API

Stressor: 148

Title

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Polychlorinated biphenyl

Stressor Overview

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AOPs Including This Stressor

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Events Including This Stressor

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Chemical Table

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AOP Evidence

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Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF

Certain polychlorinated biphenyl (PCB) congeners are potent AHR agonists, and lead to dioxin-like cardiotoxicity in birds (Carro et al. 2013a; Carro et al. 2013b; Brunstrom, B. 1989; Rifkind et al. 1984)  and fish (Clark et al. 2010; Olufsen and Arukwe 2011; Grimes et al. 2008).  Furthermore, PCB contamination in wild avian species has been correlated with altered heart size and morphology (DeWitt et al. 2006; Henshel and Sparks 2006).

Of the dioxin-like PCBs, non-ortho congeners are the most toxicologically active, while mono-ortho PCBs are generally less potent (McFarland and Clarke 1989; Safe 1994). Chlorine substitution at ortho positions increases the energetic costs of assuming the coplanar conformation required for binding to the AHR (McFarland and Clarke 1989). Thus, a smaller proportion of mono-ortho PCB molecules are able to bind to the AHR and elicit toxic effects, resulting in reduced potency of these congeners. Other PCB congeners, such as di-ortho substituted PCBs, are very weak AHR agonists and do not likely contribute to dioxin-like effects (Safe 1994).

References

Carro, T., Dean, K., and Ottinger, M. A. (2013a). Effects of an environmentally relevant polychlorinated biphenyl (PCB) mixture on embryonic survival and cardiac development in the domestic chicken. Environ.Toxicol.Chem.

Carro, T., Taneyhill, L. A., and Ottinger, M. A. (2013b). The effects of an environmentally relevant 58 congener polychlorinated biphenyl (PCB) mixture on cardiac development in the chick embryo. Environ.Toxicol.Chem.

Brunstrom, B. (1989). Toxicity of coplanar polychlorinated biphenyls in avian embryos. Chemosphere 19, 765-768.

Rifkind, A. B., Hattori, Y., Levi, R., Hughes, M. J., Quilley, C., and Alonso, D. R. (1984). The chick embryo as a model for PCB and dioxin toxicity: Evidence of cardiotoxicity and increased prostaglandin synthesis. In Biological Mechanisms of Dioxin Action (A. Poland and R. D. Kimbrough, Eds.), pp. 255–266. Cold Spring Harbor Press, Cold Spring Harbor, NY.

Clark, B.W.; Matson, C.W.; Jung, D.; Di Giulio, R.T. 2010. AHR2 mediates cardiac teratogenesis of polycyclic aromatic hydrocarbons and PCB-126 in Atlantic killifish (Fundulus heteroclitus). Aquat. Toxicol. 99, 232-240.

Olufsen, M. and Arukwe, A. (2011) Developmental effects related to angiogenesis and osteogenic differentiation in Salmon larvae continuously exposed to dioxin-like 3,3’,4,4’-tetrachlorobiphenyl (congener 77). Aquatic Toxicology 105: 669– 680

A.C. Grimes, K.N. Erwin, H.A. Stadt, G.L. Hunter, H.A. Gefroh, H.J. Tsai, M.L. Kirby (2008) PCB126 exposure disrupts zebrafish ventricular and branchial but not early neural crest development Toxicol. Sci., 106, pp. 193-205

DeWitt, J. C., Millsap, D. S., Yeager, R. L., Heise, S. S., Sparks, D. W., and Henshel, D. S. (2006). External heart deformities in passerine birds exposed to environmental mixtures of polychlorinated biphenyls during development. Environ.Toxicol.Chem. 25, 541-551.

Henshel, D. and Sparks, D.W. (2006) Site Specific PCB-Correlated Interspecies Differences in Organ Somatic Indices. Ecotoxicology, 1: 9-18

Safe, S. (1994). Polychlorinated biphenyls (PCBs): Environmental impact, biochemical and toxic responses, and implications for risk assessment. Critical Reviews in Toxicology 24, 87-149.

McFarland, V. A., and Clarke, J. U. (1989). Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: Considerations for a congener-specific analysis. Environ.Health Perspect. 81, 225-239.



