphenyl and its hydroxymetabolites on mitochondrial function." In: 10th International Meeting on Dioxins, Bayreuth , W-Germany, Vol. 1, Ecoinforma Press, Bayreuth, Germany. pp. 103-106.
71.
Lans, M.C., Klasson-Wehler, E., Willemsen, M., Meussen, E., Safe, S., and Brouwer, A. (1993). "Structure-dependent, competitive interaction of hydroxy-polychlorobiphenyls, -dibenzo-p-dioxins and -dibenzofurans with human transthyretin." Chem.-Biol. Interact.88:7-21.
72.
Lans, M.C., Spiertz, C., Brouwer, A., and Koeman, J.H. (1994). "Different competition of thyroxine binding to transthyretin and thyroxine-binding globulin by hydroxy-PCBs, PCDDs, and PCDFs ." European J. Pharmacol. [Environ. Toxicol. Pharmacol. Section]270:129-136.
73.
Leatherland, J.F. and Sonstegard, R.A. (1982). "Bioaccumulation of organochlorines by yearling coho salmon (Oncorhynchus kitutch Walbaum) fed diets containing Great Lakes coho salmon, and the pathophysiological responses of the recipients ." Comp. Biochem. Physiol.C. 72:91-99.
74.
Li, M.-H. and Hansen, L.G. (1996a). "Enzyme induction and acute endocrine effects in prepubertal female rats receiving environmental PCB/PCDF/PCDD mixtures " Environ. Health Perspect.104:712-722.
75.
Li, M.-H. and Hansen, L.G. (1996b). "Responses of prepubertal female rats to environmental PCBs with high and low dioxin equivalence." Fundam. Appl. Toxicol.33:282-293.
76.
Lilienthal, H., Neuf, M., Munoz, C., and Winneke, G. (1990). "Behavioral effects of pre- and postnatal exposure to a mixture of low chlorinated PCBs in rats." Fundam. Appl. Toxicol.15:457-467.
77.
Lucier, G.S., McDaniel, O.S., and Hook, G.E.R. (1975). "Nature of the enhancement of hepatic uridine diphosphate glucuronyl transferase activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats." Biochem. Pharmacol.24:325-331.
78.
Moccia, R.D., Fox, G.A., and Britton, A. (1986). "A quantitative assessment of thyroid histopathology of herring gulls (Larus argentatus) from the Great Lakes and a hypothesis on the causal role of environmental contaminants." J. Wildl. Dis.22:60-70.
79.
Morse, D.C., Groen, D., Veerman, M., Van Amerongen, C.J., Koeter, H.B.W.M., Smits-Van Pooije, A.E., Visser, T.J., Koeman, J.H., and Brouwer, A. (1993). "Interference of polychlorinated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats." Toxicol. Appl. Pharmacol.122:27-33.
80.
Morse, D.C., Klasson-Wehler, E., Van De Pas, M., De Bie, A.Th.H.J., Van Bladeren, P.J., and Brouwer, A. (1995a). "Metabolism and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl in pregnant and fetal rats." Chem.-Biol. Interact.95:41-56.
81.
Morse, D.C., Van Bladeren, P.J., Klasson-Wehler, E., and Brouwer, A. (1995b). "β-Naphthoflavone- and self-induced metabolism of 3,3',4,4'-tetrachlorobiphenyl in hepatic microsomes of the male, pregnant female and foetal rat." Xenobiotica25(3):245-260.
82.
Morse, D.C., Klasson-Wehler, E., Wesseling, W., Koeman, J.H., and Brouwer, A. (1996a). "Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254)." Toxicol. Appl. Pharmacol.136:269-279.
83.
Morse, D.C., Plug, A., Wesseling, W., Van Den Berg, K.J., and Brouwer, A. (1996b). "Persistent alterations in regional brain glial fibrillary acidic protein and synaptophysin levels following pre- and postnatal polychlorinated biphenyl exposure." Toxicol. Appl. Pharmacol.139:252-261.
84.
Morse, D.C., Seegal.,R.F., Brosch, K.O., and Brouwer, A. (1996c). "Long-term alterations in regional brain serotonin metabolism following maternal polychlorinated biphenyl exposure in the rat ." Neurotoxicology17(3-4):631-638.
85.
Münzel, P.A., Brück, M., and Bock, K.W. (1994). "Tissue specific constitutive and inducible expression of rat phenol UDP-glucuronyltransferase." Biochem. Pharmacol.47(8): 1445-1448.
86.
Murai, K., Okamura, K., Tsuji, H., Kajiwara, E., Watanabe, H., Akagi, K., and Fujishima, M. (1987). "Thyroid function in "Yusho" patients exposed to polychlorinated biphenyls." Environ. Res.44:179-187.
87.
Murk, A.J., Van Den Berg, J.H.J., Koeman, J.H., and Brouwer, A. (1991). "The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorobiphenyls (Aroclor 1254 and PCB 77) compared in Ah-responsive and Ah-nonresponsive mice." Environ. Pollut.72:57-67.
88.
Murk, A.J., Bosveld, A.T.C., Van Den Berg, M., and Brouwer, A. (1994a). "Effects of polyhalogenated aromatic hydrocarbons (PHAHs) on biochemical parameters in chicks of the common tern (Sterna hirundo) ." Aquatic Toxicol.30:91-115.
89.
Murk, A.J., Morse, D.C., Boon, J., and Brouwer, A. (1994b). "In vitro metabolism of 3,3',4,4'tetrachlorobiphenyl in relation to ethoxyresorufin-O-deethylase activity in liver microsomes of some wildlife species and rat." Eur. J. Pharmacol. [Environ. Toxicol. Pharmacol. section]270:253-261.
90.
Murk, A.J., Van Den Berg, J.H.J., Fellinger, M., Rozemeijer, M.J.C., Swennen, C., Duiven, P., Boon, J.P., Brouwer, A., and Koeman, J.H. (1994c). "Toxic and biochemical effects of 3,3',4,4'tetrachlorobiphenyl (CB-77) and Clophen A-50 on eider ducklings (Somateria mollissima) in a semi-field experiment." Environ. Pollut.86:21-30.
91.
Nagayama, J., Iida, T., Hirakawa, H., Matsueda, T., Tsuji, H., Okamura, K., Hasegawa, M., Sato, K., KITAHARA, E., MA, H.-Y., YANAGAWA, T., IGARASHI, H., FUKUSHIGE, J.'I., and WATANABE, T. (1996). "Effects of lactational exposure to chlorinated dioxins and related chemicals on lymphocyte subpopulations and thyroid functions in Japanese babies." Organohalogen Compounds30:228-233.
92.
Narasimhan, T.R., Kim, H.L., and Safe, S.H. (1991). "Effects of hydroxylated polychlorinated biphenyls on mouse liver mitochondrial oxidative phosphorylation." J. Biochem. Toxicol.6(3):229-236.
93.
Nedvikova, J., Pacak, K., Nedvidek, J., Goldstein, D.S., and Schreiber, V. (1996). "Triiodothyronine attenuates estradiol-induced increases in dopamine D-2 receptor number in rat anterior pituitary." Brain Res.712(1):148-152.
94.
Ness, D.K., Schantz, S.L., Moshtaghian, J., and Hansen, L.G. (1993). "Effects of perinatal exposure to specific PCB congeners on thyroid hormone concentrations and thyroid histology in the rat ." Toxicol. Lett.68:311-323.
95.
Nevue, I. and Arenas, E. (1996). "Neurotrophins promote the survival and development of neurons in the cerebellum of hypothyroid rats in vivo." J. Cell. Biol.133(3):631-646.
96.
Obregón, M.J., Ruiz De Ona, C., Calvo, R., Escobar Del Rey, F., and Morreale De Escobar, G. (1991). "Outer ring iodothyronine deiodinases and thyroid hormone economy: Responses to iodine deficiency in the rat fetus and neonate." Endocrinology129:2663-2673.
97.
O'Callaghan, J.P. and Miller, D.B. (1988). "Acute exposure of the neonatal rat to triethyltin results in persistent changes in neurotypic and gliotypic proteins." J. Pharmacol. Exp. Ther.244:368-387.
