CB-49

The concentration of 26 methyl sulfonyl metabolites of polychlorinated biphenyls (MeSO2-PCBs) and of p,p'-DDE (MeSO2-DDE) were determined in 19 liver samples from harbor porpoises (Phocoena phocoena) stranded between 1997 and 2000 on the Belgian and French North Sea Coasts. The total concentration of MeSO2-PCBs ranged from 39 to 4221 ng/g lipid weight (lw) and were generally higher in adults (age > 2 yr, range 969-4,221 ng/g lw) than in juveniles (age < 2 yr, range 39-1815 ng/g lw). The concentrations of MeSO2-DDE were generally also higher in adults (21-96 ng/g lw) than in juveniles (0.5-60 ng/g lw). Congeners 3- and 4-MeSO2-CB101 were the dominating metabolites in all samples. Due to their preferential retention in the liver, the MeSO2-PCB congeners could be divided into two groups. The first group was dominated by the 3-MeSO2-PCB congeners and consisted of MeSO2-CB31, -CB49, -CB52, -CB87, and -CB101, which all have a 2,5-chlorine substitution in the phenyl ring containing the methyl sulfonyl group. The second group was dominated by the 4-MeSO2-PCB congeners and consisted of MeSO2-CB64, -CB91, -CB110, and -CB132, which all have a 2,3,6-chlorine substitution. The ratios of sum of PCBs/sum of MeSO2-PCBs and p,p'-DDE/MeSO2-DDE differed greatly between individual subjects and ranged from 15 to 419 and from 17 to 1088, respectively. The ratio between the precursor PCB congeners and their corresponding metabolites ranged from 0.6 (CB49) to 175 (CB174). Enantiomeric fractions (EFs) for MeSO2-PCB atropisomers, which include 3-MeSO2-CB132, 3-MeSO2-CB149, 4-MeSO2-CB149, 3-MeSO2-CB174, and 4-MeSO2-CB174, were also measured in 8 out of the 19 subjects. High enantiomeric excess (EF > 0.73 or EF < 0.23) for the measured chiral MeSO2-PCB congeners was found in all samples. This result may suggest that one atropisomer may be preferentially formed in harbor porpoises or that the atropisomers are retained in a highly selective manner.

Methylsulfonyl (MeSO(2)) metabolites of polychlorinated biphenyls (PCBs) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethene (4,4'-DDE), itself a metabolite of the insecticide 4,4'-DDT, are emerging as a major class of contaminants in the tissues of wildlife and humans. We investigated the antiestrogenic capacity and potencies of 3'- and 4'-MeSO(2)-2,2',4,5,5'-pentachlorobiphenyl (CB101) and -2,2',4,5'-tetrachlorobiphenyl (CB49), which are among the most environmentally persistent MeSO(2)-PCBs, and 3-MeSO(2)-4,4'-DDE on estrogen receptor (ER)-dependent gene expression in four cell-based bioassay systems. Congener- and concentration-dependent antagonism of 17beta-estradiol (E2)-induced gene expression, rather than induction of ER-dependent gene expression, was observed for the MeSO(2)-PCBs on lucifierase activity in stably transfected human breast adenocarcinoma T47D cells (ER-CALUX) and vitellogenin (vtg) production in primary hepatocytes from male carp fish (Cyprinus carpio) (CARP-HEP/vtg). 4'-MeSO(2)-CB101 and -CB49 had the highest antagonistic potency (i.e., maximum inhibition of about 70%, LOECs of 1.0 microM and 2.5 microM), whereas 3'-MeSO(2)-CB101 and -CB49 were less antagonistic; the precursor CB101 and MeSO(2)-PCB analog MeSO(2)-2,5-dichlorobenzene had no effect. Relative to the 4-MeSO(2)-PCBs, tamoxifen (IC(50), 0.06 microM and 0.7 microM) was about 40 and 7 times more potent in the ER-CALUX and CARP-HEP/vtg assays, respectively. Congener- and concentration-dependent effects on aryl hydrocarbon receptor-mediated induction of EROD activity (carp hepatocytes), luciferase expression (H4IIE rat hepatoma [H4IIE.luc] cell line), or cell viability were not observed. 3-MeSO(2)-4,4'-DDE was neither estrogenic nor antiestrogenic in either of the bioassays. Inhibitory trends for the MeSO(2)-PCBs in a bioassay based on stably transfected human embryonic kidney cell (HEK293-ERalpha-ERE) were similar to the ER-CALUX and CARP-HEP/vtg bioassays, whereas the antagonism was weaker in a related HEK293-ERbeta-ERE bioassay. Our findings suggest that the 4'-MeSO(2)-PCBs are antiestrogenic in vitro via a reversible or surmountable interaction with fish or human ER, and that the interaction with human ERalpha is apparently favored over ERbeta. MeSO(2)-PCB metabolites are persistent and bioaccumulative contaminants, and therefore, could be potentially active as environmental antiestrogens in wildlife and humans.