Limits...
Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure.

Mesnage R, Arno M, Costanzo M, Malatesta M, Séralini GE, Antoniou MN - Environ Health (2015)

Bottom Line: 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).Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found.Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Toxicity ontology analysis of genes disturbed in liver and kidneys of Roundup-treated rats. List of top 10 scoring pathway and toxicity process networks revealed by MetaCore analysis of female liver and kidney transcriptome profiles receiving 0.1 ppb of Roundup in drinking water (p <0.01, fold changes >1.1). The p-values are determined by hyper-geometric calculation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4549093&req=5

Fig5: Toxicity ontology analysis of genes disturbed in liver and kidneys of Roundup-treated rats. List of top 10 scoring pathway and toxicity process networks revealed by MetaCore analysis of female liver and kidney transcriptome profiles receiving 0.1 ppb of Roundup in drinking water (p <0.01, fold changes >1.1). The p-values are determined by hyper-geometric calculation

Mentions: Scoring maps for pathways and toxicity processes (Fig. 5) indicates that multiple cellular functions could be involved. Out of the 4224 liver and 4447 kidney transcript clusters found to be altered, 2636 and 2933 network objects were respectively recognized by GeneGO Metacore. Mapped pathways related to inflammatory responses, which can be secondary outcomes to organ damage, are enriched (for instance, those involving NF-κB or CD28 signalling). Various pathways associated with the cytoskeleton are also enriched, suggestive of a change in cellular growth in an effort to overcome toxic effects and to regenerate damaged tissues. In this regard the enrichment of the proinsulin C-peptide signalling pathway in liver (14 genes, p = 2.4E-5, q = 1.2E-3) involving mTOR and the phosphatidylinositol signalling systems is of note since it has an established role in cellular proliferation and lipid metabolism. Other maps confirmed the induction of intracellular signalling pathways and an influence on the balance between proliferation and apoptosis. The regulation of translation by EIF4F activity (16 genes, p = 1.2E-6, q = 8.1E-5), another mTOR regulated function, is also disturbed.Fig. 5


Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure.

Mesnage R, Arno M, Costanzo M, Malatesta M, Séralini GE, Antoniou MN - Environ Health (2015)

Toxicity ontology analysis of genes disturbed in liver and kidneys of Roundup-treated rats. List of top 10 scoring pathway and toxicity process networks revealed by MetaCore analysis of female liver and kidney transcriptome profiles receiving 0.1 ppb of Roundup in drinking water (p <0.01, fold changes >1.1). The p-values are determined by hyper-geometric calculation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4549093&req=5

Fig5: Toxicity ontology analysis of genes disturbed in liver and kidneys of Roundup-treated rats. List of top 10 scoring pathway and toxicity process networks revealed by MetaCore analysis of female liver and kidney transcriptome profiles receiving 0.1 ppb of Roundup in drinking water (p <0.01, fold changes >1.1). The p-values are determined by hyper-geometric calculation
Mentions: Scoring maps for pathways and toxicity processes (Fig. 5) indicates that multiple cellular functions could be involved. Out of the 4224 liver and 4447 kidney transcript clusters found to be altered, 2636 and 2933 network objects were respectively recognized by GeneGO Metacore. Mapped pathways related to inflammatory responses, which can be secondary outcomes to organ damage, are enriched (for instance, those involving NF-κB or CD28 signalling). Various pathways associated with the cytoskeleton are also enriched, suggestive of a change in cellular growth in an effort to overcome toxic effects and to regenerate damaged tissues. In this regard the enrichment of the proinsulin C-peptide signalling pathway in liver (14 genes, p = 2.4E-5, q = 1.2E-3) involving mTOR and the phosphatidylinositol signalling systems is of note since it has an established role in cellular proliferation and lipid metabolism. Other maps confirmed the induction of intracellular signalling pathways and an influence on the balance between proliferation and apoptosis. The regulation of translation by EIF4F activity (16 genes, p = 1.2E-6, q = 8.1E-5), another mTOR regulated function, is also disturbed.Fig. 5

Bottom Line: 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).Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found.Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus