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Arthi Kanthasamy - One of the best experts on this subject based on the ideXlab platform.
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environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells relevance to epigenetic mechanisms of neurodegeneration
2010Co-Authors: Chunjuan Song, Arthi Kanthasamy, Vellareddy AnantharamAbstract:Pesticide exposure has been implicated in the etiopathogenesis of Parkinson's disease (PD); in particular, the organochlorine insecticide Dieldrin is believed to be associated with PD. Emerging evidence indicates that histone modifications play a critical role in cell death. In this study, we examined the effects of Dieldrin treatment on histone acetylation and its role in Dieldrin-induced apoptotic cell death in dopaminergic neuronal cells. In mesencephalic dopaminergic neuronal cells, Dieldrin induced a time-dependent increase in the acetylation of core histones H3 and H4. Histone acetylation occurred within 10 min of Dieldrin exposure indicating that acetylation is an early event in Dieldrin neurotoxicity. The hyperacetylation was attributed to Dieldrin-induced proteasomal dysfunction, resulting in accumulation of a key histone acetyltransferase (HAT), cAMP response element-binding protein. The novel HAT inhibitor anacardic acid significantly attenuated Dieldrin-induced histone acetylation, Protein kinase C δ proteolytic activation and DNA fragmentation in dopaminergic cells protected against dopaminergic neuronal degeneration in primary mesencephalic neuronal cultures. Furthermore, 30-day exposure of Dieldrin in mouse models induced histone hyperacetylation in the striatum and substantia nigra. For the first time, our results collectively demonstrate that exposure to the neurotoxic pesticide Dieldrin induces acetylation of core histones because of proteasomal dysfunction and that hyperacetylation plays a key role in dopaminergic neuronal degeneration after exposure of Dieldrin.
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environmental neurotoxin Dieldrin induces apoptosis via caspase 3 dependent proteolytic activation of protein kinase c delta pkcdelta implications for neurodegeneration in parkinson s disease
2008Co-Authors: Masashi Kitazawa, Vellareddy Anantharam, Yongjie Yang, Arthi KanthasamyAbstract:Background In previous work, we investigated Dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons.
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Dieldrin induces ubiquitin proteasome dysfunction in α synuclein overexpressing dopaminergic neuronal cells and enhances susceptibility to apoptotic cell death
2005Co-Authors: Faneng Sun, Arthi Kanthasamy, Vellareddy Anantharam, C LatchoumycandaneAbstract:Exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). The organochlorine pesticide Dieldrin is one of the environmental chemicals potentially linked to PD. Because recent evidence indicates that abnormal accumulation and aggregation of alpha-synuclein and ubiquitin-proteasome system dysfunction can contribute to the degenerative processes of PD, in the present study we examined whether the environmental pesticide Dieldrin impairs proteasomal function and subsequently promotes apoptotic cell death in rat mesencephalic dopaminergic neuronal cells overexpressing human alpha-synuclein. Overexpression of wild-type alpha-synuclein significantly reduced the proteasomal activity. Dieldrin exposure dose-dependently (0-70 microM) decreased proteasomal activity, and 30 microM Dieldrin inhibited activity by more than 60% in alpha-synuclein cells. Confocal microscopic analysis of Dieldrin-treated alpha-synuclein cells revealed that alpha-synuclein-positive protein aggregates colocalized with ubiquitin protein. Further characterization of the aggregates with the autophagosomal marker mondansyl cadaverine and the lysosomal marker and dot-blot analysis revealed that these protein oligomeric aggregates were distinct from autophagosomes and lysosomes. The Dieldrin-induced proteasomal dysfunction in alpha-synuclein cells was also confirmed by significant accumulation of ubiquitin protein conjugates in the detergent-insoluble fraction. We found that proteasomal inhibition preceded cell death after Dieldrin treatment and that alpha-synuclein cells were more sensitive than vector cells to the toxicity. Furthermore, measurement of caspase-3 and DNA fragmentation confirmed the enhanced sensitivity of alpha-synuclein cells to Dieldrin-induced apoptosis. Together, our results suggest that increased expression of alpha-synuclein predisposes dopaminergic cells to proteasomal dysfunction, which can be further exacerbated by environmental exposure to certain neurotoxic compounds, such as Dieldrin.
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Dieldrin promotes proteolytic cleavage of poly adp ribose polymerase and apoptosis in dopaminergic cells protective effect of mitochondrial anti apoptotic protein bcl 2
2004Co-Authors: Masashi Kitazawa, Arthi Kanthasamy, Vellareddy AnantharamAbstract:Previously, we demonstrated that the organochlorine pesticide Dieldrin induces mitochondrial depolarization, caspase-3 activation and apoptosis in dopaminergic PC12 cells. We also demonstrated that protein kinase Cdelta (PKCdelta), a member of a novel PKC family of proteins, is proteolytically activated by caspase-3 to mediate apoptotic cell death processes. In the present study, we have further characterized the protective effect of the major mitochondrial anti-apoptotic protein Bcl-2 against Dieldrin-induced apoptotic events in dopaminergic cells. Exposure to Dieldrin (30-100 microM) produced significant cytotoxicity and caspase-3 activation within 3h in vector-transfected PC12 cells, whereas human Bcl-2-transfected PC12 cells were almost completely resistant to Dieldrin-induced cytotoxicity and caspase-3 activation. Also, Dieldrin (30-300 microM) treatment induced proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), which was blocked by pretreatment with caspase-3 inhibitors Z-DEVD-FMK and Z-VAD-FMK. Additionally, Dieldrin-induced chromatin condensation and DNA fragmentation were completely blocked in Bcl-2-overexpressed PC12 cells as compared to vector control cells. Together, these results clearly indicate that overexpression of mitochondrial anti-apoptotic protein protects against Dieldrin-induced apoptotic cell death and further suggest that Dieldrin primarily alters mitochondrial function to initiate apoptotic cell death in dopaminergic cells.
