Atropisomers of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro

• Published in: Environmental science and pollution research international Vol. 25; no. 17; pp. 16411 - 16419
• Main Authors: Pěnčíková, Kateřina, Brenerová, Petra, Svržková, Lucie, Hrubá, Eva, Pálková, Lenka, Vondráček, Jan, Lehmler, Hans-Joachim, Machala, Miroslav
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2018; Springer Nature B.V
• Subjects: Activation; Androgen receptors; Androgens; Animals; Aquatic Pollution; Atmospheric Protection/Air Quality Control/Air Pollution; Biotransformation; Catabolism; Congeners; Earth and Environmental Science; Ecotoxicology; Enantiomers; Endocrine disruptors; Environment; Environmental Chemistry; Environmental Health; Environmental science; Estrogen receptors; Estrogens; Gene expression; Hexachlorobiphenyl; Human tissues; Humans; Isomers; Metabolism; Neurotoxicity; Nuclear receptors; PCB; PCBs Risk Evaluation and Environmental Protection; Polychlorinated biphenyls; Polychlorinated Biphenyls - chemistry; Receptors; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Steroid - chemistry; Receptors, Steroid - metabolism; Rotation; Stereoisomerism; Stereoisomers; Stereospecificity; Waste Water Technology; Water Management; Water Pollution Control; Xenoestrogens; Atropisomer; Chiral; Pregnane X receptor; Androgen receptor; Estrogen receptors; Constitutive androstane receptor; Polychlorinated biphenyl
• ISSN: 0944-1344; 1614-7499
• DOI: 10.1007/s11356-017-0683-x

PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (−)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (−)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral
ortho
-substituted PCB congeners.