Interference with thyroid serum binding protein transthyretin and subsequent adverse human neurodevelopmental toxicity

A number of PCBs and metabolites have been found to bind to TTR (Lans et al 1993; Grimm et al 2013; Marchesini et al 2008) and have been frequently found to be associated with interference in thyroid signaling (Boas et al 2012; Gore et al 2015; Miller et al 2009; Murk et al 2013; Preau et al 2015).  Overall, the hydroxylated metabolites of PCBs competitively bind T4 more than the parent compounds (Weiss et al 2015). Depending on the congener and/or type of metabolite (i.e. hydroxylate, sulfate, etc.), there are multiple mechanisms by which this class of environmental contaminants can affect thyroid hormone levels in many tissues, including through interfering with TTR-T4 binding and transport of T4 into the brain (Morse et al 1996; Martin and Klaassen 2010; Martin et al 2012).  Multiple epidemiological studies in humans have reported associations between exposure to PCBs and/or metabolites and serum thyroid hormone concentrations (Dallaire et al 2009a, 2009b; Eguchi et al 2015), with hydroxylated metabolites demonstrating the greatest potential for TTR interference (Cheek et al 1999; Dirinck et al 2016).

Boas, M., Feldt-Rasmussen, U., & Main, K. M. (2012). Thyroid effects of endocrine disrupting chemicals. Molecular and Cellular Endocrinology, 355(2), 240–248. http://doi.org/10.1016/j.mce.2011.09.005

Cheek, A. O., Kow, K., Chen, J., & McLachlan, J. a. (1999). Potential mechanisms of thyroid disruption in humans: Interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environmental Health Perspectives, 107(4), 273–278. http://doi.org/10.1289/ehp.99107273

Dallaire, R., Muckle, G., Dewailly, É., Jacobson, S. W., Jacobson, J. L., Sandanger, T. M., … Ayotte, P. (2009a). Thyroid hormone levels of pregnant inuit women and their infants exposed to environmental contaminants. Environmental Health Perspectives, 117(6), 1014–1020. http://doi.org/10.1289/ehp.0800219

Dallaire, R., Dewailly, É., Pereg, D., Dery, S., & Ayotte, P. (2009b). Thyroid function and plasma concentrations of polyhalogenated compounds in inuit adults. Environmental Health Perspectives, 117(9), 1380–1386. http://doi.org/10.1289/ehp.0900633

Dirinck E, Dirtu AC, Malarvannan G, Covaci A, Jorens PG, Van Gaal LF. A Preliminary Link between Hydroxylated Metabolites of Polychlorinated Biphenyls and Free Thyroxin in Humans. Int J Environ Res Public Health. 2016 Apr 13;13(4):421. doi: 10.3390/ijerph13040421.

Eguchi, A., Nomiyama, K., Minh Tue, N., Trang, P. T. K., Hung Viet, P., Takahashi, S., & Tanabe, S. (2015). Residue profiles of organohalogen compounds in human serum from e-waste recycling sites in North Vietnam: Association with thyroid hormone levels. Environmental Research, 137, 440–449. http://doi.org/10.1016/j.envres.2015.01.007

Gore, a. C., Chappell, V. a., Fenton, S. E., Flaws, J. a., Nadal, a., Prins, G. S., … Zoeller, R. T. (2015). Executive Summary to EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocrine Reviews, (October), er.2015-1093. http://doi.org/10.1210/er.2015-1093

Grimm, F. a., Lehmler, H. J., He, X., Robertson, L. W., & Duffel, M. W. (2013). Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin. Environmental Health Perspectives, 121(6), 657–662. http://doi.org/10.1289/ehp.1206198

Lans MC, Klasson-Wehler E, Willemsen M, Meussen E, Safe S Brouwer A. 1993. Structure-dependent, competitive interaction of hydroxy-polychlorobiphenyls, -dibenzo-p-dioxins and -dibenzofurans with human transthyretin. Chem Biol Interact 88(1):7–21.

Marchesini, G. R., Meimaridou, A., Haasnoot, W., Meulenberg, E., Albertus, F., Mizuguchi, M., … Murk, A. J. (2008). Biosensor discovery of thyroxine transport disrupting chemicals. Toxicology and Applied Pharmacology, 232(1), 150–160. http://doi.org/10.1016/j.taap.2008.06.014

Martin, L., & Klaassen, C. D. (2010). Differential effects of polychlorinated biphenyl congeners on serum thyroid hormone levels in rats. Toxicological Sciences : An Official Journal of the Society of Toxicology, 117(1), 36–44. http://doi.org/10.1093/toxsci/kfq187

Martin, L. A., Wilson, D. T., Reuhl, K. R., Gallo, M. A., & Klaassen, C. D. (2012). Polychlorinated biphenyl congeners that increase the glucuronidation and biliary excretion of thyroxine are distinct from the congeners that enhance the serum disappearance of thyroxine. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 40(3), 588–95. http://doi.org/10.1124/dmd.111.042796

Miller, M. D., Crofton, K. M., Rice, D. C., & Zoeller, R. T. (2009). Thyroid-disrupting compounds:  Interpreting upstream biomarkers of adverse outcomes. Environmental Health Perspectives, 117(7), 1033–1041. http://doi.org/10.1289/ehp.0800247

Morse DC, Seegal RF, Borsch KO, Brouwer A. Long-term alterations in regional brain serotonin metabolism following maternal polychlorinated biphenyl exposure in the rat. Neurotoxicology. 1996 Fall-Winter;17(3-4):631-8.

