title: RXRα, PXR and CAR xenobiotic receptors mediate the apoptotic and neurotoxic actions of nonylphenol in mouse hippocampal cells.
abstract: In the present study, we investigated the role of the retinoid X receptor (RXR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), in the apoptotic and toxic effects of nonylphenol in mouse primary neuronal cell cultures. Our study demonstrated that nonylphenol activated caspase-3 and induced lactate dehydrogenase (LDH) release in hippocampal cells, which was accompanied by an increase in the mRNA expression and protein levels of RXRα, PXR and CAR. Nonylphenol stimulated Rxra, Pxr, and Car mRNA expression. These effects were followed by increase in the protein levels of particular receptors. Immunofluorescence labeling revealed the cellular distribution of RXRα, PXR and CAR in hippocampal neurons in response to nonylphenol, shortening of neurites and cytoplasmic shrinking, as indicated by MAP2 staining. It also showed NP-induced translocation of receptor-specific immunofluorescence from cytoplasm to the nucleus. The use of specific siRNAs demonstrated that Rxra-, Pxr-, and Car-siRNA-transfected cells were less vulnerable to nonylphenol-induced activation of caspase-3 and LDH, thus confirming the key involvement of RXRα/PXR/CAR signaling pathways in the apoptotic and neurotoxic actions of nonylphenol. These new data give prospects for the targeting xenobiotic nuclear receptors to protect the developing nervous system against endocrine disrupting chemicals.
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 Cell Biology and Imaging, Confocal Microscopy Laboratory, Institute of Zoology, Jagiellonian University, 9 Gronostajowa Street, 30-387 Krakow, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Krzeptowski
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
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010636:Phenols / Q000633:toxicity*; D000077297:Pregnane X Receptor; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000090702:Constitutive Androstane Receptor; D009498:Neurotoxins; D010636:Phenols; D000077297:Pregnane X Receptor; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; C025256:nonylphenol
keywords: Apoptosis; Constitutive androstane receptor; Pregnane X receptor; Primary neuronal cell culture; Retinoid X receptor; siRNA