The Experts below are selected from a list of 138 Experts worldwide ranked by ideXlab platform
Rita Lochcaruso - One of the best experts on this subject based on the ideXlab platform.
-
transcriptional profiling of the response to the trichloroethylene metabolite s 1 2 dichlorovinyl l cysteine revealed activation of the eif2α atf4 integrated stress response in two in vitro Placental models
Archives of Toxicology, 2021Co-Authors: Elana R Elkin, Kelly M Bakulski, Justin A Colacino, Dave Bridges, Brian A Kilburn, Randall D Armant, Rita LochcarusoAbstract:Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Although TCE exposure is prevalent, epidemiological studies of TCE exposure associations with adverse birth outcomes are inconclusive. Prior studies show that the TCE metabolite S-(1,2-dichlorovinyl)-l-cysteine (DCVC) exhibits toxicity in a Placental Cell Line. In the current study, genome-wide gene expression and gene set enrichment analyses were used to identify novel genes and pathway alterations in the HTR-8/SVneo human trophoblast Cell Line and human Placental villous explants treated with DCVC at concentrations relevant to human exposures. In the Cells, concentration- and time-dependent effects were observed, as evidenced by the magnitude of altered gene expression after treatment with 20 µM DCVC versus 10 µM, and 12-h versus 6-h of treatment. Comparing the two models for the transcriptional response to 12-h 20 µM DCVC treatment, no differentially expressed genes reached significance in villous explants, whereas 301 differentially expressed genes were detected in HTR-8/SVneo Cells compared with non-treated controls (FDR 0.35 [FC > 1.3]). GSEA revealed five upregulated enriched pathways in common between explants and Cells (FDR < 0.05). Moreover, all 12-h DCVC treatment groups from both models contained upregulated pathways enriched for genes regulated by the ATF4 transcription factor. The overrepresentation of ATF4 regulation of differentially expressed genes indicated activation of the integrated stress response (ISR), a condition triggered by multiple stress stimuli, including the unfolded protein response. DCVC-induced ISR activation was confirmed by elevated eIF2α phosphorylation, ATF4 protein concentrations, and decreased global protein synthesis in HTR-8/SVneo Cells. This study identifies a mechanism of DCVC-induced cytotoxicity by revealing the involvement of a specific stress signaling pathway.
-
trichloroethylene metabolite s 1 2 dichlorovinyl l cysteine induces lipid peroxidation associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first trimester Placental Cell Line
Toxicology and Applied Pharmacology, 2018Co-Authors: Elana R Elkin, Sean M Harris, Rita LochcarusoAbstract:Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)-l-cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast Cell Line, HTR-8/SVneo. We exposed the Cells in vitro to 10-100μM DCVC for various time points up to 24h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p<0.05). DCVC also significantly stimulated caspase 3, 7, 8 and 9 activities after 12h (p<0.05), suggesting that DCVC stimulates the activation of both the intrinsic and extrinsic apoptotic signaling pathways simultaneously. Pre-treatment with the tBID inhibitor Bl-6C9 partially reduced DCVC-stimulated caspase 3 and 7 activity, signifying crosstalk between the two pathways. Additionally, DCVC treatment increased lipid peroxidation in a concentration-dependent manner. Co-treatment with the antioxidant peroxyl radical scavenger (±)-α-tocopherol attenuated caspase 3 and 7 activity, suggesting that lipid peroxidation mediates DCVC-induced apoptosis in extravillous trophoblasts. Our findings suggest that DCVC-induced apoptosis and lipid peroxidation in extravillous trophoblasts could contribute to poor placentation if similar effects occur in vivo in response to TCE exposure, indicating that further studies into this mechanism are warranted.