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Dieldrin induces apoptosis by promoting caspase 3 dependent proteolytic cleavage of protein kinase cδ in dopaminergic cells relevance to oxidative stress and dopaminergic degeneration
2003Co-Authors: Masashi Kitazawa, Vellareddy Anantharam, Arthi KanthasamyAbstract:We previously reported that Dieldrin, one of the potential environmental risk factors for development of Parkinson's disease, induces apoptosis in dopaminergic cells by generating oxidative stress. Here, we demonstrate that the caspase-3-dependent proteolytic activation of protein kinase Cdelta (PKCdelta) mediates as well as regulates the Dieldrin-induced apoptotic cascade in dopaminergic cells. Exposure of PC12 cells to Dieldrin (100-300 microM) results in the rapid release of cytochrome C, followed by the activation of caspase-9 and caspase-3 in a time- and dose-dependent manner. The superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride significantly attenuates Dieldrin-induced cytochrome C release, indicating that reactive oxygen species may contribute to the activation of pro-apoptotic factors. Interestingly, Dieldrin proteolytically cleaves native PKCdelta into a 41 kDa catalytic subunit and a 38 kDa regulatory subunit to activate the kinase. The Dieldrin-induced proteolytic cleavage of PKCdelta and induction of kinase activity are completely inhibited by pretreatment with 50-100 microM concentrations of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), indicating that the proteolytic activation of PKCdelta is caspase-3-dependent. Additionally, Z-VAD-FMK, Z-DEVD-FMK or the PKCdelta specific inhibitor rottlerin almost completely block Dieldrin-induced DNA fragmentation. Because Dieldrin dramatically increases (40-80-fold) caspase-3 activity, we examined whether proteolytically activated PKCdelta amplifies caspase-3 via positive feedback activation. The PKCdelta inhibitor rottlerin (3-20 microM) dose-dependently attenuates Dieldrin-induced caspase-3 activity, suggesting positive feedback activation of caspase-3 by PKCdelta. Indeed, delivery of catalytically active recombinant PKCdelta via a protein delivery system significantly activates caspase-3 in PC12 cells. Finally, overexpression of the kinase-inactive PKCdelta(K376R) mutant in rat mesencephalic dopaminergic neuronal cells attenuates Dieldrin-induced caspase-3 activity and DNA fragmentation, further confirming the pro-apoptotic function of PKCdelta in dopaminergic cells. Together, we conclude that caspase-3-dependent proteolytic activation of PKCdelta is a critical event in Dieldrin-induced apoptotic cell death in dopaminergic cells.
Christopher J Martyniuk - One of the best experts on this subject based on the ideXlab platform.
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Dieldrin augments mtor signaling and regulates genes associated with cardiovascular disease in the adult zebrafish heart danio rerio
2017Co-Authors: Logan Slade, Christopher J Martyniuk, Andrew M Cowie, Petra C Kienesberger, Thomas PulinilkunnilAbstract:Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiologic studies suggest that exposure to Dieldrin is associated with increased risks of neurodegenerative disease and breast cancer by inducing inflammatory responses in tissues as well as oxidative stress. However, the direct effects of organochlorine pesticides on the heart have not been adequately addressed to date given that these chemicals are detectable in human serum and are environmentally persistent; thus, individuals may show latent adverse effects in the cardiovascular system due to long-term, low-dose exposure over time. Our objective was to determine whether low-level exposure to Dieldrin at an environmentally relevant dose results in aberrant molecular signaling in the vertebrate heart. Using transcriptomic profiling and immunoblotting, we determined the global gene and targeted protein expression response to Dieldrin treatment and show that Dieldrin affects gene networks in the heart that are associated with processes related to cardiovascular disease, specifically cardiac arrest and ventricular fibrillation. We report that genes regulating inflammatory responses, a significant risk factor for cardiovascular disease, are upregulated by Dieldrin whereas transcripts related to lysosomal function are significantly downregulated. To verify these findings, proteins in these pathways were examined with immunoblotting, and our results demonstrate that Dieldrin constitutively activates Akt/mTOR signaling and downregulates lysosomal genes, participating in autophagy. Our data demonstrate that Dieldrin induces genes associated with cardiovascular dysfunction and compromised lysosomal physiology, thereby identifying a novel mechanism for pesticide-induced cardiotoxicity.
