title: Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure.
abstract: BACKGROUND
  Glyphosate-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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Our 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.
authors: Gene Expression and Therapy Group, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
authors: Robin
authors: R
authors: Mesnage
authors: Genomics Centre, King's College London, Waterloo Campus, 150 Stamford Street, London, SE1 9NH, UK.
authors: Matthew
authors: M
authors: Arno
authors: Department of Neurological and Movement Sciences, University of Verona, Verona, 37134, Italy.
authors: Manuela
authors: M
authors: Costanzo
authors: Department of Neurological and Movement Sciences, University of Verona, Verona, 37134, Italy.
authors: Manuela
authors: M
authors: Malatesta
authors: Institute of Biology, EA 2608 and Risk Pole, MRSH-CNRS, Esplanade de la Paix, University of Caen, Caen, 14032, Cedex, France.
authors: Gilles-Eric
authors: GE
authors: Séralini
authors: Gene Expression and Therapy Group, Faculty of Life Sciences & Medicine, Department of Medical and Molecular Genetics, King's College London, 8th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK. michael.antoniou@kcl.ac.uk.
authors: Michael N
authors: MN
authors: Antoniou
mesh_terms: D000818:Animals; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome / Q000187:drug effects*; D000097797:Glyphosate
chemical_list: D004785:Environmental Pollutants; D005998:Glycine; D006540:Herbicides; D000097797:Glyphosate