title: Estrogenicity and androgenicity screening of PCB sulfate monoesters in human breast cancer MCF-7 cells.
abstract: Recent studies identified polychlorinated biphenyl (PCB) sulfate esters as a major product of PCB metabolism. Since hydroxy-PCBs (HO-PCBs), the immediate precursors of PCB sulfates and important contributors to PCB toxicity, were shown to have estrogenic activity, we investigated the estrogenicity/androgenicty of a series of PCB sulfate metabolites. We synthesized the five possible structural sulfate monoester metabolites of PCB 3, a congener shown to be biotransformed to sulfates, a sulfate ester of the paint-specific congener PCB 11, and sulfate monoesters of two HO-PCBs reported to interact with sulfotransferases (PCB 39, no ortho chlorines, and PCB 53, 3 ortho chlorines). We tested these PCB sulfates and 4'-HO-PCB 3 as positive control for estrogenic, androgenic, anti-estrogenic, and anti-androgenic activity in the E- and A-screen with human breast cancer MCF7-derived cells at 100 μM-1 pM concentrations. Only 4'-HO-PCB 3 was highly cytotoxic at 100 μM. We observed structure-activity relationships: compounds with a sulfate group in the chlorine-containing ring of PCB 3 (2PCB 3 and 3PCB 3 sulfate) showed no interaction with the estrogen (ER) and androgen (AR) receptor. The 4'-HO-PCB 3 and its sulfate ester had the highest estrogenic effect, but at 100-fold different concentrations, i.e., 1 and 100 μM, respectively. Four of the PCB sulfates were estrogenic (2'PCB 3, 4'PCB 3, 4'PCB 39, and 4'PCB 53 sulfates; at 100 μM). These sulfates and 3'PCB 3 sulfate also exhibited anti-estrogenic activity, but at nM and pM concentrations. The 4'PCB 3 sulfate (para-para' substituted) had the strongest androgenic activity, followed by 3'PCB 3, 4'PCB 53, 4PCB11, and 4PCB 39 sulfates and the 4'HO-PCB 3. In contrast, anti-androgenicity was only observed with the two compounds that have the sulfate group in ortho- or meta- position in the second ring (2'PCB 3 and 3'PCB 3 sulfate). No dose-response was observed in any screen, but, with exception of estrogenic activity (only seen at 100 μM), endocrine activity was often displayed at several concentrations and even at 1 pM concentration. These data suggest that sulfation of HO-PCBs is indeed reducing their cytotoxicity and estrogenicity, but may produce other endocrine disruptive activities at very low concentrations.
authors: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, 100 Oakdale Campus, 214 IREH, Iowa City, IA, 52242-5000, USA.
authors: Susanne
authors: S
authors: Flor
authors: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, 100 Oakdale Campus, 214 IREH, Iowa City, IA, 52242-5000, USA.
authors: Xianran
authors: X
authors: He
authors: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, 100 Oakdale Campus, 214 IREH, Iowa City, IA, 52242-5000, USA.
authors: Hans-Joachim
authors: HJ
authors: Lehmler
authors: Department of Occupational and Environmental Health, College of Public Health, The University of Iowa, 100 Oakdale Campus, 214 IREH, Iowa City, IA, 52242-5000, USA. gabriele-ludewig@uiowa.edu.
authors: Gabriele
authors: G
authors: Ludewig
mesh_terms: D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D004952:Esters / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D000728:Androgens; D004952:Esters; D004965:Estrogen Antagonists; D004967:Estrogens; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013431:Sulfates; D011078:Polychlorinated Biphenyls
keywords: A-screen; Androgenicity; E-screen; Estrogenicity; MCF-7; PCB-sulfate; Polychlorinated biphenyl