Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in mice
Nonalcoholic fatty liver disease (NAFLD), which is linked to western diet (WD) intake, affects 30% of the world’s population and involves the crosstalk of liver steatosis, hypertrophy/inflammation of adipose tissue and deregulation of gut microbiome. Glyphosate and 2,4-D are some of the most applied...
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Elsevier
2023-12-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651323011922 |
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| author | Guilherme R. Romualdo Letícia Cardoso Valente Jéssica Luri Hisano de Souza Josias Rodrigues Luís Fernando Barbisan |
| author_facet | Guilherme R. Romualdo Letícia Cardoso Valente Jéssica Luri Hisano de Souza Josias Rodrigues Luís Fernando Barbisan |
| author_sort | Guilherme R. Romualdo |
| collection | DOAJ |
| description | Nonalcoholic fatty liver disease (NAFLD), which is linked to western diet (WD) intake, affects 30% of the world’s population and involves the crosstalk of liver steatosis, hypertrophy/inflammation of adipose tissue and deregulation of gut microbiome. Glyphosate and 2,4-D are some of the most applied herbicides worldwide, and their roles in NAFLD have not been investigated. Thus, the present study evaluated whether glyphosate and 2,4-D, in single or mixed exposure, alter WD-induced NAFLD in a mouse model. Male C57Bl/6 mice (n = 10/group) received a fat (30% lard, 0.02% cholesterol), and sucrose-rich diet (20%) and high sugar solution (23.1 and 18.9 g/L of fructose and glucose) for 6 months. Simultaneously, animals received glyphosate (0.05 or 5 mg/kg/day), 2,4-D (0.02 or 2 mg/kg/day), or their combination (0.05 +0.02 or 5 +2 mg/kg/day) by intragastrical administration (5 ×/week). Doses were based on the Acceptable Daily Intake (ADIs) or No Observed Adverse Effect Level (NOAEL) levels. Herbicide exposures featured differential responses. WD-induced obesity, hypercholesterolemia, and hyperglycemia remained unaltered. Compared to the group receiving only WD, only the concomitant exposure to WD and 2,4-D (2 mg) enhanced the percentage of mice with moderate/severe hepatic inflammation, CD68 macrophage infiltration, and malondialdehyde levels in the liver. In line, this herbicide modulated immune response- (including Cd4, C8b, Cd28, Cxcr3, Cxcr6) and oxidative stress-related (such as Gsta1, Gsta2, Gsta4, Gstm1, Gstm2, Gstm3, Gstm4, Nqo1, Gpx2) genes in the hepatic transcriptome analysis. This exposure also enriched pro-inflammatory Deferribacteres phylum in fecal microbiome. In general, the herbicide mixtures did not feature the same effects attributed to 2,4-D isolated exposure. Our findings indicate that 2,4-D, at a dose within the toxicological limits, was able to induce disturbances in mainly at the liver and gut axes involved in NAFLD development in male mice. |
| first_indexed | 2024-03-09T10:53:31Z |
| format | Article |
| id | doaj.art-984a57aebb914e5dad400eba76500193 |
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| issn | 0147-6513 |
| language | English |
| last_indexed | 2024-03-09T10:53:31Z |
| publishDate | 2023-12-01 |
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| series | Ecotoxicology and Environmental Safety |
| spelling | doaj.art-984a57aebb914e5dad400eba765001932023-12-01T05:00:26ZengElsevierEcotoxicology and Environmental Safety0147-65132023-12-01268115688Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in miceGuilherme R. Romualdo0Letícia Cardoso Valente1Jéssica Luri Hisano de Souza2Josias Rodrigues3Luís Fernando Barbisan4São Paulo State University (UNESP), Botucatu Medical School, Experimental Research Unit (UNIPEX), Multimodel Drug Screening Platform, Laboratory of Chemically Induced and Experimental Carcinogenesis (MDSP-LCQE), Botucatu, SP, Brazil; São Paulo State University (UNESP), Botucatu Medical School, Department of Pathology, Botucatu, SP, Brazil; São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil; Correspondence to: Experimental Research Unit (UNIPEX), Botucatu Medical School, São Paulo State University, Av. Prof. Mário Rubens Guimarães Montenegro, zip code: 18618687, Botucatu, SP, Brazil.São Paulo State University (UNESP), Botucatu Medical School, Experimental Research Unit (UNIPEX), Multimodel Drug Screening Platform, Laboratory of Chemically Induced and Experimental