98.
Perry, K.O., Diamond, B.I., Fields, J.Z., and Gordon, J.H. (1981). "Hypophysectomy induced hypersensitivity to dopamine: Antagonism by estrogen." Brain Res.226:211-219.
99.
Pesatori, A., Consonni, D., Tironi, A., Zochetti, C., Fini, A., and Bertazzi, P.A. (1993). "Cancer in a young population in a dioxin-contaminated area." Int. J. Epidemiol.22:1010-1013.
100.
Pluim, H.J., De Vijlder, J.J.M., OLIE, K., KOK, J.H., VULSMA, T., VANTIJN, D.A., VAN DER SLIKKE, J.N, and KOPPE J.G. (1993). "Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations ." Environ. Health Perspect.101:504-508.
101.
Pohjanvirta, R., Kulju, T., Morselt, A.F.W., Tuominen, R., Juvonen, R., Rozman, K., Mannisto, P., Collan, Y., Sainio, E.-L., and Tuomisto, J. (1989). "Target tissue morphology and serum biochemistry following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in a TCDDsusceptible and a TCDD-resistant strain." Fundam. Appl. Toxicol.12:698-712.
102.
Potter, C.L., Sipes, I.G., and Russel, D.H. (1983). "Hypothyroxinaemia and hypothermia in rats in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin administration." ToxicolAppl. Pharmacol.69:89-95.
103.
Potter, C.L., Moore, R.W., Inhron, S.L., Hagen, T.C., and Peterson, R.E. (1986). "Thyroid status and thermogenesis in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin." Toxicol. Appl. Pharmacol.84:45-55.
104.
Rami, A. and Rabié, A. (1988). "Effect of thyroid deficiency on the development of glia in the hippocampal formation of the rat: An immunocytochemical study ." Glia1:337-345.
105.
Rickenbacher, U., Jordan, S., and McKinney, J.D. (1989). "Structurally specific interaction of halogenated dioxin and biphenyl derivatives with iodothyronine-5'-deiodinase in rat liver ." In: Probing Bioactive Mechanisms ACS Symp. Series. 413:354-365.
106.
Rogan, W.J., Gladen, B.C., Hung, K.-L., Koong, S.-L., Shia, L.-Y., TAYLOR, J.S., WU, Y.-C., YANG, D., RAGAN, N.B., and HSU, C.-C. (1988 ). "Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan." Science241:334-336.
107.
Ross, P.S. (1995). "Seals, pollution and disease: Environmental contaminant-induced immunosuppression." Thesis University Utrecht, Netherlands. ISBN 90-393-0780-6.
108.
Roth, W., Voorman, R., and Aust, S. (1988). "Activity of thyroid hormone-inducible enzymes following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin." Toxicol. Appl. Pharmacol.92:65-74.
109.
Rozman, K., Hazelton, G.A., Klaassen, C.D., Arlotto, M.P., and Parkinson, A. (1985). "Effects of thyroid hormones on liver microsomal enzyme induction in rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin." Toxicology37:51-63.
110.
Rozman, K., Pereira, D., and Iatropoulos, M.J. (1986). "Histopathology of interscapular brown adipose tissue, thyroid and pancreas in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats." Toxicol. Appl. Pharmacol.82:551-559.
111.
Rozman, K., Gorski, J.R., Dutton, D., and Parkinson, A. (1987). "Effects of vitamin A and/or thyroidectomy on liver microsomal enzymes and their induction in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats." Toxicology46:107-117.
112.
Ruiz De Elvira, M.C., Shinha, A.K., Pickard, M., Ballabio, M., Hubank, M., and Ekins, R.P. (1989). "Effect of maternal hypothyroxinemia during fetal life on the calmodulin-regulated phosphatase activity in the brain of the adult progeny in the rat." J. Endocrinol.121:331-335.
113.
Ruiz DEOña, C., Obregón, M.J., ESCOBAR Del Rey, F., and MORREALE DE Escobar, G. (1988). "Developmental changes in rat brain 5'-deiodinase and thyroid hormones during the fetal period: The effects of fetal hypothyroidism and maternal thyroid hormones." Pediatr. Res.24:588-594.