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molecular networks related to the immune system and mitochondria are targets for the pesticide Dieldrin in the zebrafish danio rerio central nervous system
2017Co-Authors: Andrew M Cowie, Christopher J Martyniuk, Kathleena I Sarty, Angella Mercer, Jin Koh, Karen A KiddAbstract:Abstract The objectives of this study were to determine the behavioral and molecular responses in the adult zebrafish (Danio rerio) central nervous system (CNS) following a dietary exposure to the pesticide Dieldrin. Zebrafish were fed pellets spiked with 0.03, 0.15, or 1.8 μg/g Dieldrin for 21 days. Behavioral analysis revealed no difference in exploratory behaviors or those related to anxiety. Transcriptional networks for T-cell aggregation and selection were decreased in expression suggesting an immunosuppressive effect of Dieldrin, consistent with other studies investigating organochlorine pesticides. Processes related to oxidative phosphorylation were also differentially affected by Dieldrin. Quantitative proteomics (iTRAQ) using a hybrid quadrupole-Orbitrap identified 226 proteins that were different following one or more doses. These proteins included ATP synthase subunits (mitochondrial) and hypoxia up-regulated protein 1 which were decreased and NADH dehydrogenases (mitochondrial) and signal recognition particle 9 which were up-regulated. Thus, proteins affected were functionally associated with the mitochondria and a protein network analysis implicated Parkinson's disease (PD) and Huntington's disease as diseases associated with altered proteins. Molecular networks related to mitochondrial dysfunction and T-cell regulation are hypothesized to underlie the association between Dieldrin and PD. These data contribute to a comprehensive transcriptomic and proteomic biomarker framework for pesticide exposures and neurodegenerative diseases. Biological significance Dieldrin is a persistent organochlorine pesticide that has been associated with human neurodegenerative disease such as Parkinson's disease. Dieldrin is ranked 18th on the 2015 U.S. Agency for Toxic Substances and Disease Registry and continues to be a pesticide of concern for human health. Transcriptomics and quantitative proteomics (ITRAQ) were employed to characterize the molecular networks in the central nervous system that are altered with dietary exposure to Dieldrin. We found that transcriptional and protein networks related to the immune system, mitochondria, and Parkinson's disease were preferentially affected by Dieldrin. The study provides new insight into the mechanisms of Dieldrin neurotoxicity that may explain, in part, the association between this pesticide and increased risks to neurodegeneration. These data contribute in a significant way to developing a molecular framework for pesticide induced neurotoxicity.
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sexually dimorphic transcriptomic responses in the teleostean hypothalamus a case study with the organochlorine pesticide Dieldrin
2013Co-Authors: Christopher J Martyniuk, David S Barber, Nicholas J Doperalski, Kevin J Kroll, Nancy D DenslowAbstract:Organochlorine pesticides (OCPs) such as Dieldrin are a persistent class of aquatic pollutants that cause adverse neurological and reproductive effects in vertebrates. In this study, female and male largemouth bass (Micropterus salmoides) (LMB) were exposed to 3mg Dieldrin/kg feed in a 2 month feeding exposure (August-October) to (1) determine if the hypothalamic transcript responses to Dieldrin were conserved between the sexes; (2) characterize cell signaling cascades underlying Dieldrin neurotoxicity; and (3) determine whether or not co-feeding with 17β-estradiol (E(2)), a hormone with neuroprotective roles, mitigates responses in males to Dieldrin. Despite also being a weak estrogen, Dieldrin treatments did not elicit changes in reproductive endpoints (e.g. gonadosomatic index, vitellogenin, or plasma E(2)). Sub-network (SNEA) and gene set enrichment analysis (GSEA) revealed that neuro-hormone networks, neurotransmitter and nuclear receptor signaling, and the activin signaling network were altered by Dieldrin exposure. Most striking was that the majority of cell pathways identified by the gene set enrichment were significantly increased in females while the majority of cell pathways were significantly decreased in males fed Dieldrin. These data suggest that (1) there are sexually dimorphic responses in the teleost hypothalamus; (2) neurotransmitter systems are a target of Dieldrin at the transcriptomics level; and (3) males co-fed Dieldrin and E(2) had the fewest numbers of genes and cell pathways altered in the hypothalamus, suggesting that E(2) may mitigate the effects of Dieldrin in the central nervous system.
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genomic and proteomic responses to environmentally relevant exposures to Dieldrin indicators of neurodegeneration
2010Co-Authors: Christopher J Martyniuk, David S Barber, Nicholas J Doperalski, Kevin J Kroll, Nancy D DenslowAbstract:Dieldrin is a persistent organochlorine pesticide that induces neurotoxicity in the vertebrate central nervous system and impairs reproductive processes in fish. This study examined the molecular events produced by subchronic dietary exposures to 2.95 mg Dieldrin/kg feed in the neuroendocrine brain of largemouth bass, an apex predator. Microarrays, proteomics, and pathway analysis were performed to identify genes, proteins, and cell processes altered in the male hypothalamus. Fifty-four genes were induced, and 220 genes were reduced in steady-state levels (p < 0.001; fold change greater than ± 1.5). Functional enrichment analysis revealed that the biological gene ontology categories of stress response, nucleotide base excision repair, response to toxin, and metabolic processes were significantly impacted by Dieldrin. Using isobaric tagging for relative and absolute quantitation, 90 proteins in the male hypothalamus were statistically evaluated for changes in protein abundance. Several proteins altered by Dieldrin are known to be associated with human neurodegenerative diseases, including apolipoprotein E, microtubule-associated tau protein, enolase 1, stathmin 1a, myelin basic protein, and parvalbumin. Proteins altered by Dieldrin were involved in oxidative phosphorylation, differentiation, proliferation, and cell survival. This study demonstrates that a subchronic exposure to Dieldrin alters the abundance of messenger RNAs and proteins in the hypothalamus that are associated with cell metabolism, cell stability and integrity, stress, and DNA repair.