-
trichloroethylene metabolite s 1 2 dichlorovinyl l cysteine induces lipid peroxidation associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first trimester Placental Cell Line
Toxicology and Applied Pharmacology, 2018Co-Authors: Elana R Elkin, Sean M Harris, Rita LochcarusoAbstract:Abstract Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)- l -cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast Cell Line, HTR-8/SVneo. We exposed the Cells in vitro to 10–100 μM DCVC for various time points up to 24 h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p
-
reactive oxygen stimulation of interleukin 6 release in the human trophoblast Cell Line htr 8 svneo by the trichlorethylene metabolite s 1 2 dichloro l cysteine
Biology of Reproduction, 2016Co-Authors: Iman Hassan, Anjana Kumar, Hae Ryung Park, Lawrence H. Lash, Rita LochcarusoAbstract:Trichloroethylene (TCE) is a common environmental pollutant associated with adverse reproductive outcomes in humans. TCE intoxication occurs primarily through its biotransformation to bioactive metabolites, including S-(1,2-dichlorovinyl)-l-cysteine (DCVC). TCE induces oxidative stress and inflammation in the liver and kidney. Although the placenta is capable of xenobiotic metabolism and oxidative stress and inflammation in placenta have been associated with adverse pregnancy outcomes, TCE toxicity in the placenta remains poorly understood. We determined the effects of DCVC by using the human extravillous trophoblast Cell Line HTR-8/SVneo. Exposure to 10 and 20 μM DCVC for 10 h increased reactive oxygen species (ROS) as measured by carboxydichlorofluorescein fluorescence. Moreover, 10 and 20 μM DCVC increased mRNA expression and release of interleukin-6 (IL-6) after 24-h exposure, and these responses were inhibited by the cysteine conjugate beta-lyase inhibitor aminooxyacetic acid and by treatments with antioxidants (alpha-tocopherol and deferoxamine), suggesting that DCVC-stimulated IL-6 release in HTR-8/SVneo Cells is dependent on beta-lyase metabolic activation and increased generation of ROS. HTR-8/SVneo Cells exhibited decreased mitochondrial membrane potential at 5, 10, and 20 μM DCVC at 5, 10, and 24 h, showing that DCVC induces mitochondrial dysfunction in HTR-8/Svneo Cells. The present study demonstrates that DCVC stimulated ROS generation in the human Placental Cell Line HTR-8/SVneo and provides new evidence of mechanistic linkage between DCVC-stimulated ROS and increase in proinflammatory cytokine IL-6. Because abnormal activation of cytokines can disrupt trophoblast functions necessary for Placental development and successful pregnancy, follow-up investigations relating these findings to physiologic outcomes are warranted.
Mahua Choudhury - One of the best experts on this subject based on the ideXlab platform.
-
mono 2 ethylhexyl phthalate induces apoptosis through mir 16 in human first trimester Placental Cell Line htr 8 svneo
Toxicology in Vitro, 2016Co-Authors: Sunitha Meruvu, Jian Zhang, Yudhishtar Singh Bedi, Mahua ChoudhuryAbstract:Phthalates have been linked to adverse pregnancy complications. Mono-(2-ethylhexyl) phthalate, an active metabolite of di-(2-ethylhexyl) phthalate and an endocrine disruptor, has been shown to induce apoptosis in various Cell types including Placental Cells. However, the mechanism of action of MEHP induced apoptosis is still unknown. We hypothesized that apoptosis may be mediated in part through altered microRNA(s) in placenta under MEHP exposure. In the present study, we report that MEHP increases miR-16 expression in a time- and dose-dependent manner (p<0.05), while inducing apoptosis in HTR-8/SVneo. Cells treated with MEHP showed a dose-dependent increase in cytotoxicity and reactive oxygen species along with decreased Cell viability. Consistent with significant increase in apoptosis analyzed by flow cytometry, we detected decreased anti-apoptotic BCL-2 at transcriptional and translational levels with MEHP (p<0.05). Knockdown of miR-16 did not decrease the BCL-2/BAX protein expression ratio in the presence of MEHP when compared to negative control demonstrating that MEHP induces apoptosis directly through miR-16. In conclusion, our study demonstrates for the first time that MEHP induces miR-16, which in turn, alters BCL-2/BAX ratio leading to increased apoptosis. This study provides a novel insight into MEHP induced epigenetic regulation in Placental apoptosis which may lead to pregnancy complications.
