title: Isomer-nonspecific action of dichlorodiphenyltrichloroethane on aryl hydrocarbon receptor and G-protein-coupled receptor 30 intracellular signaling in apoptotic neuronal cells.
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.
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. Electronic address: kajta@if-pan.krakow.pl.
authors.forename: M
authors.initials: M
authors.lastname: Kajta
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Litwa
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Rzemieniec
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Wnuk
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Lason
authors.affiliation: Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Zelek-Molik
authors.affiliation: Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: I
authors.initials: I
authors.lastname: Nalepa
authors.affiliation: Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Grzegorzewska-Hiczwa
authors.affiliation: Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Tokarski
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, 30-387 Krakow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Golas
authors.affiliation: Department of Cell Biology and Imaging, Confocal Microscopy Laboratory, Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, 30-387 Krakow, Poland.
authors.forename: E
authors.initials: E
authors.lastname: Guzik
authors.affiliation: Department of Analytical Chemistry, University of Technology, 24 Warszawska Street, 31-155 Krakow, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Grochowalski
authors.affiliation: Laboratory of Genomics and Biotechnology, University of Agriculture, 1B Rędzina Street, 30-274 Krakow, Poland.
authors.forename: K A
authors.initials: KA
authors.lastname: Szychowski
authors.affiliation: 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.
authors.forename: A K
authors.initials: AK
authors.lastname: Wojtowicz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052117:Benzodioxoles / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D003634:DDT / Q000737:chemistry* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007536:Isomerism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: C556295:4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol; C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; D001571:Benzoflavones; D061945:Caspase Inhibitors; C532507:GPER1 protein, mouse; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C011512:alpha-naphthoflavone; D019324:beta-Naphthoflavone; D003634:DDT; D007770:L-Lactate Dehydrogenase; D019363:Cytochrome P-450 CYP1A1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3
keywords: Bcl-2; Caspases; Estrogen receptors; GSK-3β; Neurotoxicity; Primary neuronal cell cultures