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effects of acute Dieldrin exposure on neurotransmitters and global gene transcription in largemouth bass micropterus salmoides hypothalamus
2010Co-Authors: Christopher J Martyniuk, David S Barber, Kevin J Kroll, April Feswick, Daniel J Spade, Nancy D DenslowAbstract:Exposure to Dieldrin induces neurotoxic effects in the vertebrate CNS and disrupts reproductive processes in teleost fish. Reproductive impairment observed in fish by Dieldrin is likely the result of multiple effects along the hypothalamic–pituitary–gonadal axis, but the molecular signaling cascades are not well characterized. To better elucidate the mode of action of Dieldrin in the hypothalamus, this study measured neurotransmitter levels and examined the transcriptomic response in female largemouth bass (LMB) to an acute treatment of Dieldrin. Male and female LMB were injected with either vehicle or 10 mg Dieldrin/kg and sacrificed after 7 days. There were no significant changes in dopamine or DOPAC concentrations in the neuroendocrine brain of males and females after treatment but GABA levels in females were moderately increased 20–30% in the hypothalamus and cerebellum. In the female hypothalamus, there were 227 transcripts (p < 0.001) identified as being differentially regulated by Dieldrin. Functional enrichment analysis revealed transcription, DNA repair, ubiquitin-proteasome pathway, and cell communication, as biological processes over-represented in the microarray analysis. Pathway analysis identified DNA damage, inflammation, regeneration, and Alzheimer's disease as major cell processes and diseases affected by Dieldrin. Using multiple bioinformatics approaches, this study demonstrates that the teleostean hypothalamus is a target for Dieldrin-induced neurotoxicity and provides mechanistic evidence that Dieldrin activates similar cell pathways and biological processes that are also associated with the etiology of human neurological disorders.
Nancy D Denslow - One of the best experts on this subject based on the ideXlab platform.
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functional profiling discovers the Dieldrin organochlorinated pesticide affects leucine availability in yeast
2013Co-Authors: Brandon D Gaytan, Alex Loguinov, Stephen R Lantz, Janmichael Lerot, Nancy D Denslow, Chris D VulpeAbstract:Exposure to organochlorinated pesticides such as Dieldrin has been linked to Parkinson’s and Alzheimer’s diseases, endocrine disruption, and cancer, but the cellular and molecular mechanisms of toxicity behind these effects remain largely unknown. Here we demonstrate, using a functional genomics approach in the model eukaryote Saccharomyces cerevisiae, that Dieldrin alters leucine availability. This model is supported by multiple lines of congruent evidence: (1) mutants defective in amino acid signaling or transport are sensitive to Dieldrin, which is reversed by the addition of exogenous leucine; (2) Dieldrin sensitivity of wild-type or mutant strains is dependent upon leucine concentration in the media; (3) overexpression of proteins that increase intracellular leucine confer resistance to Dieldrin; (4) leucine uptake is inhibited in the presence of Dieldrin; and (5) Dieldrin induces the amino acid starvation response. Additionally, we demonstrate that appropriate negative regulation of the Ras/protein kinase A pathway, along with an intact pyruvate dehydrogenase complex, is required for Dieldrin tolerance. Many yeast genes described in this study have human orthologs that may modulate Dieldrin toxicity in humans.
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sexually dimorphic transcriptomic responses in the teleostean hypothalamus a case study with the organochlorine pesticide Dieldrin
2013Co-Authors: Christopher J Martyniuk, David S Barber, Nicholas J Doperalski, Kevin J Kroll, Nancy D DenslowAbstract:Organochlorine pesticides (OCPs) such as Dieldrin are a persistent class of aquatic pollutants that cause adverse neurological and reproductive effects in vertebrates. In this study, female and male largemouth bass (Micropterus salmoides) (LMB) were exposed to 3mg Dieldrin/kg feed in a 2 month feeding exposure (August-October) to (1) determine if the hypothalamic transcript responses to Dieldrin were conserved between the sexes; (2) characterize cell signaling cascades underlying Dieldrin neurotoxicity; and (3) determine whether or not co-feeding with 17β-estradiol (E(2)), a hormone with neuroprotective roles, mitigates responses in males to Dieldrin. Despite also being a weak estrogen, Dieldrin treatments did not elicit changes in reproductive endpoints (e.g. gonadosomatic index, vitellogenin, or plasma E(2)). Sub-network (SNEA) and gene set enrichment analysis (GSEA) revealed that neuro-hormone networks, neurotransmitter and nuclear receptor signaling, and the activin signaling network were altered by Dieldrin exposure. Most striking was that the majority of cell pathways identified by the gene set enrichment were significantly increased in females while the majority of cell pathways were significantly decreased in males fed Dieldrin. These data suggest that (1) there are sexually dimorphic responses in the teleost hypothalamus; (2) neurotransmitter systems are a target of Dieldrin at the transcriptomics level; and (3) males co-fed Dieldrin and E(2) had the fewest numbers of genes and cell pathways altered in the hypothalamus, suggesting that E(2) may mitigate the effects of Dieldrin in the central nervous system.