-
mono 2 ethylhexyl phthalate increases oxidative stress responsive mirnas in first trimester Placental Cell Line htr8 svneo
Chemical Research in Toxicology, 2016Co-Authors: Sunitha Meruvu, Jian Zhang, Mahua ChoudhuryAbstract:Phthalates, an endocrine disruptor group, cause oxidative stress (OS) in the placenta. However, no studies have reported OS-related miRNAs induced by phthalates. In the present study, we demonstrate that mono-(2-ethylhexyl) phthalate (MEHP) induces OS responsive miR-17-5p, miR-155-5p, and miR-126-3p in HTR8/SVneo in a dose- and time-dependent manner. Furthermore, MEHP altered the expression of phosphoinositide-3-kinase regulatory subunit 1α, phosphatase and tensin homolog, CDKN2A interacting protein, superoxide dismutase 2, and 3β-hydroxysterol-D24 reductase, which are involved in OS and predicted to be regulated by these miRNAs. Our results suggest that Placental exposure to MEHP may result in aberrant miRNA expression leading to pregnancy complications.
Elana R Elkin - One of the best experts on this subject based on the ideXlab platform.
-
transcriptional profiling of the response to the trichloroethylene metabolite s 1 2 dichlorovinyl l cysteine revealed activation of the eif2α atf4 integrated stress response in two in vitro Placental models
Archives of Toxicology, 2021Co-Authors: Elana R Elkin, Kelly M Bakulski, Justin A Colacino, Dave Bridges, Brian A Kilburn, Randall D Armant, Rita LochcarusoAbstract:Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Although TCE exposure is prevalent, epidemiological studies of TCE exposure associations with adverse birth outcomes are inconclusive. Prior studies show that the TCE metabolite S-(1,2-dichlorovinyl)-l-cysteine (DCVC) exhibits toxicity in a Placental Cell Line. In the current study, genome-wide gene expression and gene set enrichment analyses were used to identify novel genes and pathway alterations in the HTR-8/SVneo human trophoblast Cell Line and human Placental villous explants treated with DCVC at concentrations relevant to human exposures. In the Cells, concentration- and time-dependent effects were observed, as evidenced by the magnitude of altered gene expression after treatment with 20 µM DCVC versus 10 µM, and 12-h versus 6-h of treatment. Comparing the two models for the transcriptional response to 12-h 20 µM DCVC treatment, no differentially expressed genes reached significance in villous explants, whereas 301 differentially expressed genes were detected in HTR-8/SVneo Cells compared with non-treated controls (FDR 0.35 [FC > 1.3]). GSEA revealed five upregulated enriched pathways in common between explants and Cells (FDR < 0.05). Moreover, all 12-h DCVC treatment groups from both models contained upregulated pathways enriched for genes regulated by the ATF4 transcription factor. The overrepresentation of ATF4 regulation of differentially expressed genes indicated activation of the integrated stress response (ISR), a condition triggered by multiple stress stimuli, including the unfolded protein response. DCVC-induced ISR activation was confirmed by elevated eIF2α phosphorylation, ATF4 protein concentrations, and decreased global protein synthesis in HTR-8/SVneo Cells. This study identifies a mechanism of DCVC-induced cytotoxicity by revealing the involvement of a specific stress signaling pathway.