Murk, A. J., Rijntjes, E., Blaauboer, B. J., Clewell, R., Crofton, K. M., Dingemans, M. M. L., … Gutleb, A. C. (2013). Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals. Toxicology in Vitro, 27(4), 1320–1346. http://doi.org/10.1016/j.tiv.2013.02.012

Préau, L., Fini, J. B., Morvan-Dubois, G., & Demeneix, B. (2014). Thyroid hormone signaling during early neurogenesis and its significance as a vulnerable window for endocrine disruption. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1849(2), 112–121. http://doi.org/10.1016/j.bbagrm.2014.06.015

Weiss, J. M., Andersson, P. L., Zhang, J., Simon, E., Leonards, P. E. G., Hamers, T., & Lamoree, M. H. (2015). Tracing thyroid hormone-disrupting compounds: database compilation and structure-activity evaluation for an effect-directed analysis of sediment. Analytical and Bioanalytical Chemistry, 5625–5634. http://doi.org/10.1007/s00216-015-8736-9



Aryl hydrocarbon receptor activation leading to uroporphyria

Some polychlorinated biphenyls (namely non-ortho substituted congeners) cause porphyrin accumulation in mice (Hahn et al. 1988; Gorman et al. 2002) and chicken (Lorenzen et al 1997; Lorenzen and Kennedy 1995; Goldstein et al. 1976).

Hahn, M.E., Gasiewicz, T.A., Linko, P., Goldstein, J.A. (1988) The role of the Ah locus in hexachlorobenzene-induced porphyria: Studies in congenic C57BL/6J mice. Biochem. J. 254, 245-254.

Gorman, N., Ross, K. L., Walton, H. S., Bement, W. J., Szakacs, J. G., Gerhard, G. S., Dalton, T. P., Nebert, D. W., Eisenstein, R. S., Sinclair, J. F., and Sinclair, P. R. (2002) Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron. Hepatology 35 (4), 912-921.

Lorenzen, A., Kennedy, S. W., Bastien, L. J., and Hahn, M. E. (1997) Halogenated aromatic hydrocarbon-mediated porphyrin accumulation and induction of cytochrome P4501A in chicken embryo hepatocytes. Biochemical Pharmacology 53 (3), 373-384.

Lorenzen, A., and Kennedy, S. W. (1995). Sensitivities of Chicken and Pheasant Embryos and Cultured Embryonic Hepatocytes to Cytochrome P4501A Induction and Porphyrin Accumulation by TCDD, TCDF and PCBs. Organohalogen Compounds 25, 65-68.

Goldstein, J. A., McKinney, J. D., Lucier, G. W., Hickman, P., Bergman, H., and Moore, J. A. (1976) Toxicological assessment of hexachlorobiphenyl isomers and 2,3,7,8,-tetrachlorodibenzofuran in chicks. II. Effects on drug metabolism and porphyrin accumulation. Toxicol. Appl. Pharmacol. 36 (1), 81-92.

 




Event Evidence

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Activation, AhR

Of the dioxin-like PCBs, non-ortho congeners are the most toxicologically active, while mono-ortho PCBs are generally less potent (McFarland and Clarke 1989; Safe 1994). Chlorine substitution at ortho positions increases the energetic costs of assuming the coplanar conformation required for binding to the AHR (McFarland and Clarke 1989). Thus, a smaller proportion of mono-ortho PCB molecules are able to bind to the AHR and elicit toxic effects, resulting in reduced potency of these congeners. Other PCB congeners, such as di-ortho substituted PCBs, are very weak AHR agonists and do not likely contribute to dioxin-like effects (Safe 1994).

 

Safe, S. (1994). Polychlorinated biphenyls (PCBs): Environmental impact, biochemical and toxic responses, and implications for risk assessment. Critical Reviews in Toxicology 24, 87-149.

McFarland, V. A., and Clarke, J. U. (1989). Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: Considerations for a congener-specific analysis. Environ.Health Perspect81, 225-239.



Binding, Transthyretin in serum

There is no evidence text for this event.



dimerization, AHR/ARNT

There is no evidence text for this event.




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