Isomer-nonspecific action of dichlorodiphenyltrichloroethane on aryl hydrocarbon receptor and G-protein-coupled receptor 30 intracellular signaling in apoptotic neuronal cells

M Kajta; E Litwa; J Rzemieniec; A Wnuk; W Lason; A Zelek-Molik; I Nalepa; M Grzegorzewska-Hiczwa; K Tokarski; A Golas; E Guzik; A Grochowalski; K A Szychowski; A K Wojtowicz

doi:10.1016/j.mce.2014.05.008

Isomer-nonspecific action of dichlorodiphenyltrichloroethane on aryl hydrocarbon receptor and G-protein-coupled receptor 30 intracellular signaling in apoptotic neuronal cells

Mol Cell Endocrinol. 2014 Jul 5;392(1-2):90-105. doi: 10.1016/j.mce.2014.05.008. Epub 2014 May 21.

Authors

M Kajta¹, E Litwa², J Rzemieniec², A Wnuk², W Lason², A Zelek-Molik³, I Nalepa³, M Grzegorzewska-Hiczwa⁴, K Tokarski⁴, A Golas⁵, E Guzik⁶, A Grochowalski⁷, K A Szychowski⁸, A K Wojtowicz⁹

Affiliations

¹ Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. Electronic address: [email protected].
² Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
³ Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
⁴ Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
⁵ Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, 30-387 Krakow, Poland.
⁶ Department of Cell Biology and Imaging, Confocal Microscopy Laboratory, Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, 30-387 Krakow, Poland.
⁷ Department of Analytical Chemistry, University of Technology, 24 Warszawska Street, 31-155 Krakow, Poland.
⁸ Laboratory of Genomics and Biotechnology, University of Agriculture, 1B Rędzina Street, 30-274 Krakow, Poland.
⁹ Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland; Laboratory of Genomics and Biotechnology, University of Agriculture, 1B Rędzina Street, 30-274 Krakow, Poland.

PMID: 24859647
DOI: 10.1016/j.mce.2014.05.008

Abstract

Extended residual persistence of the pesticide dichlorodiphenyltrichloroethane (DDT) raises concerns about its long-term neurotoxic effects. Little is known, however, about DDT toxicity during the early stages of neural development. This study demonstrated that DDT-induced apoptosis of mouse embryonic neuronal cells is a caspase-9-, caspase-3-, and GSK-3β-dependent process, which involves p,p'-DDT-specific impairment of classical ERs. It also provided evidence for DDT-isomer-nonspecific alterations of AhR- and GPR30-mediated intracellular signaling, including changes in the levels of the receptor and receptor-regulated mRNAs, and also changes in the protein levels of the receptors. DDT-induced stimulation of AhR-signaling and reduction of GPR30-signaling were verified using selective ligands and specific siRNAs. Co-localization of the receptors was demonstrated with confocal microscopy, and the presence of functional GPR30 was detected by electrophysiology. This study demonstrates that stimulation of AhR-signaling and impairment of GPR30-signaling play important roles in the propagation of DDT-induced apoptosis during the early stages of neural development.

Keywords: Bcl-2; Caspases; Estrogen receptors; GSK-3β; Neurotoxicity; Primary neuronal cell cultures.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects*
Benzodioxoles / pharmacology
Benzoflavones / pharmacology
Caspase 3 / metabolism
Caspase Inhibitors / pharmacology
Cells, Cultured
Cytochrome P-450 CYP1A1 / genetics
Cytochrome P-450 CYP1A1 / metabolism
DDT / chemistry*
DDT / pharmacology*
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Isomerism
L-Lactate Dehydrogenase / metabolism
Mice
Neurons / cytology
Neurons / drug effects
Neurons / enzymology
Neurons / metabolism*
Pyrazoles / pharmacology
Pyrimidines / pharmacology
Quinolines / pharmacology
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Aryl Hydrocarbon / antagonists & inhibitors
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism*
Receptors, Estrogen / antagonists & inhibitors
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism
Receptors, G-Protein-Coupled / agonists
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction / drug effects*
Time Factors
beta-Naphthoflavone / pharmacology

Substances

4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline
Benzodioxoles
Benzoflavones
Caspase Inhibitors
GPER1 protein, mouse
Pyrazoles
Pyrimidines
Quinolines
RNA, Messenger
Receptors, Aryl Hydrocarbon
Receptors, Estrogen
Receptors, G-Protein-Coupled
alpha-naphthoflavone
beta-Naphthoflavone
DDT
L-Lactate Dehydrogenase
Cytochrome P-450 CYP1A1
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Glycogen Synthase Kinase 3
Caspase 3