-
trichloroethylene metabolite s 1 2 dichlorovinyl l cysteine induces lipid peroxidation associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first trimester Placental Cell Line
Toxicology and Applied Pharmacology, 2018Co-Authors: Elana R Elkin, Sean M Harris, Rita LochcarusoAbstract:Abstract Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)- l -cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast Cell Line, HTR-8/SVneo. We exposed the Cells in vitro to 10–100 μM DCVC for various time points up to 24 h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p
-
trichloroethylene metabolite s 1 2 dichlorovinyl l cysteine induces lipid peroxidation associated apoptosis via the intrinsic and extrinsic apoptosis pathways in a first trimester Placental Cell Line
Toxicology and Applied Pharmacology, 2018Co-Authors: Elana R Elkin, Sean M Harris, Rita LochcarusoAbstract:Trichloroethylene (TCE), a prevalent environmental contaminant, is a potent renal and hepatic toxicant through metabolites such as S-(1, 2-dichlorovinyl)-l-cysteine (DCVC). However, effects of TCE on other target organs such as the placenta have been minimally explored. Because elevated apoptosis and lipid peroxidation in placenta have been observed in pregnancy morbidities involving poor placentation, we evaluated the effects of DCVC exposure on apoptosis and lipid peroxidation in a human extravillous trophoblast Cell Line, HTR-8/SVneo. We exposed the Cells in vitro to 10-100μM DCVC for various time points up to 24h. Following exposure, we measured apoptosis using flow cytometry, caspase activity using luminescence assays, gene expression using qRT-PCR, and lipid peroxidation using a malondialdehyde quantification assay. DCVC significantly increased apoptosis in time- and concentration-dependent manners (p<0.05). DCVC also significantly stimulated caspase 3, 7, 8 and 9 activities after 12h (p<0.05), suggesting that DCVC stimulates the activation of both the intrinsic and extrinsic apoptotic signaling pathways simultaneously. Pre-treatment with the tBID inhibitor Bl-6C9 partially reduced DCVC-stimulated caspase 3 and 7 activity, signifying crosstalk between the two pathways. Additionally, DCVC treatment increased lipid peroxidation in a concentration-dependent manner. Co-treatment with the antioxidant peroxyl radical scavenger (±)-α-tocopherol attenuated caspase 3 and 7 activity, suggesting that lipid peroxidation mediates DCVC-induced apoptosis in extravillous trophoblasts. Our findings suggest that DCVC-induced apoptosis and lipid peroxidation in extravillous trophoblasts could contribute to poor placentation if similar effects occur in vivo in response to TCE exposure, indicating that further studies into this mechanism are warranted.
Sunitha Meruvu - One of the best experts on this subject based on the ideXlab platform.
-
mono 2 ethylhexyl phthalate induces apoptosis through mir 16 in human first trimester Placental Cell Line htr 8 svneo
Toxicology in Vitro, 2016Co-Authors: Sunitha Meruvu, Jian Zhang, Yudhishtar Singh Bedi, Mahua ChoudhuryAbstract:Phthalates have been linked to adverse pregnancy complications. Mono-(2-ethylhexyl) phthalate, an active metabolite of di-(2-ethylhexyl) phthalate and an endocrine disruptor, has been shown to induce apoptosis in various Cell types including Placental Cells. However, the mechanism of action of MEHP induced apoptosis is still unknown. We hypothesized that apoptosis may be mediated in part through altered microRNA(s) in placenta under MEHP exposure. In the present study, we report that MEHP increases miR-16 expression in a time- and dose-dependent manner (p<0.05), while inducing apoptosis in HTR-8/SVneo. Cells treated with MEHP showed a dose-dependent increase in cytotoxicity and reactive oxygen species along with decreased Cell viability. Consistent with significant increase in apoptosis analyzed by flow cytometry, we detected decreased anti-apoptotic BCL-2 at transcriptional and translational levels with MEHP (p<0.05). Knockdown of miR-16 did not decrease the BCL-2/BAX protein expression ratio in the presence of MEHP when compared to negative control demonstrating that MEHP induces apoptosis directly through miR-16. In conclusion, our study demonstrates for the first time that MEHP induces miR-16, which in turn, alters BCL-2/BAX ratio leading to increased apoptosis. This study provides a novel insight into MEHP induced epigenetic regulation in Placental apoptosis which may lead to pregnancy complications.
