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Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules

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Abstract

The persistent environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo and causes decreased glucocorticoid production and cell death in the zona fasciculata. This study presents extended investigations of the cytotoxic and endocrine disrupting effects of 3-MeSO2-DDE and some structurally related molecules in the mouse adrenocortical cell line Y-1. Both 3-MeSO2-DDE and, to a lesser extent, 3,3′(bis)-MeSO2-DDE decreased corticosterone production and produced CYP11B1-dependent cytotoxicity in Y-1 cells. Neither 2-MeSO2-DDE nor p,p′-DDE had any significant effect on either cell viability or corticosterone production, indicating that the presence and position of the methylsulfonyl moiety of 3-MeSO2-DDE is crucial for its biological activity. The adrenocortical toxicant o,p′-DDD decreased corticosterone production but was not cytotoxic in this cell line. None of the compounds altered Cyp11b1 gene expression, indicating that 3-MeSO2-DDE inhibits CYP11B1 activity on the protein level.

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References

  • Ahlman H, Khorram-Manesh A, Jansson S, Wangberg B, Nilsson O, Jacobsson CE, Lindstedt S (2001) Cytotoxic treatment of adrenocortical carcinoma. World J Surg 25:927–933

    Article  PubMed  CAS  Google Scholar 

  • Azeredo A, Torres JPM, de Freitas Fonseca M, Britto JL, Bastos WR, Azevedo e Silva CE, Cavalcanti G, Meire RO, Sarcinelli PN, Claudio L, Markowitz S and Malm O (2008) DDT and its metabolites in breast milk from the Madeira River basin in the Amazon, Brazil. Chemosphere. Corrected proof (in press)

  • Brandt I, Jönsson CJ, Lund BO (1992) Comparative studies on adrenocorticolytic DDT-metabolites. Ambio 21:602–605

    Google Scholar 

  • Bureik M, Schiffler B, Hiraoka Y, Vogel F, Bernhardt R (2002) Functional expression of human mitochondrial CYP11B2 in fission yeast and identification of a new internal electron transfer protein, etp1. Biochemistry 41:2311–2321

    Article  PubMed  CAS  Google Scholar 

  • Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL (1997) Adrenal proteins bound by a reactive intermediate of mitotane. Cancer Chemother Pharmacol 39:537–540

    Article  PubMed  CAS  Google Scholar 

  • Cai W, Djanegara T, Sinsheimer J, Wotring L, Counsell E, Schteingart D (1995) Metabolic activation and binding of mitotane in adrenal cortex homogenates. J Pharm Sci 84:134–138

    Article  PubMed  CAS  Google Scholar 

  • Chu S, Covaci A, Jacobs W, Haraguchi K, Schepens P (2003) Distribution of methyl sulfone metabolites of polychlorinated biphenyls and p,p′-DDE in human tissues. Environ Health Perspect 111:1222–1227

    PubMed  CAS  Google Scholar 

  • Hart MM, Reagan RL, Adamson RH (1973) The effect of isomers of DDD on the ACTH-induced steroid output, histology and ultrastructure of the dog adrenal cortex. Toxicol Appl Pharmacol 24:101–113

    Article  PubMed  CAS  Google Scholar 

  • Hermansson V, Asp V, Bergström U, Brandt I (2007) Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells. Arch Toxicol 81:793–801

    Article  PubMed  CAS  Google Scholar 

  • Hermansson V, Cantillana T, Hovander L, Bergman Å, Ljungvall K, Magnusson U, Törneke K, Brandt I (2008) Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p′-DDD (mitotane) in Minipigs. Cancer Chemother Pharmacol 61:267–274

    Article  PubMed  CAS  Google Scholar 

  • Hornsby PJ (1989) Steroid and xenobiotic effects on the adrenal cortex: mediation by oxidative and other mechanisms. Free Rad Biol Med 6:103–115

    Article  PubMed  CAS  Google Scholar 

  • Jensen S, Jansson B (1976) Methyl sulfone metabolites of PCB and DDE. Ambio 5:257–260

    CAS  Google Scholar 

  • Johansson M, Larsson C, Bergman Å, Lund BO (1998) Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones. Pharmacol Toxicol 83:225–230

    Article  PubMed  CAS  Google Scholar 

  • Johansson MK, Sanderson JT, Lund BO (2002) Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line. Toxicol In Vitro 16:113–121

    Article  PubMed  CAS  Google Scholar 

  • Jönsson CJ, Lund BO (1994) In vitro bioactivation of the environmental pollutant 3-methylsulphonyl-2, 2-bis(4-chlorophenyl)-1, 1-dichloroethene in the human adrenal gland. Toxicol Lett 71:169–175

    Article  PubMed  Google Scholar 

  • Jönsson CJ, Lund BO, Brunström B, Brandt I (1994) Toxicity and irreversible binding of two DDT metabolites - 3-methylsulfonyl-DDE and o,p′-DDD - in adrenal interrenal cells in birds. Environ Toxicol Chem 13:1303–1310

