TY - JOUR
T1 - Enantioselective effects of alpha-hexachlorocyclohexane (HCH) isomers on androgen receptor activity in vitro
AU - Pavlíková, Nela
AU - Bláhová, Lucie
AU - Klán, Petr
AU - Bathula, Sreenivas Reddy
AU - Sklenář, Vladimír
AU - Giesy, John P.
AU - Bláha, Ludek
PY - 2012/1
Y1 - 2012/1
N2 - Alpha-hexachlorocyclohexane (alpha-HCH), a part of the HCH pesticide mixture, is one of the most widespread persistent organic pollutants. Interestingly, only limited number of studies addressed the toxicity of alpha-HCH and the effects of its individual optical isomers have not been investigated in detail. In the present study we separated two alpha-HCH enantiomers by preparative HPLC and studied their activities towards androgen receptor (AR) using the MDA-kb2 cell line stably transfected with the luciferase reporter gene under the control of AR. There was no direct effect of alpha-HCH on AR but both isomers significantly suppressed the activity of AR in co-exposure with the natural ligand dihydrotestosterone in a concentration-dependent manner. One of the enantiomers appeared to be more active at lower concentration, which was also supported by the molecular modeling calculations with AR that showed a slight difference in estimated free energy of binding and inhibition constant between two enantiomers. Although studies with other pesticides demonstrated strong enantioselective differences in toxicity, the present research shows rather minor differences in modulations of AR by both alpha-HCH enantiomers. For the first time, enantioselective effects of alpha-HCH were demonstrated and the results suggest interaction with multiple regulatory events controlling the AR activity. Full elucidation of the toxicity mechanism will require further research. © 2011 Elsevier Ltd.
AB - Alpha-hexachlorocyclohexane (alpha-HCH), a part of the HCH pesticide mixture, is one of the most widespread persistent organic pollutants. Interestingly, only limited number of studies addressed the toxicity of alpha-HCH and the effects of its individual optical isomers have not been investigated in detail. In the present study we separated two alpha-HCH enantiomers by preparative HPLC and studied their activities towards androgen receptor (AR) using the MDA-kb2 cell line stably transfected with the luciferase reporter gene under the control of AR. There was no direct effect of alpha-HCH on AR but both isomers significantly suppressed the activity of AR in co-exposure with the natural ligand dihydrotestosterone in a concentration-dependent manner. One of the enantiomers appeared to be more active at lower concentration, which was also supported by the molecular modeling calculations with AR that showed a slight difference in estimated free energy of binding and inhibition constant between two enantiomers. Although studies with other pesticides demonstrated strong enantioselective differences in toxicity, the present research shows rather minor differences in modulations of AR by both alpha-HCH enantiomers. For the first time, enantioselective effects of alpha-HCH were demonstrated and the results suggest interaction with multiple regulatory events controlling the AR activity. Full elucidation of the toxicity mechanism will require further research. © 2011 Elsevier Ltd.
KW - Anti-androgenicity
KW - Hexachlorocyclohexane
KW - Optical isomers
KW - Pesticide
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UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-82555166001&origin=recordpage
U2 - 10.1016/j.chemosphere.2011.08.052
DO - 10.1016/j.chemosphere.2011.08.052
M3 - RGC 21 - Publication in refereed journal
C2 - 21962538
SN - 0045-6535
VL - 86
SP - 65
EP - 69
JO - Chemosphere
JF - Chemosphere
IS - 1
ER -