Project description:BackgroundGlyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH, such as Roundup, pose a particular health risk to liver and kidneys although low environmentally relevant doses have not been examined. To address this issue, a 2-year study in rats administering 0.1 ppb Roundup (50 ng/L glyphosate equivalent) via drinking water (giving a daily intake of 4 ng/kg bw/day of glyphosate) was conducted. A marked increased incidence of anatomorphological and blood/urine biochemical changes was indicative of liver and kidney structure and functional pathology. In order to confirm these findings we have conducted a transcriptome microarray analysis of the liver and kidneys from these same animals.ResultsThe expression of 4224 and 4447 transcript clusters (a group of probes corresponding to a known or putative gene) were found to be altered respectively in liver and kidney (p < 0.01, q < 0.08). Changes in gene expression varied from -3.5 to 3.7 fold in liver and from -4.3 to 5.3 in kidneys. Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. Pathway analysis suggests a modulation of the mTOR and phosphatidylinositol signalling pathways. Gene disturbances associated with the chronic administration of ultra-low dose Roundup reflect a liver and kidney lipotoxic condition and increased cellular growth that may be linked with regeneration in response to toxic effects causing damage to tissues. Observed alterations in gene expression were consistent with fibrosis, necrosis, phospholipidosis, mitochondrial membrane dysfunction and ischemia, which correlate with and thus confirm observations of pathology made at an anatomical, histological and biochemical level.ConclusionOur results suggest that chronic exposure to a GBH in an established laboratory animal toxicity model system at an ultra-low, environmental dose can result in liver and kidney damage with potential significant health implications for animal and human populations.

Project description:Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH residues pose a particular risk to the kidneys and liver. However, the existence of biological effects with negative health implications at low environmentally relevant doses remains unresolved. A previous investigation addressed this issue, by conducting a 2-year feeding study, which included 10 female Sprague Dawley rats administered via drinking water with 0.1 ppb of a major Roundup formulation (50 ng/L glyphosate equivalent dilution). Hepatorenal toxicities, as well as urine and blood biochemistry disturbances at the 15th month of age were observed. In an effort to obtain molecular mechanistic insight into the underlying causes of these pathologies, we have carried out a transcriptome microarray analysis of the liver and kidneys from these same animals. The expression of 4224 and 4447 genes were found to be disturbed respectively in liver and kidney (p<0.01, q<0.08, fold change >1.1). Among the 1319 genes whose expression was altered in both tissues, 3 functional categories were over-represented. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. The transcription factor networks that can account for these disruptions were centered on CREB1, ESR1, YY1, c-Myc and Oct3/4 activity, which are known to closely cooperate in the regulation of gene expression after hormonal stimulation. The analysis of pathways and toxicity processes showed that these disturbances in gene expression were representative of fibrosis, necrosis, phospholipidosis, mitochondrial membrane dysfunction and ischemia, which correlate with the pathologies observed at an anatomical and histological level. Our results suggest that new studies incorporating testing principles from endocrinology and developmental epigenetics need to be performed to investigate potential consequences of exposure to low dose, environmental levels of GBH and glyphosate.

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Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide.

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Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide.

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