Search tips
Search criteria 


Logo of envhperEnvironmental Health PerspectivesBrowse ArticlesAbout EHPGeneral InformationAuthorsMediaProgramsPartnerships
Environ Health Perspect. 1994 March; 102(3): 290–297.
PMCID: PMC1567120
Research Article

Polychlorinated biphenyls as hormonally active structural analogues.


Among the environmental chemicals that may be able to disrupt the endocrine systems of animals and humans, the polychlorinated biphenyls (PCBs) are a chemical class of considerable concern. One possible mechanism by which PCBs may interfere with endocrine function is their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB molecular structure and the responses they evoke in biological systems. These physicochemical properties determine the molecular reactivities of PCBs and are responsible for their recognition at biological acceptors and receptors, as well as for triggering molecular mechanisms that lead to tissue response. "Coplanarity" of PCB phenyl rings and "laterality" of chlorine atoms are important structural features determining specific binding behavior with proteins and certain toxic responses in biological systems. We compare qualitative structure-activity relationships for PCBs with the limited information on the related non-coplanar chlorinated diphenyl ethers, providing further insights into the nature of the molecular recognition processes and support for the structural relationship of PCBs to thyroid hormones. Steroidlike activity requires conformational restriction and possibly hydroxylation. We offer some simple molecular recognition models to account for the importance of these different structural features in the structure-activity relationships that permit one to express PCB reactivities in terms of dioxin, thyroxine, and estradiol equivalents. The available data support the involvement of PCBs as mimics of thyroid and other steroidal hormones. The potential for reproductive and developmental toxicity associated with human exposure to PCBs is of particular concern.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (3.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • McFarland VA, Clarke JU. Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis. Environ Health Perspect. 1989 May;81:225–239. [PMC free article] [PubMed]
  • Weinstein H, Rabinowitz J, Liebman MN, Osman R. Determinants of molecular reactivity as criteria for predicting toxicity: problems and approaches. Environ Health Perspect. 1985 Sep;61:147–162. [PMC free article] [PubMed]
  • McKinney JD, Fawkes J, Jordan S, Chae K, Oatley S, Coleman RE, Briner W. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) as a potent and persistent thyroxine agonist: a mechanistic model for toxicity based on molecular reactivity. Environ Health Perspect. 1985 Sep;61:41–53. [PMC free article] [PubMed]
  • McKinney JD. Multifunctional receptor model for dioxin and related compound toxic action: possible thyroid hormone-responsive effector-linked site. Environ Health Perspect. 1989 Jul;82:323–336. [PMC free article] [PubMed]
  • McKinney JD, Singh P. Structure-activity relationships in halogenated biphenyls: unifying hypothesis for structural specificity. Chem Biol Interact. 1981 Jan;33(2-3):271–283. [PubMed]
  • Ishida T, Kamiichi K, Kuwahara A, Doi M, Inoue M. Stacking and hydrogen bonding interactions between phenylalanine and guanine nucleotide: crystal structure of L-phenylalanine-7-methylguanosine-5'-monophosphate complex. Biochem Biophys Res Commun. 1986 Apr 14;136(1):294–299. [PubMed]
  • McKinney JD, Chae K, McConnell EE, Birnbaum LS. Structure-induction versus structure-toxicity relationships for polychlorinated biphenyls and related aromatic hydrocarbons. Environ Health Perspect. 1985 May;60:57–68. [PMC free article] [PubMed]
  • Rickenbacher U, McKinney JD, Oatley SJ, Blake CC. Structurally specific binding of halogenated biphenyls to thyroxine transport protein. J Med Chem. 1986 May;29(5):641–648. [PubMed]
  • McKinney J, Fannin R, Jordan S, Chae K, Rickenbacher U, Pedersen L. Polychlorinated biphenyls and related compound interactions with specific binding sites for thyroxine in rat liver nuclear extracts. J Med Chem. 1987 Jan;30(1):79–86. [PubMed]
  • Kato S, McKinney JD, Matthews HB. Metabolism of symmetrical hexachlorobiphenyl isomers in the rat. Toxicol Appl Pharmacol. 1980 May;53(3):389–398. [PubMed]
  • Yamamoto H, Yoshimura H. Metabolic studies on polychlorinated biphenyls. 3. Complete structure and acute toxicity of the metabolites of 2,4,3',4'-tetrachlorobiphenyl. Chem Pharm Bull (Tokyo) 1973 Oct;21(10):2237–2242. [PubMed]
  • Sjoberg P, Murray JS, Brinck T, Evans P, Politzer P. The use of the electrostatic potential at the molecular surface in recognition interactions: dibenzo-p-dioxins and related systems. J Mol Graph. 1990 Jun;8(2):81–90. [PubMed]
  • Kafafi SA, Afeefy HY, Said HK, Hakimi JM. A new structure-activity model for Ah receptor binding. Polychlorinated dibenzo-p-dioxins and dibenzofurans. Chem Res Toxicol. 1992 Nov-Dec;5(6):856–862. [PubMed]
