In vitro inhibition of aromatase activity and activation of the GABAA receptor by NDLPCBs and their OH-metabolites
Despite the large ban on the industrial and commercial use of PCBs since the 1980s, these are still abundant pollutants in humans and wildlife. Of the 209 PCBs, the 12 dioxin-like PCBs have been the focus of most studies, though some studies indicated that non-dioxin-like PCBs (NDL-PCBs) and PCB metabolites can also act as endocrine disruptors by affecting steroidogenesis and are potentially neurotoxic. Still, their toxicological properties have been poorly characterized. In the present study, the effects of six common NDL congeners (PCB28, 52, 101, 138, 153 and 180) on human GABAA receptors expressed in Xenopus oocytes were investigated using the two-electrode voltage clamp technique. None of the tested congeners had antagonistic effects. However, PCB28 and PCB52 were able to potentiate the GABA response under conditions of low receptor occupancy, indicating that in vitro these NDL-PCBs act as partial GABA agonists in a concentrationdependent manner. In additional experiments, human placental microsomes were used to investigate effects of these NDL-PCBs and four OH-metabolites of PCB180 (4OH-CB172, 3OH-CB180, 3OH-PCB182 and 5OHCB183) on aromatase activity, a key enzyme in steroidogenesis. PCB28 and all four OH-PCBs inhibited aromatase activity with IC50 values ranging from 1.3 μM for PCB28 to 41.6 μM for 3OH-PCB182. Taken together, our observed inhibition of aromatase activity as well as the potentiation of GABAA receptor activation further supports the suggestion of the neurotoxic and endocrine disruptive effect of some NDL-PCBs, more specifically the lower chlorinated like PCB28.
Antunes Fernandes EC Daamen FEJ Kleef RGDM Duursen MBM Westerink RHS Berg M
Institute for Risk Assessment Sciences (IRAS),Division Toxicology,Utrecht University,P.O.Box 80177,NL-3508 TD Utrecht,The Netherlands
国际会议
北京
英文
1-5
2009-08-24（万方平台首次上网日期，不代表论文的发表时间）