title: The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity.
abstract: Dichlorodiphenyldichloroethylene (DDE) is a primary environmental and metabolic degradation product of the pesticide dichlorodiphenyltrichloroethane (DDT). It is one of the most toxic compounds belonging to organochlorines. DDE has never been commercially produced; however, the parent pesticide DDT is still used in some developing countries for disease-vector control of malaria. DDT and DDE remain in the environment because these chemicals are resistant to degradation and bioaccumulate in the food chain. Little is known, however, about DDE toxicity during the early stages of neural development. The results of the present study demonstrate that DDE induced a caspase-3-dependent apoptosis and caused the global DNA hypomethylation in mouse embryonic neuronal cells. This study also provided evidence for DDE-isomer-non-specific alterations of retinoid X receptor α (RXRα)- and retinoid X receptor β (RXRβ)-mediated intracellular signaling, including changes in the levels of the receptor mRNAs and changes in the protein levels of the receptors. DDE-induced stimulation of RXRα and RXRβ was verified using selective antagonist and specific siRNAs. Co-localization of RXRα and RXRβ was demonstrated using confocal microscopy. The apoptotic action of DDE was supported at the cellular level through Hoechst 33342 and calcein AM staining experiments. In conclusion, the results of the present study demonstrated that the stimulation of RXRα- and RXRβ-mediated intracellular signaling plays an important role in the propagation of DDE-induced apoptosis during early stages of neural development.
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, 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, Kraków, 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, Kraków, 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, Kraków, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Lasoń
authors.affiliation: Department of Genetics and Evolution, Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, 30-387, Kraków, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Krzeptowski
authors.affiliation: Department of Animal Biotechnology, Faculty of Animal Sciences, University of Agriculture, Redzina 1B, 30-248, Kraków, Poland.
authors.forename: A K
authors.initials: AK
authors.lastname: Wójtowicz
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland. kajta@if-pan.krakow.pl.
authors.forename: M
authors.initials: M
authors.lastname: Kajta
mesh_terms: D000818:Animals; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D003633:Dichlorodiphenyl Dichloroethylene / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005452:Fluoresceins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D001565:Benzoates; D001713:Biphenyl Compounds; D005452:Fluoresceins; D009498:Neurotoxins; D034741:RNA, Small Interfering; D047488:Retinoid X Receptors; C438269:diazepinylbenzoic acid; C085925:calcein AM; D003633:Dichlorodiphenyl Dichloroethylene; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3
keywords: DDE; DDT; Neurotoxicity; Primary neuronal cell cultures; RXR; Retinoid X receptor