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genomic and proteomic responses to environmentally relevant exposures to Dieldrin indicators of neurodegeneration
2010Co-Authors: Christopher J Martyniuk, David S Barber, Nicholas J Doperalski, Kevin J Kroll, Nancy D DenslowAbstract:Dieldrin is a persistent organochlorine pesticide that induces neurotoxicity in the vertebrate central nervous system and impairs reproductive processes in fish. This study examined the molecular events produced by subchronic dietary exposures to 2.95 mg Dieldrin/kg feed in the neuroendocrine brain of largemouth bass, an apex predator. Microarrays, proteomics, and pathway analysis were performed to identify genes, proteins, and cell processes altered in the male hypothalamus. Fifty-four genes were induced, and 220 genes were reduced in steady-state levels (p < 0.001; fold change greater than ± 1.5). Functional enrichment analysis revealed that the biological gene ontology categories of stress response, nucleotide base excision repair, response to toxin, and metabolic processes were significantly impacted by Dieldrin. Using isobaric tagging for relative and absolute quantitation, 90 proteins in the male hypothalamus were statistically evaluated for changes in protein abundance. Several proteins altered by Dieldrin are known to be associated with human neurodegenerative diseases, including apolipoprotein E, microtubule-associated tau protein, enolase 1, stathmin 1a, myelin basic protein, and parvalbumin. Proteins altered by Dieldrin were involved in oxidative phosphorylation, differentiation, proliferation, and cell survival. This study demonstrates that a subchronic exposure to Dieldrin alters the abundance of messenger RNAs and proteins in the hypothalamus that are associated with cell metabolism, cell stability and integrity, stress, and DNA repair.
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effects of acute Dieldrin exposure on neurotransmitters and global gene transcription in largemouth bass micropterus salmoides hypothalamus
2010Co-Authors: Christopher J Martyniuk, David S Barber, Kevin J Kroll, April Feswick, Daniel J Spade, Nancy D DenslowAbstract:Exposure to Dieldrin induces neurotoxic effects in the vertebrate CNS and disrupts reproductive processes in teleost fish. Reproductive impairment observed in fish by Dieldrin is likely the result of multiple effects along the hypothalamic–pituitary–gonadal axis, but the molecular signaling cascades are not well characterized. To better elucidate the mode of action of Dieldrin in the hypothalamus, this study measured neurotransmitter levels and examined the transcriptomic response in female largemouth bass (LMB) to an acute treatment of Dieldrin. Male and female LMB were injected with either vehicle or 10 mg Dieldrin/kg and sacrificed after 7 days. There were no significant changes in dopamine or DOPAC concentrations in the neuroendocrine brain of males and females after treatment but GABA levels in females were moderately increased 20–30% in the hypothalamus and cerebellum. In the female hypothalamus, there were 227 transcripts (p < 0.001) identified as being differentially regulated by Dieldrin. Functional enrichment analysis revealed transcription, DNA repair, ubiquitin-proteasome pathway, and cell communication, as biological processes over-represented in the microarray analysis. Pathway analysis identified DNA damage, inflammation, regeneration, and Alzheimer's disease as major cell processes and diseases affected by Dieldrin. Using multiple bioinformatics approaches, this study demonstrates that the teleostean hypothalamus is a target for Dieldrin-induced neurotoxicity and provides mechanistic evidence that Dieldrin activates similar cell pathways and biological processes that are also associated with the etiology of human neurological disorders.
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effects of acute Dieldrin exposure on neurotransmitters and global gene transcription in largemouth bass micropterus salmoides hypothalamus
2010Co-Authors: Christopher J Martyniuk, David S Barber, Kevin J Kroll, April Feswick, Daniel J Spade, Nancy D DenslowAbstract:Abstract Exposure to Dieldrin induces neurotoxic effects in the vertebrate CNS and disrupts reproductive processes in teleost fish. Reproductive impairment observed in fish by Dieldrin is likely the result of multiple effects along the hypothalamic–pituitary–gonadal axis, but the molecular signaling cascades are not well characterized. To better elucidate the mode of action of Dieldrin in the hypothalamus, this study measured neurotransmitter levels and examined the transcriptomic response in female largemouth bass (LMB) to an acute treatment of Dieldrin. Male and female LMB were injected with either vehicle or 10 mg Dieldrin/kg and sacrificed after 7 days. There were no significant changes in dopamine or DOPAC concentrations in the neuroendocrine brain of males and females after treatment but GABA levels in females were moderately increased 20–30% in the hypothalamus and cerebellum. In the female hypothalamus, there were 227 transcripts (p
Cristina Sunol - One of the best experts on this subject based on the ideXlab platform.