114.
Safe, S.H., Astroff, B., Harris, M., Zacharewsi, T., Dickerson, R., Romkes, M., and Biegel, L. (1991). "2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds as antiestrogens: Characterization and mechanism of action ." Pharmacol. Toxicol.69:400-409.
115.
Saito, K., Kaneko, H., Sato, K., Yoshitake, A., and Yamada, H. (1991). "Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: Induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers." Toxicol. Appl. Pharmacol.111:99-106.
116.
Sandrini, M., Vitale, G., Vergoni, A.V., Ottani, A., and Bertolini, A. (1996). "Effect of acute and chronic treatment with triiodothyronine on serotonin levels and serotonergic receptor subtypes in the rat brain." Life Sci.58(18):1551-1559.
117.
Sauer, P.J.J., Huisman, M., Koopman-Esseboom, C., MORSE, D.C., SMITS-VAN PROOIJE, A.E., VAN DEN BERG, K.J., TUINSTRA, L.G.M.T., VAN DER PAAUW, C.G., BOERSMA, E.R., WEISGLAS-KUPERUS, N., LAMMERS, J.H.C.M., KULIG, B.M., and BROUWER, A. (1994). "Effects of polychlorinated biphenyls (PCBs) and dioxins on growth and development." Hum. Exp. Toxicol.13:900-906.
118.
Savard, P., Merand, Y., Di Paolo, T., and Dupont, A. (1984). "Effect of neonatal hypothyroidism on the serotonin system of the rat brain." Brain Res.292:99-108.
119.
Schantz, S.L. and Bowman, R.E. (1989). "Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)." Neurotoxicol. Teratol.11:13-19.
120.
Schantz, S.L., Levin, E.D., Bowman, R.E., Heironimus, M.P., and Laughlin, N.K. (1989). "Effects of perinatal PCB exposure on discriminated-reversal learning in monkeys." Neurotoxicol. Teratol.11:243-250.
121.
Schantz, S.L., Ferguson, S.A., and Bowman, R.E. (1992). "Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on behavior of monkeys in peer groups." Neurotoxicol. Teratol.14:433-446.
122.
Schuur, A.G., Van Meeteren, M.E., Jong, W.M.C., Bergman, Å., Visser, T.J., and Brouwer, A. (1996). "Inhibition of thyroid hormone sulfation by hydroxylated metabolites of polychlorinated biphenyls in vitro." Organohalogen Compounds28:509-512.
123.
Schuur, A.G., Brouwer, A., Bergman, Å., Coughtrie, M.W.H., and Visser, T.J. (1997). "Inhibition of thyroid hormone sulfation by hydroxylated metabolites of polychlorinated biphenyls." Chem.-Biol. Interact. In press.
124.
Seegal, R.F. (1992). "Perinatal exposure to Aroclor 1016 elevates brain dopamine concentrations in the rat." The Toxicologist12:320.
125.
Seegal, R.F. (1994). "The neurochemical effects of PCB exposure are age-dependent." Arch. Toxicol. Suppl.16:128-137.
126.
Seegal, R.F. and Shain, W. (1992). "Neurotoxicity of polychlorinated biphenyls." In: The Vulnerable Brain and Environmental Risks (R.L. Isaacson and K.F. Jensen , eds.). Vol. 3. Plenum Press , New York, NY. pp. 169-195.
127.
Seegal, R.F., Bush, B., and Shain, W. (1990). "Lightly chlorinated ortho-substituted PCB congeners decrease dopamine in nonhuman primate brain and in tissue culture." Toxicol. Appl. Pharmacol.106:136-134.
128.
Seegal, R.F., Bush, B., and Brosch, K.O. (1991). "Sub-chronic exposure of the adult rat to Aroclor 1254 yields regionally-specific changes in central dopamine function." Neurotoxicology12:55-65.
129.
Seegal, R.F., Bush, B., and Brosch, K.O. (1994). "Decreases in dopamine concentrations in adult, nonhuman primate brain persist following removal from polychlorinated biphenyls ." Toxicology86:71-87.
130.
