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publication de l'étude originale  dans Food & Chemical Toxicology: http://www.sciencedirect.com/science/article/pii/S0278691512005637

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

  • a University of Caen, Institute of Biology, CRIIGEN and Risk Pole, MRSH-CNRS, EA 2608, Esplanade de la Paix, Caen Cedex 14032, France
  • b University of Verona, Department of Neurological, Neuropsychological, Morphological and Motor Sciences, Verona 37134, Italy
  • c University of Caen, UR ABTE, EA 4651, Bd Maréchal Juin, Caen Cedex 14032, France

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Abstract

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.


Highlights

► A Roundup-tolerant maize and Roundup provoked chronic hormone and sex dependent pathologies. ► Female mortality was 2–3 times increased mostly due to large mammary tumors and disabled pituitary. ► Males had liver congestions, necrosis, severe kidney nephropathies and large palpable tumors. ► This may be due to an endocrine disruption linked to Roundup and a new metabolism due to the transgene. ► GMOs and formulated pesticides must be evaluated by long term studies to measure toxic effects..

Abbreviations

  • GM, genetically modified; 
  • R, Roundup; 
  • MRL, maximal residual levels; 
  • GMO, genetically modified organism; 
  • OECD, Organization for Economic Co-operation and Development; 
  • GT, glutamyl-transferase;
  • PCA, principal component analysis; 
  • PLS, partial least-squares; 
  • OPLS, orthogonal partial least-squares;
  • NIPALS, Nonlinear Iterative Partial Least Squares; 
  • OPLS-DA, Orthogonal Partial Least Squares Discriminant Analysis; 
  • G, glycogen; 
  • L, lipid droplet; 
  • N, nucleus; 
  • R, rough endoplasmic reticulum (on microscopy pictures only); 
  • U, urinary; 
  • UEx, excreted in urine during 24 h; 
  • APPT, Activated Partial Thromboplastin Time; 
  • MCV, Mean Corpuscular Volume; 
  • PT, Prothrombine Time; 
  • RBC, Red Blood Cells;
  • ALT, alanine aminotransferase; 
  • MCHC, Mean Corpuscular Hemoglobin Concentration; 
  • A/G, Albumin/Globulin ratio; 
  • WBC, White Blood Cells; 
  • AST, aspartate aminotransferase

Keywords

  • GMO; 
  • Roundup; 
  • NK603; 
  • Rat; 
  • Glyphosate-based herbicides; 
  • Endocrine disrupting effects

Figures and tables from this article:

Full-size image (76 K)

Fig. 1. Mortality of rats fed GMO treated or not with Roundup, and effects of Roundup alone. Rats were fed with NK603 GM maize (with or without application of Roundup) at three different doses (11, 22, 33% in their diet: thin, medium and bold lines, respectively) compared to the substantially equivalent closest isogenic non-GM maize (control, dotted line). Roundup was administrated in drinking water at 3 increasing doses, same symbols (environmental (A), MRL in agricultural GMOs (B) and half of minimal agricultural levels (C), see Section 2). Lifespan during the experiment for the control group is represented by the vertical bar ± SEM (grey area). In bar histograms, the causes of mortality before the grey area are detailed in comparison to the controls (0). In black are represented the necessary euthanasia because of suffering in accordance with ethical rules (tumors over 25% body weight, more than 25% weight loss, hemorrhagic bleeding, etc.); and in hatched areas, spontaneous mortality.

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Fig. 2. Largest non-regressive tumors in rats fed GMO treated or not by Roundup, and effects of Roundup alone. The symbols of curves and treatments are explained in the caption of Fig. 1. The largest tumors were palpable during the experiment and numbered from 20 mm in diameter for males and 17.5 mm for females. Above this size, 95% of growths were non-regressive tumors. Summary of all tumors are shown in the bar histograms: black, non regressive largest tumors; white, small internal tumors; grey, metastases.

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Fig. 3. Anatomopathological observations in rats fed GMO treated or not by Roundup, and effects of Roundup alone. Macroscopic and microscopic photographs show male livers (A–E) and left kidneys (F–I′), female mammary glands (J–P) and pituitaries (Q–T), according to Table 2. The number of each animal and its treatment is specified. Macroscopic pale spots (D) and microscopic necrotic foci in liver (C clear-cell focus, E basophilic focus with atypia), and marked or severe chronic progressive nephropathies, are illustrated. In females, mammary tumors (J,J′,N adenocarcinoma and K,K′,L,L′,O,P fibroadenomas) and pituitary adenomas (R–T) are shown and compared to controls (C after the rat number).

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Fig. 4. Ultrastructure of hepatocytes in male rats from groups presenting the greatest degree of liver pathology. (1) Typical control rat hepatocyte (Bar 2 μm except in 4). (2) Effects with Roundup at the lowest dose. Glycogen (G) is dispersed in the cytoplasm. L, lipid droplet; N, nucleus; R rough endoplasmic reticulum. (3) Hepatocytes of animal fed GM maize (GMO) at 22% of total diet. Large lakes of glycogen occur in the cytoplasm. M, mitochondria. (4) Details of treatment effects with 22% dietary GMO (Bar 1 μm). (a) Cluster of residual bodies (asterisks). (b) Mitochondria show many enlarged cristae (arrows).

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Fig. 5. Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) for biochemical data (females fed 33% GMO versus controls). (A) OPLS-DA regression coefficients for predictive component, with jack-knifed confidence intervals at 99% confidence level, indicate discriminant parameters versus controls at month 15 (Abbreviations: U Urinary, UEx Excreted in urine during 24 h, APPT Activated Partial Thromboplastin Time, MCV Mean Corpuscular Volume, PT Prothrombine Time, RBC Red Blood Cells, ALT ALanine aminoTransferase, MCHC Mean Corpuscular Hemoglobin Concentration, A/G Albumin/Globulin ratio, WBC White Blood Cells, AST aspartate aminotransferase). (B) In this case, detailed examples of significant discriminant variables distribution between females fed 33% GMO (bold line) and controls (dotted line). On x axis: animals; on y axis: serum or urine biochemical values for Na, Cl, estradiol, testosterone. Profiles evidence kidney ion leakages and sex hormonal imbalance versus controls.

Table 1. Protocol used and comparison to existing assessment, and to non-mandatory regulatory tests.

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The protocol used in this work was compared to the regulatory assessment of NK603 maize by the company (Hammond et al., 2004), and to non mandatory regulatory in vivo tests for GMOs, or mandatory for chemicals (OECD 408). Most relevant results are shown in this paper.

Table 2. Summary of the most frequent anatomical pathologies observed.

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After the number of pathological abnormalities, the number of rats reached is indicated in parentheses. In male animals pathological signs are liver congestions, macroscopic spots and microscopic necrotic foci. Hepatodigestive pathological signs concern the liver, stomach and small intestine (duodenum, ileum or jejunum). Only marked or severe chronic progressive nephropathies (CPN) are listed, excluding two nephroblastomas in groups consuming GMO 11% and GMO 22% + Roundup. In females, mammary fibroadenomas and adenocarcinomas are the major tumors detected; galactoceles and hyperplasias with atypia are also found and added in mammary glands pathological signs. Pituitary dysfunctions include adenomas, hyperplasias and hypertrophies. For details of the various treatment groups see Fig. 1.

Table 3. Percentage variation of parameters indicating kidney failures of female animals.

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OPLS-DA was performed on 48 variables at month 15. Here we showed mean differences (%) of variables (discriminant at 99% confidence level, in bold character) indicating kidney parameters of female animals, together with sex hormones. Male kidney pathologies are already illustrated in Table 2.

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