Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize.

The health effects of a Roundup-tolerant genetically modified maize (from 11% in the diet), cultivated with or without Roundup, and Roundup alone (from 0.1 ppb in water), were studied 2 years in rats. In females, all treated groups died 2-3 times more than controls, and more rapidly. This difference was visible in 3 male groups fed GMOs. All results were hormone and sex dependent, and the pathological profiles were comparable. Females developed large mammary tumors almost always more often than and before controls, the pituitary was the second most disabled organ; the sex hormonal balance was modified by GMO and Roundup treatments. In treated males, liver congestions and necrosis were 2.5-5.5 times higher. This pathology was confirmed by optic and transmission electron microscopy. Marked and severe kidney nephropathies were also generally 1.3-2.3 greater. Males presented 4 times more large palpable tumors than controls which occurred up to 600 days earlier. Biochemistry data confirmed very significant kidney chronic deficiencies; for all treatments and both sexes, 76% of the altered parameters were kidney related. These results can be explained by the non linear endocrine-disrupting effects of Roundup, but also by the overexpression of the transgene in the GMO and its metabolic consequences.

[1]  M. Abdul Aziz,et al.  The oral and intratracheal toxicities of ROUNDUP and its components to rats. , 1997, Veterinary and human toxicology.

[2]  M. Buiatti,et al.  Characterisation of 3′ transgene insertion site and derived mRNAs in MON810 YieldGard® maize , 2008, Plant Molecular Biology.

[3]  R. Mesnage,et al.  Debate on GMOs Health Risks after Statistical Findings in Regulatory Tests , 2010, International journal of biological sciences.

[4]  R. Watson,et al.  Developmental and Reproductive Outcomes in Humans and Animals After Glyphosate Exposure: A Critical Analysis , 2012, Journal of toxicology and environmental health. Part B, Critical reviews.

[5]  Manuela Malatesta,et al.  Ultrastructural morphometrical and immunocytochemical analyses of hepatocyte nuclei from mice fed on genetically modified soybean. , 2002, Cell structure and function.

[6]  Johan Trygg,et al.  Multi- and Megavariate Data Analysis : Part II: Advanced Applications and Method Extensions , 2006 .

[7]  R. Mesnage,et al.  Major Pesticides Are More Toxic to Human Cells Than Their Declared Active Principles , 2014, BioMed research international.

[8]  W. Schrödl,et al.  Field Investigations of Glyphosate in Urine of Danish Dairy Cows , 2013 .

[9]  N. Bénachour,et al.  Dig1 protects against cell death provoked by glyphosate-based herbicides in human liver cell lines , 2010, Journal of occupational medicine and toxicology.

[10]  Laura N. Vandenberg,et al.  Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. , 2012, Endocrine reviews.

[11]  I C Munro,et al.  Report of an Expert Panel on the reanalysis by of a 90-day study conducted by Monsanto in support of the safety of a genetically modified corn variety (MON 863). , 2007, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[12]  M. Roller,et al.  Food and Chemical Toxicology , 2013 .

[13]  M. Chagnon,et al.  Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines. , 2009, Toxicology.

[14]  R. M. Romano,et al.  Prepubertal exposure to commercial formulation of the herbicide glyphosate alters testosterone levels and testicular morphology , 2010, Archives of Toxicology.

[15]  J. Mandel,et al.  Epidemiologic studies of glyphosate and non-cancer health outcomes: a review. , 2011, Regulatory toxicology and pharmacology : RTP.

[16]  Alain Paris,et al.  Assessment of the health impact of GM plant diets in long-term and multigenerational animal feeding trials: a literature review. , 2012, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[17]  R. Mesnage,et al.  Ethoxylated adjuvants of glyphosate-based herbicides are active principles of human cell toxicity. , 2013, Toxicology.

[18]  B. Halling‐Sørensen,et al.  Liquid chromatography-mass spectrometry method to determine alcohol ethoxylates and alkylamine ethoxylates in soil interstitial water, ground water and surface water samples. , 2002, Journal of chromatography. A.

[19]  M. T. Nunes,et al.  Glyphosate impairs male offspring reproductive development by disrupting gonadotropin expression , 2012, Archives of Toxicology.

[20]  Charles Tyler,et al.  Statistical Modeling Suggests that Antiandrogens in Effluents from Wastewater Treatment Works Contribute to Widespread Sexual Disruption in Fish Living in English Rivers , 2009, Environmental health perspectives.

[21]  G. Hard,et al.  Invited Review: A Contemporary Overview of Chronic Progressive Nephropathy in the Laboratory Rat, and Its Significance for Human Risk Assessment , 2004, Toxicologic pathology.

[22]  M. Buiatti,et al.  How Subchronic and Chronic Health Effects can be Neglected for GMOs, Pesticides or Chemicals , 2009, International journal of biological sciences.

