Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals
Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints. Bisphenol A (BPA), pregnenolone-16α-carbonitrile (PCN), and perfluorooctanoic acid (PFOA) were used as reference compounds. Male and female wild-type C57BL/6 mice were orally exposed to 5, 50, and 500 μg/kg of BPA, 1000, 10 000, and 100 000 µg/kg of PCN and 50 and 300 μg/kg of PFOA for 28 days next to normal chow diet. Primary endpoints were glucose tolerance, hepatic lipid accumulation, and plasma lipids. After 28-day exposure, no changes in body weight and glucose tolerance were observed in BPA-, PCN-, or PFOA-treated males or females. PCN and PFOA at the highest dose in both sexes and BPA at the middle and high dose in males increased relative liver weight. PFOA reduced plasma triglycerides in males and females, and increased hepatic triglyceride content in males. PCN and PFOA induced hepatic expression of typical pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)α target genes, respectively. Exposure to BPA resulted in limited gene expression changes. In conclusion, the observed changes on metabolic health parameters were modest, suggesting that a standard repeated dose 28-day oral toxicity test is not a sensitive method for the detection of the metabolic effect of EDCs.
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Format: | Article/Letter to editor biblioteca |
Language: | English |
Subjects: | Endocrine-disrupting chemicals (EDCs), Glucose metabolism, Hepatic steatosis, Lipid metabolism, Metabolic disruption, Metabolism-disrupting chemicals, Nuclear receptors, |
Online Access: | https://research.wur.nl/en/publications/metabolic-effects-of-nuclear-receptor-activation-in-vivo-after-28 |
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dig-wur-nl-wurpubs-6250042024-10-02 Attema, Brecht Kummu, Outi Pitkänen, Sini Weisell, Jonna Vuorio, Taina Pennanen, Erika Vorimo, Maria Rysä, Jaana Kersten, Sander Levonen, Anna Liisa Hakkola, Jukka Article/Letter to editor Archives of Toxicology 98 (2024) 3 ISSN: 0340-5761 Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals 2024 Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints. Bisphenol A (BPA), pregnenolone-16α-carbonitrile (PCN), and perfluorooctanoic acid (PFOA) were used as reference compounds. Male and female wild-type C57BL/6 mice were orally exposed to 5, 50, and 500 μg/kg of BPA, 1000, 10 000, and 100 000 µg/kg of PCN and 50 and 300 μg/kg of PFOA for 28 days next to normal chow diet. Primary endpoints were glucose tolerance, hepatic lipid accumulation, and plasma lipids. After 28-day exposure, no changes in body weight and glucose tolerance were observed in BPA-, PCN-, or PFOA-treated males or females. PCN and PFOA at the highest dose in both sexes and BPA at the middle and high dose in males increased relative liver weight. PFOA reduced plasma triglycerides in males and females, and increased hepatic triglyceride content in males. PCN and PFOA induced hepatic expression of typical pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)α target genes, respectively. Exposure to BPA resulted in limited gene expression changes. In conclusion, the observed changes on metabolic health parameters were modest, suggesting that a standard repeated dose 28-day oral toxicity test is not a sensitive method for the detection of the metabolic effect of EDCs. en application/pdf https://research.wur.nl/en/publications/metabolic-effects-of-nuclear-receptor-activation-in-vivo-after-28 10.1007/s00204-023-03658-2 https://edepot.wur.nl/646825 Endocrine-disrupting chemicals (EDCs) Glucose metabolism Hepatic steatosis Lipid metabolism Metabolic disruption Metabolism-disrupting chemicals Nuclear receptors https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Wageningen University & Research |
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Endocrine-disrupting chemicals (EDCs) Glucose metabolism Hepatic steatosis Lipid metabolism Metabolic disruption Metabolism-disrupting chemicals Nuclear receptors Endocrine-disrupting chemicals (EDCs) Glucose metabolism Hepatic steatosis Lipid metabolism Metabolic disruption Metabolism-disrupting chemicals Nuclear receptors |
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Endocrine-disrupting chemicals (EDCs) Glucose metabolism Hepatic steatosis Lipid metabolism Metabolic disruption Metabolism-disrupting chemicals Nuclear receptors Endocrine-disrupting chemicals (EDCs) Glucose metabolism Hepatic steatosis Lipid metabolism Metabolic disruption Metabolism-disrupting chemicals Nuclear receptors Attema, Brecht Kummu, Outi Pitkänen, Sini Weisell, Jonna Vuorio, Taina Pennanen, Erika Vorimo, Maria Rysä, Jaana Kersten, Sander Levonen, Anna Liisa Hakkola, Jukka Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals |
description |
Environmental exposure to endocrine-disrupting chemicals (EDCs) can lead to metabolic disruption, resulting in metabolic complications including adiposity, dyslipidemia, hepatic lipid accumulation, and glucose intolerance. Hepatic nuclear receptor activation is one of the mechanisms mediating metabolic effects of EDCs. Here, we investigated the potential to use a repeated dose 28-day oral toxicity test for identification of EDCs with metabolic endpoints. Bisphenol A (BPA), pregnenolone-16α-carbonitrile (PCN), and perfluorooctanoic acid (PFOA) were used as reference compounds. Male and female wild-type C57BL/6 mice were orally exposed to 5, 50, and 500 μg/kg of BPA, 1000, 10 000, and 100 000 µg/kg of PCN and 50 and 300 μg/kg of PFOA for 28 days next to normal chow diet. Primary endpoints were glucose tolerance, hepatic lipid accumulation, and plasma lipids. After 28-day exposure, no changes in body weight and glucose tolerance were observed in BPA-, PCN-, or PFOA-treated males or females. PCN and PFOA at the highest dose in both sexes and BPA at the middle and high dose in males increased relative liver weight. PFOA reduced plasma triglycerides in males and females, and increased hepatic triglyceride content in males. PCN and PFOA induced hepatic expression of typical pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR)α target genes, respectively. Exposure to BPA resulted in limited gene expression changes. In conclusion, the observed changes on metabolic health parameters were modest, suggesting that a standard repeated dose 28-day oral toxicity test is not a sensitive method for the detection of the metabolic effect of EDCs. |
format |
Article/Letter to editor |
topic_facet |
Endocrine-disrupting chemicals (EDCs) Glucose metabolism Hepatic steatosis Lipid metabolism Metabolic disruption Metabolism-disrupting chemicals Nuclear receptors |
author |
Attema, Brecht Kummu, Outi Pitkänen, Sini Weisell, Jonna Vuorio, Taina Pennanen, Erika Vorimo, Maria Rysä, Jaana Kersten, Sander Levonen, Anna Liisa Hakkola, Jukka |
author_facet |
Attema, Brecht Kummu, Outi Pitkänen, Sini Weisell, Jonna Vuorio, Taina Pennanen, Erika Vorimo, Maria Rysä, Jaana Kersten, Sander Levonen, Anna Liisa Hakkola, Jukka |
author_sort |
Attema, Brecht |
title |
Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals |
title_short |
Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals |
title_full |
Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals |
title_fullStr |
Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals |
title_full_unstemmed |
Metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals |
title_sort |
metabolic effects of nuclear receptor activation in vivo after 28-day oral exposure to three endocrine-disrupting chemicals |
url |
https://research.wur.nl/en/publications/metabolic-effects-of-nuclear-receptor-activation-in-vivo-after-28 |
work_keys_str_mv |
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