Carcinogenesis (MDSP-LCQE), Botucatu, SP, Brazil; São Paulo State University (UNESP), Botucatu Medical School, Department of Pathology, Botucatu, SP, Brazil; São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil; Federal University of Grande Dourados (UFGD), Faculty of Health Sciences, Dourados, MS, BrazilSão Paulo State University (UNESP), Botucatu Medical School, Experimental Research Unit (UNIPEX), Multimodel Drug Screening Platform, Laboratory of Chemically Induced and Experimental Carcinogenesis (MDSP-LCQE), Botucatu, SP, Brazil; São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, BrazilSão Paulo State University (UNESP), Biosciences Institute, Department of Chemical and Biological Sciences, Botucatu, SP, BrazilSão Paulo State University (UNESP), Botucatu Medical School, Experimental Research Unit (UNIPEX), Multimodel Drug Screening Platform, Laboratory of Chemically Induced and Experimental Carcinogenesis (MDSP-LCQE), Botucatu, SP, Brazil; São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, BrazilNonalcoholic fatty liver disease (NAFLD), which is linked to western diet (WD) intake, affects 30% of the world’s population and involves the crosstalk of liver steatosis, hypertrophy/inflammation of adipose tissue and deregulation of gut microbiome. Glyphosate and 2,4-D are some of the most applied herbicides worldwide, and their roles in NAFLD have not been investigated. Thus, the present study evaluated whether glyphosate and 2,4-D, in single or mixed exposure, alter WD-induced NAFLD in a mouse model. Male C57Bl/6 mice (n = 10/group) received a fat (30% lard, 0.02% cholesterol), and sucrose-rich diet (20%) and high sugar solution (23.1 and 18.9 g/L of fructose and glucose) for 6 months. Simultaneously, animals received glyphosate (0.05 or 5 mg/kg/day), 2,4-D (0.02 or 2 mg/kg/day), or their combination (0.05 +0.02 or 5 +2 mg/kg/day) by intragastrical administration (5 ×/week). Doses were based on the Acceptable Daily Intake (ADIs) or No Observed Adverse Effect Level (NOAEL) levels. Herbicide exposures featured differential responses. WD-induced obesity, hypercholesterolemia, and hyperglycemia remained unaltered. Compared to the group receiving only WD, only the concomitant exposure to WD and 2,4-D (2 mg) enhanced the percentage of mice with moderate/severe hepatic inflammation, CD68 macrophage infiltration, and malondialdehyde levels in the liver. In line, this herbicide modulated immune response- (including Cd4, C8b, Cd28, Cxcr3, Cxcr6) and oxidative stress-related (such as Gsta1, Gsta2, Gsta4, Gstm1, Gstm2, Gstm3, Gstm4, Nqo1, Gpx2) genes in the hepatic transcriptome analysis. This exposure also enriched pro-inflammatory Deferribacteres phylum in fecal microbiome. In general, the herbicide mixtures did not feature the same effects attributed to 2,4-D isolated exposure. Our findings indicate that 2,4-D, at a dose within the toxicological limits, was able to induce disturbances in mainly at the liver and gut axes involved in NAFLD development in male mice.http://www.sciencedirect.com/science/article/pii/S0147651323011922Nonalcoholic fatty liver diseaseNonalcoholic steatohepatitis2,4-DGlyphosateHerbicidesLiver |
| spellingShingle | Guilherme R. Romualdo Letícia Cardoso Valente Jéssica Luri Hisano de Souza Josias Rodrigues Luís Fernando Barbisan Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in mice Ecotoxicology and Environmental Safety Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis 2,4-D Glyphosate Herbicides Liver |
| title | Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in mice |
| title_full | Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in mice |
| title_fullStr | Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in mice |
| title_full_unstemmed | Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in mice |
| title_short | Modifying effects of 2,4-D and Glyphosate exposures on gut-liver-adipose tissue axis of diet-induced non-alcoholic fatty liver disease in mice |
| title_sort | modifying effects of 2 4 d and glyphosate exposures on gut liver adipose tissue axis of diet induced non alcoholic fatty liver disease in mice |
| topic | Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis 2,4-D Glyphosate Herbicides Liver |
| url | http://www.sciencedirect.com/science/article/pii/S0147651323011922 |
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