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allopregnanolone prevents Dieldrin induced nmda receptor internalization and neurotoxicity by preserving gabaa receptor function
2012Co-Authors: Victor Briz, Sara Sanchezredondo, Jyoti Parkash, Vincent Prevot, Cristina SunolAbstract:Dieldrin is an endocrine disruptor that accumulates in mammalian adipose tissue and brain. It induces convulsions due to its antagonism of the γ-aminobutyric acid A receptor (GABAAR). We have previously reported that long-term exposure to Dieldrin causes the internalization of the N-methyl-d-aspartate receptor (NMDAR) as a result of persistent GABAAR inhibition. Because the neurosteroids 17β-estradiol (E2) and allopregnanolone are known to modulate the function and trafficking of GABAAR and NMDAR, we examined the effects of E2 and allopregnanolone on Dieldrin-induced GABAAR inhibition, NMDAR internalization, and neuronal death in cortical neurons. We found that 1 nm E2 increased the membrane expression of NR1/NR2B receptors and postsynaptic density 95 but did not induce their physical association. In contrast, 10 nm E2 had no effect on these proteins but reduced NR2A membrane expression. We also found that exposure to 60 nm Dieldrin for 6 d in vitro caused the internalization of NR1 and NR2B but not NR2A....
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differential estrogenic effects of the persistent organochlorine pesticides Dieldrin endosulfan and lindane in primary neuronal cultures
2011Co-Authors: Victor Briz, Josemanuel Molinamolina, Sara Sanchezredondo, Mariana F Fernandez, Joan O Grimalt, Nicolas Olea, Eduard Rodriguezfarre, Cristina SunolAbstract:The organochlorine chemicals endosulfan, Dieldrin, and ghexachlorocyclohexane (lindane) are persistent pesticides to which people are exposed mainly via diet. Their antagonism of the g-aminobutyric acid-A (GABAA) receptor makes them convulsants. They are also endocrine disruptors because of their interaction with the estrogen receptor (ER). Here, we study the effects of Dieldrin, endosulfan, and lindane on ERs in primary cultures of cortical neurons (CN) and cerebellar granule cells (CGC). All the compounds tested inhibited the binding of [ 3 H]-estradiol to the ER in both CN and CGC, with Dieldrin in CGC showing the highest affinity. We also determined the effects of the pesticides on protein kinase B (Akt) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation. Dieldrin and endosulfan increased Akt phosphorylation in CN, which was inhibited by the ERb antagonist 4-[2-phenyl-5,7bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol. Instead, Akt and ERK1/2 phosphorylation induced by Dieldrin in CGC was mediated by multiple activation of ERa ,E R b ,a nd Gp rotein‐ coupled receptor 30. Lindane did not activate these pathways, but it inhibited estradiol-mediated Akt and ERK1/2 activation. In CN, all the chemicals activated ERK1/2 through a mechanism involving GABAA and glutamate receptors. Long-term exposure to these pesticides reduced the levels of ERa, but not of ERb. Moreover, extracts of CN treated with endosulfan, Dieldrin, or lindane induced cell proliferation in MCF-7 human breast cancer‐derived cells, whereas only extracts of CGC treated with Dieldrin induced MCF-7 cell proliferation. Overall, the observed alterations on ER-mediated signaling and ER levels in neurons might contribute to the neurotoxicity of these organochlorine pesticides.
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reduction of glutamatergic neurotransmission by prolonged exposure to Dieldrin involves nmda receptor internalization and metabotropic glutamate receptor 5 downregulation
2010Co-Authors: Victor Briz, Mireia Galofre, Cristina SunolAbstract:Dieldrin was previously used as a pesticide. Although its use has been discontinued, humans are still exposed to it due to its high environmental persistence and because it accumulates in the adipose tissue of animals. Acute exposure to Dieldrin provokes convulsions due to its antagonism on the gamma-aminobutyric acid-A (GABA(A)) receptor. However, little is known about the effects of low chronic exposure to this pollutant. In the present work, we use primary cultures of cortical neurons to study the mechanisms involved in the toxic action of Dieldrin. We found that 2 and 6 days in vitro (DIV) exposure to a subcytotoxic concentration (60nM) of Dieldrin reduced the increase in intracellular calcium concentration ([Ca(2+)](i)) and the excitotoxicity caused by glutamate. Exposure to Dieldrin for 6 DIV induced N-methyl-D-aspartate receptor (NMDAR) internalization and reduced metabotropic glutamate receptor 5 (mGLUR5) levels. Double immunostaining for NMDAR and mGLUR5 showed that these receptors lose colocalization on the cell membrane in neurons treated with Dieldrin. No changes were observed in receptor functionalities or receptor levels after 2 DIV of exposure to Dieldrin. However, the increase in [Ca(2+)](i) induced by coactivation of NMDAR and mGLUR5 was significantly reduced. Thus, a functional interaction between the two receptors seems to play an important role in glutamate-induced excitotoxicity. We confirm that permanent blockade of the GABA(A) receptor by this persistent pesticide triggers adaptive neuronal changes consisting of a reduction of glutamatergic neurotransmission. This might explain the cognitive and learning deficits observed in animals after chronic treatment with Dieldrin.
