title: Some OH-PCBs are more potent inhibitors of aromatase activity and (anti-) glucocorticoids than non-dioxin like (NDL)-PCBs and MeSO₂-PCBs.
abstract: Traditional risk assessment of potential endocrine-disruptive pollutants, including PCBs, focus mainly on the effects of parent compounds. Still, biotransformation results in systemic exposure to PCBs and their bioactive metabolites. In the present paper, the effects of twenty ultra-pure non-dioxin-like (NDL) PCBs and their environmentally relevant hydroxy- (OH-) and methylsulfonyl- (MeSO(2)-) metabolites on aromatase activity and their glucocorticoid properties were investigated. Although most NDL-PCBs were inactive, PCB28 inhibited aromatase activity in human placenta microsomes with an IC(50) of 2.2μM. Most of these NDL-PCBs were weak (ant-)agonist of the glucocorticoid receptor (GR). Interestingly, four OH-metabolites of the commonly found NDL-PCB180 were able to inhibit aromatase activity (LOECs in the low μM range) and showed anti-glucocorticoid properties (LOECs in the low nM range), in a concentration-dependent manner. Further, four MeSO(2)-PCBs slightly inhibited aromatase activity and showed anti-glucocorticoid properties. Although, these effects were also associated with cytotoxicity, they were dependent on the position of the MeSO(2)-group on the biphenyl ring. Our results are the first to show that OH-PCBs are both anti-glucocorticoids and aromatase inhibitors. Taken together, these results for PCBs again support the common idea that risk assessment of the endocrine disruptive potential of PCBs should also include their metabolites.
authors.affiliation: Toxicology Division, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Elsa C
authors.initials: EC
authors.lastname: Antunes-Fernandes
authors.forename: Toine F H
authors.initials: TF
authors.lastname: Bovee
authors.forename: Frieda E J
authors.initials: FE
authors.lastname: Daamen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Helsdingen
authors.forename: Martin
authors.initials: M
authors.lastname: van den Berg
authors.forename: Majorie B M
authors.initials: MB
authors.lastname: van Duursen
mesh_terms: D001141:Aromatase / Q000096:biosynthesis / Q000737:chemistry; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D052244:Endocrine Disruptors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D008698:Mesylates / Q000737:chemistry / Q000633:toxicity*; D008861:Microsomes / Q000201:enzymology; D009994:Osmolar Concentration; D010920:Placenta / Q000201:enzymology; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D018570:Risk Assessment / Q000379:methods
chemical_list: D047072:Aromatase Inhibitors; D052244:Endocrine Disruptors; D008698:Mesylates; D011257:Pregnancy Proteins; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; C410127:PCB 180; D011078:Polychlorinated Biphenyls; D001141:Aromatase