Some OH-PCBs are more potent inhibitors of aromatase activity and (anti-) glucocorticoids than non-dioxin like (NDL)-PCBs and MeSO2-PCBs

► We investigated the effects of NDL-PCBs and their metabolites on aromatase activity and glucocorticoid receptor. ► Most NDL-PCBs and MeSO2-PCBs had no effect or were mild aromatase activity inhibitors and (anti-) glucocorticoids. ► The tested OH-PCBs were stronger aromatase activity inhibitors and (anti-) glucocorticoid than the tested NDL-PCBs or MeSO2-PCBs. 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- (MeSO2-) 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 IC50 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 MeSO2-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 MeSO2-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.