Seo, B.-Y., Li, M.-H., Hansen, L.G., Moore, R.W., Peterson, R.E., and Schantz, S.L. (1995). "Effects of gestational and lactational exposure to coplanar PCB congeners or TCDD on thyroid hormone concentrations in weanling rats." Toxicol. Lett.78:253-262.
131.
Sepkovic, D.W. and Byrne, J.J. (1984). "Kinetic parameters of L-[125I]-triiodothyronine degradation in rats pretreated with polyhalogenated biphenyls." Food Chem. Toxicol.22:743-747.
132.
Shain, W., Bush, B., and Seegal, R.F. (1991). "Neurotoxicity of polychlorinated biphenyls: Structure-activity relationships of individual congeners." Toxicol. Appl. Pharmacol.111(1):33-42.
133.
Silva, J.E. and Matthews, P.S. (1984). "Production rates and turnover of triiodothyronine in rat developing cerebral cortex and cerebellum." J. Clin. Invest.74:1035-1049.
134.
Southwell., B.R., Duan, W., Alcorn, D., Brack, C., Richardson, S.J., Kohrle, J., and Schreiber, G. (1993). "Thyroxine transport to the brain: Role of protein synthesis by the choroid plexus." Endocrinology133(5):2116-2126.
135.
Spear, P.A. and Moon, T.W. (1985). "Low dietary iodine and thyroid anomalies in ring doves (Streptopelia risoria) exposed to 3,4,3',4'-tetrachlorobiphenyl." Arch. Environ. Contam. Toxicol.14:547-553.
136.
Spear, P.A., Higueret, P., and Garcin, H. (1990). "Increased thyroxine turnover after 3,3',4,4',5,5'hexabromobiphenyl injection and lack of effect on peripheral triiodothyronine production." Can. J. Physiol. Pharmacol.68:1079-1084.
137.
Spear, P.A., Higueret, P., and Garcin, H. (1994). "Effects of fasting and 3,3',4,4',5,5'hexabromobiphenyl on plasma transport of thyroxine and retinol: Fasting reverses elevation of retinol." J. Toxicol. Environ. Health42:173-183.
138.
Stein, S.A., Kirkpatrick, L.L., Shanklin, D.R., Adams, P.M., and Brady, S.T. (1991). "Hypothyroidism reduces the rate of slow component A (SCa) axonal transport and the amount of transported tubulin in the hyt/hyt mouse optic nerve." J. Neurosci. Res.28(1):121-133.
139.
Sutter, T.R. and Greenlee, W.F. (1992). "Classification of members of the Ah gene battery ." Chemosphere25:223-226.
140.
Tilson, H.A. and Harry, G.J. (1994). "Developmental neurotoxicology of polychlorinated biphenyls and related compounds." In: The Vulnerable Brain and Environmental Risks: Toxins in Air and Water, Vol. 3. (R.L. Isaacson and K.F. Jensen, eds.). Plenum Press, New York, NY. pp. 276.
141.
Tryphonas, L., Truelove, J., Zawidzka, Z., WONG, J., MES, J., CHARBONNEAU, S., GRANT, D.L., and CAMPBELL, J.S. ( 1984). "Polychlorinated biphenyl (PCB) toxicity in adult cynomolgus monkeys (Macaca fascicularis): A pilot study." Toxicol. Pathol.12(1):10-25.
142.
Umbreit, T.H., Scala, P.L., Mackenzie, S.A., and Gallo, M.A. (1989). "Alteration of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by estradiol and tamoxifen." Toxicology59:163-169.
143.
Van Birgelen, A.P.J.M., Van Der Kolk, J., Fase, K., Bol, I., Poiger, H., Brouwer, A., and Van Den Berg, M. (1994a). "Toxic potency of 3,3',4,4',5-pentachlorobiphenyl relative to and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin in a subchronic feeding study in the rat." Toxicol. Appl. Pharmacol . 127(2):209-221.
144.
Van Birgelen, A.P.J.M., Van Der Kolk, J., Fase, K., Bol, I., Poiger, H., Van Den Berg, M., and Brouwer, A. (1994b). "Toxic potency of 2,3,3',4,4'-5-hexachlorobiphenyl relative to and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin in a subchronic feeding study in the rat." Toxicol. Appl. Pharmacol.126:202-213.