[23]  Allison K. Wilson,et al.  The Mutational Consequences of Plant Transformation , 2006, Journal of biomedicine & biotechnology.

[24]  Emily Monosson,et al.  Chemical Mixtures: Considering the Evolution of Toxicology and Chemical Assessment , 2004, Environmental health perspectives.

[25]  J. Sastre,et al.  Why females live longer than males? Importance of the upregulation of longevity‐associated genes by oestrogenic compounds , 2005, FEBS letters.

[26]  A. Walf,et al.  Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats , 2010, Behavioural pharmacology.

[27]  F. Peixoto Comparative effects of the Roundup and glyphosate on mitochondrial oxidative phosphorylation. , 2005, Chemosphere.

[28]  J. Crowley,et al.  Leukotoxin Diols from Ground Corncob Bedding Disrupt Estrous Cyclicity in Rats and Stimulate MCF-7 Breast Cancer Cell Proliferation , 2005, Environmental health perspectives.

[29]  J. Bucher,et al.  Commentary: Update on Animal Models for NTP Studies , 2010, Toxicologic pathology.

[30]  A. Conney,et al.  Caffeic and ferulic acid as blockers of nitrosamine formation. , 1984, Carcinogenesis.

[31]  K. N. Reddy,et al.  Isoflavone, glyphosate, and aminomethylphosphonic acid levels in seeds of glyphosate-treated, glyphosate-resistant soybean. , 2003, Journal of agricultural and food chemistry.

[32]  J. Shull,et al.  Rat strain-specific actions of 17beta-estradiol in the mammary gland: correlation between estrogen-induced lobuloalveolar hyperplasia and susceptibility to estrogen-induced mammary cancers. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  K. Stowman World health statistics. , 1949, The Milbank Memorial Fund quarterly.

[34]  B. Hammond,et al.  Results of a 90-day safety assurance study with rats fed grain from corn rootworm-protected corn. , 2006, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[35]  M. Rocchi,et al.  Ultrastructural analysis of pancreatic acinar cells from mice fed on genetically modified soybean , 2002, Journal of anatomy.

[36]  N. Bénachour,et al.  Glyphosate formulations induce apoptosis and necrosis in human umbilical, embryonic, and placental cells. , 2009, Chemical research in toxicology.

[37]  S. Sultana,et al.  Attenuation of oxidative stress, inflammation and early markers of tumor promotion by caffeic acid in Fe-NTA exposed kidneys of Wistar rats , 2011, Molecular and Cellular Biochemistry.

[38]  T. Hampton,et al.  Laboratory diet profoundly alters gene expression and confounds genomic analysis in mouse liver and lung. , 2008, Chemico-biological interactions.

[39]  P. Deheuvels On Testing Stochastic Dominance by Exceedance, Precedence and Other Distribution‐Free Tests, with Applications , 2014 .

[40]  M. Biggiogera,et al.  A long-term study on female mice fed on a genetically modified soybean: effects on liver ageing , 2008, Histochemistry and Cell Biology.

[41]  G. Séralini,et al.  New Analysis of a Rat Feeding Study with a Genetically Modified Maize Reveals Signs of Hepatorenal Toxicity , 2007, Archives of environmental contamination and toxicology.

[42]  J. Satayavivad,et al.  Glyphosate induces human breast cancer cells growth via estrogen receptors. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[43]  Allison K. Wilson,et al.  Transformation-induced Mutations in Transgenic Plants: Analysis and Biosafety Implications , 2006, Biotechnology & genetic engineering reviews.

[44]  Chuan-Hsiung Chang,et al.  Modulation of HER2 expression by ferulic acid on human breast cancer MCF7 cells , 2006, European journal of clinical investigation.

[45]  G. Séralini,et al.  A Comparison of the Effects of Three GM Corn Varieties on Mammalian Health , 2009, International journal of biological sciences.

[46]  N. Bénachour,et al.  Differential Effects of Glyphosate and Roundup on Human Placental Cells and Aromatase , 2009 .

[47]  J. Haseman,et al.  Incidences of Selected Lesions in Control Female Harlan Sprague–Dawley Rats from Two-Year Studies Performed by the National Toxicology Program , 2005, Toxicologic pathology.

[48]  X. Chen,et al.  Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA , 2011, Cell Research.

[49]  R. Mesnage,et al.  Defined plant extracts can protect human cells against combined xenobiotic effects , 2011, Journal of occupational medicine and toxicology.

[50]  Yoshimitsu SAKAMOTO,et al.  Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[51]  Z. Rékási,et al.  Regulation of pituitary inhibin/activin subunits and follistatin gene expression by GnRH in female rats. , 2011, The Journal of endocrinology.