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long term exposure to Dieldrin reduces γ aminobutyric acid type a and n methyl d aspartate receptor function in primary cultures of mouse cerebellar granule cells
2007Co-Authors: Zoila Babot, Teresa M Vilaro, Cristina SunolAbstract:The organochlorine pesticide Dieldrin is a persistent organic pollutant that accumulates in the fatty tissue of living organisms. In mammals, it antagonizes the GABA(A) receptor, producing convulsions after acute exposure. Although accumulation in human brain has been reported, little is known about the effects of long-term exposure to Dieldrin in the nervous system. Homeostatic control of the balance between excitation and inhibition has been reported when neuronal activity is chronically altered. We hypothesized that noncytotoxic concentrations of Dieldrin could decrease glutamatergic neurotransmission as a consequence of a prolonged reduction in GABA(A) receptor function. Long-term exposure of primary cerebellar granule cell cultures to 3 microM Dieldrin reduced the GABA(A) receptor function to 55% of control, as measured by the GABA-induced (36)Cl(-) uptake. This exposure produced a significant reduction (approximately 35%) of the NMDA-induced increase in [Ca(2+)](i) and of the [(3)H]MK-801 binding, which was not accompanied by a reduction in the NMDA receptor subunit NR1, as determined by Western blot. Consistent with the decreased NMDA receptor function, Dieldrin-treated cultures were insensitive to an excitotoxic stimulus induced by exposure to high potassium. In summary, we report that the chronic reduction of GABA(A) receptor function induced by Dieldrin decreases the number of functional NMDA receptors, which may be attributable to a mechanism of synaptic scaling. These effects could underlie neural mechanisms involved in cognitive impairment produced by low-level exposure to Dieldrin.
Vellareddy Anantharam - One of the best experts on this subject based on the ideXlab platform.
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environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells relevance to epigenetic mechanisms of neurodegeneration
2010Co-Authors: Chunjuan Song, Arthi Kanthasamy, Vellareddy AnantharamAbstract:Pesticide exposure has been implicated in the etiopathogenesis of Parkinson's disease (PD); in particular, the organochlorine insecticide Dieldrin is believed to be associated with PD. Emerging evidence indicates that histone modifications play a critical role in cell death. In this study, we examined the effects of Dieldrin treatment on histone acetylation and its role in Dieldrin-induced apoptotic cell death in dopaminergic neuronal cells. In mesencephalic dopaminergic neuronal cells, Dieldrin induced a time-dependent increase in the acetylation of core histones H3 and H4. Histone acetylation occurred within 10 min of Dieldrin exposure indicating that acetylation is an early event in Dieldrin neurotoxicity. The hyperacetylation was attributed to Dieldrin-induced proteasomal dysfunction, resulting in accumulation of a key histone acetyltransferase (HAT), cAMP response element-binding protein. The novel HAT inhibitor anacardic acid significantly attenuated Dieldrin-induced histone acetylation, Protein kinase C δ proteolytic activation and DNA fragmentation in dopaminergic cells protected against dopaminergic neuronal degeneration in primary mesencephalic neuronal cultures. Furthermore, 30-day exposure of Dieldrin in mouse models induced histone hyperacetylation in the striatum and substantia nigra. For the first time, our results collectively demonstrate that exposure to the neurotoxic pesticide Dieldrin induces acetylation of core histones because of proteasomal dysfunction and that hyperacetylation plays a key role in dopaminergic neuronal degeneration after exposure of Dieldrin.
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environmental neurotoxin Dieldrin induces apoptosis via caspase 3 dependent proteolytic activation of protein kinase c delta pkcdelta implications for neurodegeneration in parkinson s disease
2008Co-Authors: Masashi Kitazawa, Vellareddy Anantharam, Yongjie Yang, Arthi KanthasamyAbstract:Background In previous work, we investigated Dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons.
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Dieldrin induces ubiquitin proteasome dysfunction in α synuclein overexpressing dopaminergic neuronal cells and enhances susceptibility to apoptotic cell death
2005Co-Authors: Faneng Sun, Arthi Kanthasamy, Vellareddy Anantharam, C LatchoumycandaneAbstract:Exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). The organochlorine pesticide Dieldrin is one of the environmental chemicals potentially linked to PD. Because recent evidence indicates that abnormal accumulation and aggregation of alpha-synuclein and ubiquitin-proteasome system dysfunction can contribute to the degenerative processes of PD, in the present study we examined whether the environmental pesticide Dieldrin impairs proteasomal function and subsequently promotes apoptotic cell death in rat mesencephalic dopaminergic neuronal cells overexpressing human alpha-synuclein. Overexpression of wild-type alpha-synuclein significantly reduced the proteasomal activity. Dieldrin exposure dose-dependently (0-70 microM) decreased proteasomal activity, and 30 microM Dieldrin inhibited activity by more than 60% in alpha-synuclein cells. Confocal microscopic analysis of Dieldrin-treated alpha-synuclein cells revealed that alpha-synuclein-positive protein aggregates colocalized with ubiquitin protein. Further characterization of the aggregates with the autophagosomal marker mondansyl cadaverine and the lysosomal marker and dot-blot analysis revealed that these protein oligomeric aggregates were distinct from autophagosomes and lysosomes. The Dieldrin-induced proteasomal dysfunction in alpha-synuclein cells was also confirmed by significant accumulation of ubiquitin protein conjugates in the detergent-insoluble fraction. We found that proteasomal inhibition preceded cell death after Dieldrin treatment and that alpha-synuclein cells were more sensitive than vector cells to the toxicity. Furthermore, measurement of caspase-3 and DNA fragmentation confirmed the enhanced sensitivity of alpha-synuclein cells to Dieldrin-induced apoptosis. Together, our results suggest that increased expression of alpha-synuclein predisposes dopaminergic cells to proteasomal dysfunction, which can be further exacerbated by environmental exposure to certain neurotoxic compounds, such as Dieldrin.