  • Abraham K, Wiesmüller T, Brunner H, Krowke R, Hagenmaier H, Neubert D. Absorption and tissue distribution of various polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) in the rat. Arch Toxicol. 1989;63(3):193–202. [PubMed]
  • Blake CC, Oatley SJ. Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor? Nature. 1977 Jul 14;268(5616):115–120. [PubMed]
  • Korach KS, Sarver P, Chae K, McLachlan JA, McKinney JD. Estrogen receptor-binding activity of polychlorinated hydroxybiphenyls: conformationally restricted structural probes. Mol Pharmacol. 1988 Jan;33(1):120–126. [PubMed]
  • Landvatter SW, Katzenellenbogen JA. Stereochemical considerations in the binding of nonsteroidal estrogens to the estrogen receptor. Mol Pharmacol. 1981 Jul;20(1):43–51. [PubMed]
  • Albro PW, Parker CE. General approach to the fractionation and class determination of complex mixtures of chlorinated aromatic compounds. J Chromatogr. 1980 Sep 19;197(2):155–169. [PubMed]
  • McKinney JD, Pedersen LG. Biological activity of polychlorinated biphenyls related to conformational structure. Biochem J. 1986 Dec 1;240(2):621–622. [PubMed]
  • Waller CL, McKinney JD. Comparative molecular field analysis of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls. J Med Chem. 1992 Oct 2;35(20):3660–3666. [PubMed]
  • Howie L, Dickerson R, Davis D, Safe S. Immunosuppressive and monooxygenase induction activities of polychlorinated diphenyl ether congeners in C57BL/6N mice: quantitative structure-activity relationships. Toxicol Appl Pharmacol. 1990 Sep 1;105(2):254–263. [PubMed]
  • Harper N, Howie L, Connor K, Arellano L, Craig A, Dickerson R, Safe S. Immunosuppressive and monooxygenase induction activities of highly chlorinated diphenyl ether congeners in C57BL/6 and DBA/2 mice. Fundam Appl Toxicol. 1993 May;20(4):496–502. [PubMed]
  • Chae K, McKinney JD. Molecular complexes of thyroid hormone tyrosyl rings with aromatic donors. Possible relationship to receptor protein interactions. J Med Chem. 1988 Feb;31(2):357–362. [PubMed]
  • Cody V. Thyroid hormones: crystal structure, molecular conformation, binding, and structure-function relationships. Recent Prog Horm Res. 1978;34:437–475. [PubMed]
  • Brouwer A, van den Berg KJ. 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. 1986 Sep 30;85(3):301–312. [PubMed]
  • Ramaker J, Wood WG. Transthyretin--an explanation of "anomalous" serum thyroid hormone values in severe illness? J Clin Chem Clin Biochem. 1990 Mar;28(3):155–161. [PubMed]
  • Dickson PW, Aldred AR, Marley PD, Tu GF, Howlett GJ, Schreiber G. High prealbumin and transferrin mRNA levels in the choroid plexus of rat brain. Biochem Biophys Res Commun. 1985 Mar 29;127(3):890–895. [PubMed]
  • Yen PM, Sugawara A, Chin WW. Triiodothyronine (T3) differentially affects T3-receptor/retinoic acid receptor and T3-receptor/retinoid X receptor heterodimer binding to DNA. J Biol Chem. 1992 Nov 15;267(32):23248–23252. [PubMed]
  • Peterson PA. Studies on the interaction between prealbumin, retinol-binding protein, and vitamin A. J Biol Chem. 1971 Jan 10;246(1):44–49. [PubMed]
  • Albro PW, Corbett JT, Harris M, Lawson LD. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on lipid profiles in tissue of the Fischer rat. Chem Biol Interact. 1978 Dec;23(3):315–330. [PubMed]
  • Chen LC, Berberian I, Koch B, Mercier M, Azais-Braesco V, Glauert HP, Chow CK, Robertson LW. Polychlorinated and polybrominated biphenyl congeners and retinoid levels in rat tissues: structure-activity relationships. Toxicol Appl Pharmacol. 1992 May;114(1):47–55. [PubMed]
  • Freyschuss B, Eriksson H. Evidence for a direct effect of thyroid hormones on the hepatic synthesis of estrogen receptors in the rat. J Steroid Biochem. 1988 Aug;31(2):247–249. [PubMed]
  • DeVito MJ, Thomas T, Martin E, Umbreit TH, Gallo MA. Antiestrogenic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin: tissue-specific regulation of estrogen receptor in CD1 mice. Toxicol Appl Pharmacol. 1992 Apr;113(2):284–292. [PubMed]
  • Jansen HT, Cooke PS, Porcelli J, Liu TC, Hansen LG. Estrogenic and antiestrogenic actions of PCBs in the female rat: in vitro and in vivo studies. Reprod Toxicol. 1993 May-Jun;7(3):237–248. [PubMed]
  • White TE, Gasiewicz TA. The human estrogen receptor structural gene contains a DNA sequence that binds activated mouse and human Ah receptors: a possible mechanism of estrogen receptor regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Biophys Res Commun. 1993 Jun 30;193(3):956–962. [PubMed]
  • Gray LE, Jr, Ostby J, Marshall R, Andrews J. Reproductive and thyroid effects of low-level polychlorinated biphenyl (Aroclor 1254) exposure. Fundam Appl Toxicol. 1993 Apr;20(3):288–294. [PubMed]
  • EAYRS JT. ENDOCRINE INFLUENCE ON CEREBRAL DEVELOPMENT. Arch Biol (Liege) 1964;75:529–565. [PubMed]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Science