Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia
Early life exposure to Endocrine Disruptor Chemicals (EDCs), such as the organophosphate pesticide Chlorpyrifos (CPF), affects the thyroid activity and dependent process, including the glucose metabolism. The damage of thyroid hormones (THs) as a mechanism of action of CPF is underestimated because...
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MDPI AG
2023-05-01
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| author | Teresa Peluso Valeria Nittoli Carla Reale Immacolata Porreca Filomena Russo Luca Roberto Antonia Giacco Elena Silvestri Massimo Mallardo Mario De Felice Concetta Ambrosino |
| author_facet | Teresa Peluso Valeria Nittoli Carla Reale Immacolata Porreca Filomena Russo Luca Roberto Antonia Giacco Elena Silvestri Massimo Mallardo Mario De Felice Concetta Ambrosino |
| author_sort | Teresa Peluso |
| collection | DOAJ |
| description | Early life exposure to Endocrine Disruptor Chemicals (EDCs), such as the organophosphate pesticide Chlorpyrifos (CPF), affects the thyroid activity and dependent process, including the glucose metabolism. The damage of thyroid hormones (THs) as a mechanism of action of CPF is underestimated because the studies rarely consider that TH levels and signaling are customized peripherally. Here, we investigated the impairment of metabolism/signaling of THs and lipid/glucose metabolism in the livers of 6-month-old mice, developmentally and lifelong exposed to 0.1, 1, and 10 mg/kg/die CPF (F1) and their offspring similarly exposed (F2), analyzing the levels of transcripts of the enzymes involved in the metabolism of T3 (<i>Dio1</i>), lipids (<i>Fasn</i>, <i>Acc1</i>), and glucose (<i>G6pase</i>, <i>Pck1</i>). Both processes were altered only in F2 males, affected by hypothyroidism and by a systemic hyperglycemia linked to the activation of gluconeogenesis in mice exposed to 1 and 10 mg/kg/die CPF. Interestingly, we observed an increase in active FOXO1 protein due to a decrease in AKT phosphorylation, despite insulin signaling activation. Experiments in vitro revealed that chronic exposure to CPF affected glucose metabolism via the direct modulation of FOXO1 activity and T3 levels in hepatic cells. In conclusion, we described different sex and intergenerational effects of CPF exposure on the hepatic homeostasis of THs, their signaling, and, finally, glucose metabolism. The data points to FOXO1-T3-glucose signaling as a target of CPF in liver. |
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| language | English |
| last_indexed | 2024-03-11T03:05:06Z |
| publishDate | 2023-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-de902d522e3b485b9f44b14b8709e42d2023-11-18T08:01:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-012411958210.3390/ijms24119582Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by HyperglycemiaTeresa Peluso0Valeria Nittoli1Carla Reale2Immacolata Porreca3Filomena Russo4Luca Roberto5Antonia Giacco6Elena Silvestri7Massimo Mallardo8Mario De Felice9Concetta Ambrosino10Department of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, ItalyBiogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, ItalyBiogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, ItalyBiogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, ItalyBiogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, ItalyBiogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, ItalyDepartment of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, ItalyDepartment of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, ItalyDepartment of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, ItalyEarly life exposure to Endocrine Disruptor Chemicals (EDCs), such as the organophosphate pesticide Chlorpyrifos (CPF), affects the thyroid activity and dependent process, including the glucose metabolism. The damage of thyroid hormones (THs) as a mechanism of action of CPF is underestimated because the studies rarely consider that TH levels and signaling are customized peripherally. Here, we investigated the impairment of metabolism/signaling of THs and lipid/glucose metabolism in the livers of 6-month-old mice, developmentally and lifelong exposed to 0.1, 1, and 10 mg/kg/die CPF (F1) and their offspring similarly exposed (F2), analyzing the levels of transcripts of the enzymes involved in the metabolism of T3 (<i>Dio1</i>), lipids (<i>Fasn</i>, <i>Acc1</i>), and glucose (<i>G6pase</i>, <i>Pck1</i>). Both processes were altered only in F2 males, affected by hypothyroidism and by a systemic hyperglycemia linked to the activation of gluconeogenesis in mice exposed to 1 and 10 mg/kg/die CPF. Interestingly, we observed an increase in active FOXO1 protein due to a decrease in AKT phosphorylation, despite insulin signaling activation. Experiments in vitro revealed that chronic exposure to CPF affected glucose metabolism via the direct modulation of FOXO1 activity and T3 levels in hepatic cells. In conclusion, we described different sex and intergenerational effects of CPF exposure on the hepatic homeostasis of THs, their signaling, and, finally, glucose metabolism. The data points to FOXO1-T3-glucose signaling as a target of CPF in liver.https://www.mdpi.com/1422-0067/24/11/9582thyroid hormonesendocrine disruptorglucose metabolismdeiodinases |
| spellingShingle | Teresa Peluso Valeria Nittoli Carla Reale Immacolata Porreca Filomena Russo Luca Roberto Antonia Giacco Elena Silvestri Massimo Mallardo Mario De Felice Concetta Ambrosino Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia International Journal of Molecular Sciences thyroid hormones endocrine disruptor glucose metabolism deiodinases |
| title | Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia |
| title_full | Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia |
| title_fullStr | Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia |
| title_full_unstemmed | Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia |
| title_short | Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia |
| title_sort | chronic exposure to chlorpyrifos damages thyroid activity and imbalances hepatic thyroid hormones signaling and glucose metabolism dependency of t3 foxo1 axis by hyperglycemia |
| topic | thyroid hormones endocrine disruptor glucose metabolism deiodinases |
| url | https://www.mdpi.com/1422-0067/24/11/9582 |
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