-
mono 2 ethylhexyl phthalate increases oxidative stress responsive mirnas in first trimester Placental Cell Line htr8 svneo
Chemical Research in Toxicology, 2016Co-Authors: Sunitha Meruvu, Jian Zhang, Mahua ChoudhuryAbstract:Phthalates, an endocrine disruptor group, cause oxidative stress (OS) in the placenta. However, no studies have reported OS-related miRNAs induced by phthalates. In the present study, we demonstrate that mono-(2-ethylhexyl) phthalate (MEHP) induces OS responsive miR-17-5p, miR-155-5p, and miR-126-3p in HTR8/SVneo in a dose- and time-dependent manner. Furthermore, MEHP altered the expression of phosphoinositide-3-kinase regulatory subunit 1α, phosphatase and tensin homolog, CDKN2A interacting protein, superoxide dismutase 2, and 3β-hydroxysterol-D24 reductase, which are involved in OS and predicted to be regulated by these miRNAs. Our results suggest that Placental exposure to MEHP may result in aberrant miRNA expression leading to pregnancy complications.
Jian Zhang - One of the best experts on this subject based on the ideXlab platform.
-
mono 2 ethylhexyl phthalate induces apoptosis through mir 16 in human first trimester Placental Cell Line htr 8 svneo
Toxicology in Vitro, 2016Co-Authors: Sunitha Meruvu, Jian Zhang, Yudhishtar Singh Bedi, Mahua ChoudhuryAbstract:Phthalates have been linked to adverse pregnancy complications. Mono-(2-ethylhexyl) phthalate, an active metabolite of di-(2-ethylhexyl) phthalate and an endocrine disruptor, has been shown to induce apoptosis in various Cell types including Placental Cells. However, the mechanism of action of MEHP induced apoptosis is still unknown. We hypothesized that apoptosis may be mediated in part through altered microRNA(s) in placenta under MEHP exposure. In the present study, we report that MEHP increases miR-16 expression in a time- and dose-dependent manner (p<0.05), while inducing apoptosis in HTR-8/SVneo. Cells treated with MEHP showed a dose-dependent increase in cytotoxicity and reactive oxygen species along with decreased Cell viability. Consistent with significant increase in apoptosis analyzed by flow cytometry, we detected decreased anti-apoptotic BCL-2 at transcriptional and translational levels with MEHP (p<0.05). Knockdown of miR-16 did not decrease the BCL-2/BAX protein expression ratio in the presence of MEHP when compared to negative control demonstrating that MEHP induces apoptosis directly through miR-16. In conclusion, our study demonstrates for the first time that MEHP induces miR-16, which in turn, alters BCL-2/BAX ratio leading to increased apoptosis. This study provides a novel insight into MEHP induced epigenetic regulation in Placental apoptosis which may lead to pregnancy complications.
-
mono 2 ethylhexyl phthalate increases oxidative stress responsive mirnas in first trimester Placental Cell Line htr8 svneo
Chemical Research in Toxicology, 2016Co-Authors: Sunitha Meruvu, Jian Zhang, Mahua ChoudhuryAbstract:Phthalates, an endocrine disruptor group, cause oxidative stress (OS) in the placenta. However, no studies have reported OS-related miRNAs induced by phthalates. In the present study, we demonstrate that mono-(2-ethylhexyl) phthalate (MEHP) induces OS responsive miR-17-5p, miR-155-5p, and miR-126-3p in HTR8/SVneo in a dose- and time-dependent manner. Furthermore, MEHP altered the expression of phosphoinositide-3-kinase regulatory subunit 1α, phosphatase and tensin homolog, CDKN2A interacting protein, superoxide dismutase 2, and 3β-hydroxysterol-D24 reductase, which are involved in OS and predicted to be regulated by these miRNAs. Our results suggest that Placental exposure to MEHP may result in aberrant miRNA expression leading to pregnancy complications.