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Glyphosate and 2,4-D implications on Non-alcoholic fatty liver disease in vivo: transcriptome and microbiome analysis

Abstract

Considered a modern disease, the non-alcoholic fatty liver disease (NAFLD) affects around 25% of the world's population, respectively. Its complex development is associated to dietary factors, obesity, sedentarism and metabolic disorders, involving molecular alterations and the crosstalk between liver, adipose tissue and the intestinal microbiota. In preclinical studies, the herbicides glyphosate or 2,4-D have showed pro-oxidant, lipogenic and/or inflammatory effects in the liver, in interventions below the currently established toxicological limits. These molecules are widely applied for agricultural purposes and are often identified in food and water. Thus, it will be assessed whether glyphosate and 2,4D, alone or in combination, promote NASH in vivo. NASH will be induced in male C57Bl/6J mice (n=10/group) by providing a high fat- (20% lard) and sucrose- (20%) rich diet and drinking high sugar solution (23.1 g/L fructose; 18.9 g/L glucose) for 6 months. Simultaneously, the animals will receive glyphosate (0.05, 5 or 50 mg/kg/day), 2.4-D (0.02, 2 or 20 mg/kg/ day) or a combination of both (0.05+0.02; 5 + 2 or 50 + 20 mg kg / day) intragastrically (5 times/week). Doses will be based on Acceptable Daily Intake (ADI) or No Observed Adverse Effect Level (NOAEL) values. The glycemic curve will be calculated, and the serum will be obtained for biochemical analysis (ALT, triglycerides and cholesterol). Liver will be sampled for histological (NASH grade, collagen and immunohistochemistry for Ki-67, cleaved caspase-3, CD68 and alfa-SMA), biochemical (HPLC for glyphosate and 2,4-D, ELISA for TNF-alfa and IL-6, antioxidant and fatty acid profile) and molecular (mRNA-seq) analysis. Adipose tissue will be sampled for histological (morphometry, mast cells, immunohistochemistry for CD68), biochemical (ELISA for TNF-alfa and IL-6) and molecular (mRNA-seq) analysis. Small intestine and cecal fecal pellets will be collected for immunohistochemical analysis (ZO-1 and occludin) and microbiome (16S rRNA sequencing), respectively. Our findings could contribute to the re-evaluation of current safety assessments on NAFLD condition. (AU)

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