Apoptotic and neurotoxic actions of 4-para-nonylphenol are accompanied by activation of retinoid X receptor and impairment of classical estrogen receptor signaling

Litwa, Ewa; Rzemieniec, Joanna; Wnuk, Agnieszka; Lasoń, W.; Krzeptowski, Wojciech; Kajta, Małgorzata

doi:10.1016/j.jsbmb.2014.07.014

Cited by 32 publications

(13 citation statements)

References 75 publications

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“…These opposite effects are probably due to variety of heterodimerization partners of RXRs which may either mediate pro-survival or apoptotic pathways. RXRs are xenobiotic receptors involved in the propagation of xenobiotic-induced effects, including NP, TBT, TPT, bisphenol A (BPA), methoprene acid, and arsenite (Kanayama et al 2005 ; Litwa et al 2014 ; Nishizawa et al 2005 ; Li et al 2008 ). Recently, Li et al 2008 showed that p,p ′-DDE induced RXR -gene activity using a two-hydrid assay (Li et al 2008 ).…”

Section: Discussionmentioning

confidence: 99%

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The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%

“…In a recent study, we demonstrated that RXR mediates the apoptotic effects of 4- para -nonylphenol (NP) in mouse embryonic neuronal cells (Litwa et al 2014 ). The aim of present study was to investigate the role of RXR in DDE-induced apoptotic and neurotoxic effects.…”

Section: Introductionmentioning

confidence: 99%

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

et al. 2015

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“…9-cis-RA inhibits activation-induced apoptosis in T-cell hybridomas and thymocytes by blocking the expression of Fas ligand following activation. RXRα has a protective role in cellular apoptosis of keratinocytes and melanocytes [60] , and RXRα antagonist HX531 inhibits the apoptotic effect of 4-para-Nonylphenol in mouse embryonic neuronal cells through an RXR-mediated mitochondria-dependent signaling pathway [61] . Activation of RXRα induces apoptosis in NB4 acute promyelocytic leukemia cells [3] .…”

Section: Nongenomic Activity Of Rxr and Apoptosismentioning

confidence: 99%

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Zhang

Chen

et al. 2014

Acta Pharmacol Sin

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Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/ AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.

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“…Although most researchers have focused on NP reproductive toxicity (Cheng et al, ; Jambor et al, ; Laurenzana et al, ), increasing attention is being directed at its neurotoxicity, which remains poorly understood. Recent studies showed NP caused damages to hippocampal cells, which is involved in xenobiotic nuclear receptors (Litwa et al, ; Litwa et al, ). In this study, we focused on the NP‐induced inflammatory responses of MG, which may contribute to neuronal damages.…”

Section: Discussionmentioning

confidence: 99%

Mitogen‐activated protein kinase signaling is involved in nonylphenol‐induced proinflammatory cytokines secretion by BV2 microglia

Wang

Qiu

et al. 2018

J of Applied Toxicology

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Microglia (MG) are the key cells involved in the innate immune response in the central nervous system, and their activation has been linked to inflammation and neurotoxicity by the production of proinflammatory cytokines. Recently, researchers have found that nonylphenol (NP), a ubiquitous endocrine disrupting chemical, could impair neurodevelopment and cognitive memory performance. However, whether NP affects the inflammatory responses of MG remains to be elucidated. The aim of this study was to explore the effects of NP on the inflammatory responses of BV2 MG and the underlying mechanisms. Our results showed that NP increased the secretion of interleukin (IL)-6 and IL-1β in BV2 MG. Increased phosphorylation of Akt, JNK and p38 mitogen-activated protein kinase and decreased phosphorylation of ERK were observed in NP-treated MG. The inflammatory transcription factor activator protein 1 was also activated in NP-treated BV2 MG. These results suggest that NP may activate Akt/mitogen-activated protein kinase/activator protein 1 signaling in MG and subsequently increase IL-6 and IL-1β secretion.

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Apoptotic and neurotoxic actions of 4-para-nonylphenol are accompanied by activation of retinoid X receptor and impairment of classical estrogen receptor signaling

Cited by 32 publications

References 75 publications

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

The Crucial Involvement of Retinoid X Receptors in DDE Neurotoxicity

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Mitogen‐activated protein kinase signaling is involved in nonylphenol‐induced proinflammatory cytokines secretion by BV2 microglia

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