Toxicology Letters 206 (2011) 158–165 Contents lists available at ScienceDirect Toxicology Letters j ourna l ho me pag e: www.elsevier.com/locate/toxlet Some OH-PCBs are more potent inhibitors of aromatase activity and (anti-) glucocorticoids than non-dioxin like (NDL)-PCBs and MeSO 2 -PCBs Elsa C. Antunes-Fernandes a , Toine F.H. Bovee b , Frieda E.J. Daamen a , Richard J. Helsdingen b , Martin van den Berg a , Majorie B.M. van Duursen a,∗ a Toxicology Division, Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands b RIKILT-Institute of Food Safety, Wageningen University and Research Centre, P.O. Box 230, 6700 AE Wageningen, The Netherlands a r t i c l e i n f o Article history: Received 4 March 2011 Received in revised form 4 July 2011 Accepted 6 July 2011 Available online 12 July 2011 Keywords: Non-dioxin-like PCBs Aromatase activity Glucocorticoid receptor Hydroxy-metabolite Methylsulfonyl-metabolite Human risk assessment a b s t r a c t 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 micro- somes with an IC 50 of 2.2 M. 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 M range) and showed anti-glucocorticoid properties (LOECs in the low nM range), in a concentration-dependent manner. Further, four MeSO 2 -PCBs slightly inhib- ited 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. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Production and commercialization of polychlorinated biphenyls (PCBs) has been largely prohibited since the 1970s. Still PCBs are ubiquitous pollutants as their chemical stability, persistency and lipophilicity result in their tendency to bioacumulate in food chain, wild life, environment and humans. In animals, biotransformation of PCBs into hydroxy-PCBs (OH-PCBs) involves oxidation by cytochrome P-450 (CYP-450) enzymes, resulting in more water soluble congeners. However, not all the OH-PCBs are excreted but further metabolized into methylsulfonyl-PCBs (MeSO 2 -PCBs) involving additional CYP-450 monooxygenation and phase II conjugation (for review see Letcher et al., 2000). The hydroxy or methylsulfonyl group attached to the biphenyl backbone circumstantiate different toxicological char- acteristics. In fact, the difference in lipophilicity of OH- and MeSO 2 -PCBs results in these two classes of metabolites accumu- lating and exerting their effects in different target tissues. OH-PCBs ∗ Corresponding author. Tel.: +31 30 2535398; fax: +31 30 2535077. E-mail address: m.vanduursen@uu.nl (M.B.M. van Duursen). can be found in human and animals at concentrations as high as 10–40% of the total PCB concentration in human serum, which can be as high as 268 ng/g lipid (Bergman et al., 1994; Sandanger et al., 2004; Sandau et al., 2000; Sjodin et al., 2000). These metabolites are hardly retained in the lipid fraction of tissues, but bind to blood proteins such as transthyretin, which facilitates OH-PCBs passing to the blood cord (Morse et al., 1995). Further, several studies have reported that OH-PCBs are present in human cord blood in simi- lar concentrations as their parent compounds (Park et al., 2008), whereas MeSO 2 -PCBs are only found in much lower amounts in human blood (Linderholm et al., 2007). In contrast, MeSO 2 -PCBs tend to accumulate in human liver, lung, adipose tissue and breast milk, and concentrations can be as high as 358 ng/g lipid, depending on the tissue (Chu et al., 2003; Weistrand and Noren, 1997). Today, the existence and occurrence of OH-PCBs and MeSO 2 - PCBs in biota has widely been described, but their toxicological characteristics are still largely unknown. PCBs are a class of pollutants composed of 209 congeners that, according to their chemical and toxicological properties, can be divided into dioxin-like PCBs (DL-PCBs) and non-dioxin-like PCBs (NDL-PCBs) (Van den Berg et al., 2006). The main route of human exposure to NDL-PCBs is through food, although recent studies also 0378-4274/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.toxlet.2011.07.008