[52]  B. Hammond,et al.  Results of a 90-day safety assurance study with rats fed grain from corn borer-protected corn. , 2006, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[53]  S. Manoharan,et al.  Chemopreventive potential of ferulic acid in 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis in Sprague-Dawley rats. , 2010, European journal of pharmacology.

[54]  Manik Chandra,et al.  Spontaneous neoplasms in aged sprague-dawley rats , 2005, Archives of Toxicology.

[55]  N. Bénachour,et al.  Time- and Dose-Dependent Effects of Roundup on Human Embryonic and Placental Cells , 2007, Archives of environmental contamination and toxicology.

[56]  A. Schecter,et al.  Exposure of laboratory animals to polychlorinated dibenzodioxins and polychlorinated dibenzofurans from commerical rodent chow. , 1996, Chemosphere.

[57]  U. Edlund,et al.  Visualization of GC/TOF-MS-based metabolomics data for identification of biochemically interesting compounds using OPLS class models. , 2008, Analytical chemistry.

[58]  Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat. , 2001 .

[59]  Zhuo Zhang,et al.  Unintended compositional changes in transgenic rice seeds ( Oryza sativa L.) studied by spectral and chromatographic analysis coupled with chemometrics methods. , 2010, Journal of agricultural and food chemistry.

[60]  John P. Giesy,et al.  Ecotoxicological Risk Assessment for Roundup ® Herbicide , 2000 .

[61]  L. Zolla,et al.  Proteomics as a complementary tool for identifying unintended side effects occurring in transgenic maize seeds as a result of genetic modifications. , 2008, Journal of proteome research.

[62]  J. Domingo,et al.  A literature review on the safety assessment of genetically modified plants. , 2011, Environment international.

[63]  R. Mesnage,et al.  Genetically modified crops safety assessments: present limits and possible improvements , 2011 .

[64]  B. Hammond,et al.  Results of a 13 week safety assurance study with rats fed grain from glyphosate tolerant corn. , 2004, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[65]  J. Russo,et al.  Modulatory effects of neonatal exposure to TCDD, or a mixture of PCBs, p,p'-DDT, and p-p'-DDE, on methylnitrosourea-induced mammary tumor development in the rat. , 2001, Environmental health perspectives.

[66]  V. Bollati,et al.  Epigenetics and pesticides. , 2013, Toxicology.

[67]  Xin Lu,et al.  Metabolic profiling of transgenic rice with cryIAc and sck genes: an evaluation of unintended effects at metabolic level by using GC-FID and GC-MS. , 2009, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[68]  S. Muller,et al.  Hepatoma tissue culture (HTC) cells as a model for investigating the effects of low concentrations of herbicide on cell structure and function. , 2008, Toxicology in vitro : an international journal published in association with BIBRA.

[69]  R Kroes,et al.  Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans. , 2000, Regulatory toxicology and pharmacology : RTP.

[70]  C. Cox,et al.  Unidentified Inert Ingredients in Pesticides: Implications for Human and Environmental Health , 2006, Environmental health perspectives.

[71]  Ping Zang,et al.  1H NMR metabolomics identification of markers of hypoxia-induced metabolic shifts in a breast cancer model system , 2011, Journal of biomolecular NMR.

[72]  V. Menon,et al.  Ferulic acid, a natural protector against carbon tetrachloride‐induced toxicity , 2005, Fundamental & clinical pharmacology.

[73]  J. Mathers,et al.  Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize , 2013 .

[74]  J. Mandel,et al.  Epidemiologic studies of glyphosate and cancer: a review. , 2012, Regulatory toxicology and pharmacology : RTP.

[75]  O. Shaltout,et al.  Feeding Study with Bt Corn (MON810: Ajeeb YG) on Rats: Biochemical Analysis and Liver Histopathology , 2014 .

[76]  Wade V Welshons,et al.  Bisphenol A is released from used polycarbonate animal cages into water at room temperature. , 2003, Environmental health perspectives.

[77]  T. Hayes,et al.  There Is No Denying This: Defusing the Confusion about Atrazine , 2004 .

[78]  N. El-Shenawy,et al.  Oxidative stress responses of rats exposed to Roundup and its active ingredient glyphosate. , 2009, Environmental toxicology and pharmacology.

[79]  R. Mesnage,et al.  Roundup ® in genetically modified plants : Regulation and toxicity in mammals 1 , 2010 .

[80]  Opinion of the Scientific Panel on Genetically Modified Organisms on a request from the Commission related to the safety of foods and food ingredients derived from herbicide-tolerant genetically modified maize NK 603 , 2003 .

[81]  최승은 Sprague-Dawley rats 쥐의 정삭 조작 실험이 고환 성장 및 생식에 미치는 영향에 대한 연구 , 2003 .