145.
Van Birgelen, A.P.J.M., Smit, E.A., Kampen, I.M., Groeneveld, C.N., Fase, K.M., Van Der Kolk, J., Poiger, H., Van Den Berg, M., Koeman, J.H., and Brouwer, A. (1995). "Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism: Use in risk assessment." Eur. J. Pharmacol. [Environ. Toxicol. and Pharmacol. section]293:77-85.
146.
Van Den Berg, K.J. (1990). "Interaction of chlorinated phenols with thyroxine binding sites of human transthyretin, albumin and thyroid binding globulin ." Chem.-Biol. Interact.76:63-75.
147.
Van Den Berg, K.J., Zurcher, C., and Brouwer, A. (1988). "Effects of 3,4,3',4'-tetrachlorobiphenyl on thyroid function and histology in marmoset monkeys." Toxicol. Lett.41:77-86.
148.
Van Den Berg, M., Craane, B.L.H.J., Sinnige, T., Van Mourik, S., Dirksen, S., Boudewijn, T., Van Der Gaag, M., Lutke-Schipholt, I.J., Spenkelink, A., and Brouwer, A. (1994). "Biochemical and toxic effects of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in the cormorant (Phalacrocorax carbo) after in ovo exposure." Environ. Toxicol. Chem.13(5):803-816.
149.
Van Den Heuvel, J.P. and Lucier, G. (1993). "Environmental toxicology of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans." Environ. Health Perspect.100:189-200.
150.
Van Hartesveldt, C. and Joyce, J.N. (1986). "Effects of estrogen on basal ganglia." Neurosci. Biobehav. Rev.10(1):1-14.
151.
Van Raaij, J.A.G.M., Kaptein, E., Visser, T.J., and VAN Den Berg, K.J. (1993). "Increased glucuronidation of thyroid hormone in hexachlorobenzene treated rats." Biochem. Pharmacol.45:627-631.
152.
Vega-Nunez, E., Menendez-Hurtado, A., Garesse, R., Santos, A., and Perez-Castillo, A. (1995). "Thyroid hormone-regulated brain mitochondrial genes revealed by differential cDNA cloning." J. Clin. Invest.96(2):893-899.
153.
Visser, T.J. (1990). "Importance of deiodination and conjugation in the hepatic metabolism of thyroid hormone." In: The Thyroid Gland (M.A. Greer, ed). Raven Press, Ltd., New York, NY. pp. 255-283.
154.
Visser, T.J. (1994). "Role of sulfation in thyroid hormone metabolism ." Chem.-Biol. Interact.92(1-3):293-303.
155.
Visser, T.J. (1996). "Pathways of thyroid hormone metabolism." Acta Med. Austriaca23(1-2):10-16.
156.
Visser, T.J., Leonard, J.L., Kaptein, M.M., and Larsen, P.R. (1982). "Kinetic evidence suggesting two mechanisms for iodothyronine 5'-deiodination in rat cerebral cortex." Proc. Natl. Acad. Sci. USA. 79:5080-5084.
157.
Visser, T.J., Fekkes, D., Otten, M.H., Mol, J.A., Docter, R., and Hennemann, G. (1984). "Deiodination and conjugation of thyroid hormone in rat liver." In: Hormones and Cell Regulation, Vol. 8 (J.E. Dumont and J. Nunez, eds.). INSERM European Symposium. pp. 179-191.
158.
Visser, T.J., Kaptein, E., and Harper, E.S. (1990). "The role of sulfation in thyroid hormone metabolism ." Trends Endocrinol. Metab.1:211-218.
159.
Visser, T.J., Kaptein, E., Van Toor, H., Van Raay, J.A.G.M., Van Den Berg, K.J., Tjong Tjin Joe, C., Van Engelen, J.G.M., and Brouwer, A. (1993). "Glucuronidation of thyroid hormone in rat liver: Effects of in vivo treatment with microsomal enzyme inducers and in vitro assay conditions." Endocrinology133(5):2177-2186.