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Dieldrin promotes proteolytic cleavage of poly adp ribose polymerase and apoptosis in dopaminergic cells protective effect of mitochondrial anti apoptotic protein bcl 2
2004Co-Authors: Masashi Kitazawa, Arthi Kanthasamy, Vellareddy AnantharamAbstract:Previously, we demonstrated that the organochlorine pesticide Dieldrin induces mitochondrial depolarization, caspase-3 activation and apoptosis in dopaminergic PC12 cells. We also demonstrated that protein kinase Cdelta (PKCdelta), a member of a novel PKC family of proteins, is proteolytically activated by caspase-3 to mediate apoptotic cell death processes. In the present study, we have further characterized the protective effect of the major mitochondrial anti-apoptotic protein Bcl-2 against Dieldrin-induced apoptotic events in dopaminergic cells. Exposure to Dieldrin (30-100 microM) produced significant cytotoxicity and caspase-3 activation within 3h in vector-transfected PC12 cells, whereas human Bcl-2-transfected PC12 cells were almost completely resistant to Dieldrin-induced cytotoxicity and caspase-3 activation. Also, Dieldrin (30-300 microM) treatment induced proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), which was blocked by pretreatment with caspase-3 inhibitors Z-DEVD-FMK and Z-VAD-FMK. Additionally, Dieldrin-induced chromatin condensation and DNA fragmentation were completely blocked in Bcl-2-overexpressed PC12 cells as compared to vector control cells. Together, these results clearly indicate that overexpression of mitochondrial anti-apoptotic protein protects against Dieldrin-induced apoptotic cell death and further suggest that Dieldrin primarily alters mitochondrial function to initiate apoptotic cell death in dopaminergic cells.
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Dieldrin induces apoptosis by promoting caspase 3 dependent proteolytic cleavage of protein kinase cδ in dopaminergic cells relevance to oxidative stress and dopaminergic degeneration
2003Co-Authors: Masashi Kitazawa, Vellareddy Anantharam, Arthi KanthasamyAbstract:We previously reported that Dieldrin, one of the potential environmental risk factors for development of Parkinson's disease, induces apoptosis in dopaminergic cells by generating oxidative stress. Here, we demonstrate that the caspase-3-dependent proteolytic activation of protein kinase Cdelta (PKCdelta) mediates as well as regulates the Dieldrin-induced apoptotic cascade in dopaminergic cells. Exposure of PC12 cells to Dieldrin (100-300 microM) results in the rapid release of cytochrome C, followed by the activation of caspase-9 and caspase-3 in a time- and dose-dependent manner. The superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride significantly attenuates Dieldrin-induced cytochrome C release, indicating that reactive oxygen species may contribute to the activation of pro-apoptotic factors. Interestingly, Dieldrin proteolytically cleaves native PKCdelta into a 41 kDa catalytic subunit and a 38 kDa regulatory subunit to activate the kinase. The Dieldrin-induced proteolytic cleavage of PKCdelta and induction of kinase activity are completely inhibited by pretreatment with 50-100 microM concentrations of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), indicating that the proteolytic activation of PKCdelta is caspase-3-dependent. Additionally, Z-VAD-FMK, Z-DEVD-FMK or the PKCdelta specific inhibitor rottlerin almost completely block Dieldrin-induced DNA fragmentation. Because Dieldrin dramatically increases (40-80-fold) caspase-3 activity, we examined whether proteolytically activated PKCdelta amplifies caspase-3 via positive feedback activation. The PKCdelta inhibitor rottlerin (3-20 microM) dose-dependently attenuates Dieldrin-induced caspase-3 activity, suggesting positive feedback activation of caspase-3 by PKCdelta. Indeed, delivery of catalytically active recombinant PKCdelta via a protein delivery system significantly activates caspase-3 in PC12 cells. Finally, overexpression of the kinase-inactive PKCdelta(K376R) mutant in rat mesencephalic dopaminergic neuronal cells attenuates Dieldrin-induced caspase-3 activity and DNA fragmentation, further confirming the pro-apoptotic function of PKCdelta in dopaminergic cells. Together, we conclude that caspase-3-dependent proteolytic activation of PKCdelta is a critical event in Dieldrin-induced apoptotic cell death in dopaminergic cells.