    Article  Google Scholar 

  • Jönsson CJ, Rodriguez-Martinez H, Lund BO, Bergman Å, Brandt I (1991) Adrenocortical toxicity of 3-methylsulfonyl-DDE in mice II. Mitochondrial changes following ecologically relevant doses. Fundam Appl Toxicol 16:365–374

    Article  PubMed  Google Scholar 

  • Lindhe Ö, Lund BO, Bergman Å, Brandt I (2001) Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture. Environ Health Perspect 109:105–110

    Article  PubMed  CAS  Google Scholar 

  • Lindhe Ö, Skogseid B, Brandt I (2002) Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p′-DDD in human adrenal zona fasciculata/reticularis. J Clin Endocrinol Metab 87:1319–1326

    Article  PubMed  CAS  Google Scholar 

  • Lund BO, Bergman Å, Brandt I (1988) Metabolic activation and toxicity of a DDT-metabolite, 3-methylsulphonyl-DDE, in the adrenal zona fasciculata in mice. Chem Biol Interact 65:25–40

    Article  PubMed  CAS  Google Scholar 

  • Lund BO, Klasson-Wehler E, Brandt I (1986) o,p′-DDD in the mouse lung: selective uptake, covalent binding and effect on drug metabolism. Chem Biol Interact 60:129–141

    Article  PubMed  CAS  Google Scholar 

  • Lund BO, Lund J (1995) Novel involvement of a mitochondrial steroid hydroxylase (P450c11) in xenobiotic metabolism. J Biol Chem 270:20895–20897

    Article  PubMed  CAS  Google Scholar 

  • Martz F, Straw JA (1977) The in vitro metabolism of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2, 2-dichloroethane (o,p′-DDD) by dog adrenal mitochondria and metabolite covalent binding to mitochondrial macromolecules: a possible mechanism for the adrenocorticolytic effect. Drug Metab Dispos 5:482–486

    PubMed  CAS  Google Scholar 

  • Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. The Lancet 367:1605–1617

    Article  CAS  Google Scholar 

  • Norén K, Lunden A, Pettersson E, Bergman A (1996) Methylsulfonyl metabolites of PCBs and DDE in human milk in Sweden, 1972–1992. Environ Health Perspect 104:766–772

    Article  PubMed  Google Scholar 

  • Norén K, Meironyte D (2000) Certain organochlorine and organobromine contaminants in Swedish human milk in perspective of past 20–30 years. Chemosphere 40:1111–1123

    Article  PubMed  Google Scholar 

  • Papadopoulos D, Seidegard J, Rydstrom J (1984) Metabolism of xenobiotics in the human adrenal gland. Cancer Lett 22:23–30

    Article  PubMed  CAS  Google Scholar 

  • Parker KL, Chaplin DD, Wong M, Seidman JG, Smith JA, Schimmer BP (1985) Expression of murine 21-hydroxylase in mouse adrenal glands and in transfected Y1 adrenocortical tumor cells. Proc Natl Acad Sci USA 82:7860–7864

    Article  PubMed  CAS  Google Scholar 

  • R development Core Team (2006) R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing.

  • Rainey WE, Saner K, Schimmer BP (2004) Adrenocortical cell lines. Mol Cell Endocrinol 228:23–38

    Article  PubMed  CAS  Google Scholar 

  • Rapoport R, Sklan D, Hanukoglu I (1995) Electron leakage from the adrenal-cortex mitochondrial P450Scc and P450C11 systems: NADPH and steroid dependence. Arch Biochem Biophys 317:412–416

    Article  PubMed  CAS  Google Scholar 

  • Seamon KB, Padgett W, Daly JW (1981) Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci USA 78:3363–3367

    Article  PubMed  CAS  Google Scholar 

  • Tada H, Shiho O, Kuroshima K, Koyama M, Tsukamoto K (1986) An improved colorimetric assay for interleukin 2. J Immunol Meth 93:157–165

    Article  CAS  Google Scholar 

  • Yasumura Y, Buonassisi V, Sato G (1966) Clonal analysis of differentiated function in animal cell cultures I. Possible correlated maintenance of differentiated function and the diploid karyotype. Cancer Res 26:529–535

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Hans Garmo, Ph.D., at Mathematical Statistics, Department of Mathematics, Uppsala University for helping with the statistical analysis of the cytotoxicity data. Economic support was given by the Foundation for Strategic Environmental Research (Mistra) through the NewS research program, and from the Swedish Animal Welfare Agency.

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  1. Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, 752 36, Uppsala, Sweden

    Vendela Asp, Veronica Lindström, Jan A. Olsson, Ulrika Bergström & Ingvar Brandt

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  1. Vendela Asp
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  2. Veronica Lindström
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  3. Jan A. Olsson
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  4. Ulrika Bergström
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  5. Ingvar Brandt
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Correspondence to Ingvar Brandt.

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Asp, V., Lindström, V., Olsson, J.A. et al. Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules. Arch Toxicol 83, 389–396 (2009). https://doi.org/10.1007/s00204-008-0342-6

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  • DOI: https://doi.org/10.1007/s00204-008-0342-6

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