Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules.
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.
Asp
Vendela
V
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, 75236 Uppsala, Sweden.
Lindström
Veronica
V
Olsson
Jan A
JA
Bergström
Ulrika
U
Brandt
Ingvar
I
D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism*; D003633:Dichlorodiphenyl Dichloroethylene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004336:Drug Antagonism; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005045:Etomidate / Q000494:pharmacology; D005562:Formazans / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051379:Mice; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000378:metabolism
D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D005562:Formazans; D013778:Tetrazolium Salts; C079782:MTT formazan; D003633:Dichlorodiphenyl Dichloroethylene; C055238:1-chloro-4-(2,2-dichloro-1-(4-chlorophenyl)ethenyl)-3-(methylsulfonyl)benzene; D013252:Steroid 11-beta-Hydroxylase; D003345:Corticosterone; D005045:Etomidate