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Comments on the human health impact of Bacillus thuringiensis toxin gene product in genetically modified crops


EPA Review Docket Number OPP-00678B

Professor Joe Cummins

I have studied the Environment Protection Agency (EPA) document "Bt Plant-Pesticides Biopesticides Registration Action Document B. HUMAN HEALTH ASSESSMENT" and comment in the following areas. First, there is evidence that Bacillus thuringirnsis (Bt) cry 1 toxin will impact directly on human health through damage to the ileum , second , the use of synthetic Bt cry toxin genes has not been proven to be equivalent to the natural bacterial gene and finally, the introduction of natural and synthetic bacterial genes into crops and food sources for human or farm animals has not been evaluated regarding its introduction of high levels of the bacterial CpG trigger that activated the innate immune response.

The study below shows that Bt Cry 1 toxin which is used extensively in corn and cotton products (oil and seed meal) used in human and animal food damages the mammalian ileum. Damage to the ileum can produce chronic illness such as fecal incontinence and/or flu like upsets of the digestive system. A brief description of the ileum and its function follows the article abstract.

The article: Natural Toxins Volume 6, Issue 6, 1998. Pages: 219-233 Published Online: 29 Jun 1999 "Fine Structural Changes in the Ileum of Mice Fed on -Endotoxin-Treated Potatoes and Transgenic Potatoes" Nagui H. Fares 1 *, Adel K. El-Sayed 2 1Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt 2Department of Entomology, Faculty of Science, Ain Shams University,Cairo, Egypt email: Nagui H. Fares ([email protected])

Abstract The present work has been designed to study the effect of feeding on transgenic potatoes, which carry the CryI gene of Bacillus thuringiensis var. kurstaki strain HD1, on the light and electron microscopic structure of the mice ileum, in comparison with feeding on

potatoes treated with the -endotoxin isolated from the same bacterial strain. The microscopic architecture of the enterocytes of the ileum of both groups of mice revealed certain common features such as the appearance of mitochondria with signs of degeneration and disrupted short microvilli at the luminal surface. However, in the group of mice fed on the -endotoxin, several villi appeared with an abnormally large number of enterocytes (151.8 in control group versus 197 and 155.8 in endotoxin and transgenic-treated groups, respectively). Fifty percent of these cells were hypertrophied and multinucleated. The mean area of enterocyte was significantly increased (105.3 =B5m2 in control group versus 165.4 =B5m2 and 116.5 =B5m2 in endotoxin and transgenic-treated groups, respectively). Several forms of secondary lysosomes or auotophagic vacuoles were recognized in these cells. These changes were confirmed with the scanning electron microscope which revealed a remarkable increase in the topographic contour of enterocytes (23 =B5m = in control group versus 44 =B5m and 28 =B5m in endotoxin and transgenic-treated groups, respectively) at the divulged surface of the villi. The basal lamina along the base of the enterocytes was damaged at several foci.

Several disrupted microvilli appeared in association with variable-shaped cytoplasmic fragments. Some of these fragments contained endoplasmic reticulum, as well as ring-shaped annulate lamellae. In addition, the Paneth cells were highly activated and contained a large

number of secretory granules. These changes may suggest that endotoxin-treated potatoes resulted in the development of hyperplastic cells in the mice ileum. Although mild changes are reported in the structural configuration of the ileum of mice fed on transgenic potatoes, nevertheless, thorough tests of these new types of genetically engineered crops must be made to avoid the risks before marketing.

Ileum: Final and longest segment of the small intestine. It is specifically responsible for the absorption of vitamin B12 and the reabsorption of conjugated bile salts . The ileum is about 4 m (13 feet) in length and extends from the jejunum (the middle section of the small intestine) to the ileocecal valve, which empties into the colon (large intestine). The ileum is suspended from the abdominal wall by the mesentery.

The smooth muscle of the ileum's walls is thinner than the walls of other parts of the intestines, and its peristaltic contractions are slower. The ileum's lining is also less permeable than that of the upper small intestine. Small collections of lymphatic tissue (Peyer's patches)are embedded in the ileal wall, and specific receptors for bile salts and vitamin B12 are contained exclusively in its lining; about 90 percent of the conjugated bile salts in the intestinal contents is absorbed by the ileum.

Presuming that there has been a major impact of the injury from ingesting the BtCry1 gene product among humans , farm animals or wildlife it is unlikely that the minds of those viewing the injury are prepared to associate the injury to its source. The GM food products are not labeled and frequently disguised in processed foods. The precautionary principle demands that the potentially dangerous foods be removed from production until proven safe. The Industrial Biotest Laboratory (IBT) scandal of the early nineteen eighties was the careless and false reporting of pesticide safety tests on a large scale by a laboratory favored by industry and regulatory agencies. The laboratory fraud led to approval of a number of dangerous pesticides. The lesson that EPA should have learned was to view the results of industry supported studies for product approval with skepticism and to seriously respond to studies that show potentially harmful impact. The failure of EPA to report and evaluate the Egyptian study is perplexing and must be remedied.

EPA reviews have presumed that the genetic code (A,T,G and C words) are both necessary and sufficient to establish the equivalence of synthetic genes or genes from bacteria in crop plants. However, it is elementary to recognize that DNA modifications exist and they are fundamental to the origin of a gene (whether synthetic, bacterial or from a crop plant). It is unwise to assume that the modification pattern of a transgene immediately assumes the characteristics of the crop into which it is inserted. The pattern of DNA modification fundamentally influences gene activity in crop plants (Martienssen and Colot 2001) and impacts upon development and cancer in animals (Laird and Jaenisch 1996). DNA modifications such as the phosphotriesters have been known for many years but the function of such modifications have only begun to be studied and resolved (Verma and Ekstein 1998). The point of this discussion is to question the assumption that only the four letter code establishes gene function and that DNA modifications are not relevant to the safety of transgenes in crops or in the diet of humans and animals. DNA modifications have not been fully and fairly evaluated in the EPA reviews on GM crop safety.

The impact of bacterial DNA on the immune system (the CpG effect): Essentially all of the GM crops marketed or being field tested presently contain bacterial sequences as a part of the plasmids used for delivering genes and many of the primary crop protection genes are of bacterial origin. Such genes include Bt and most herbicide tolerance genes. DNA vaccines have generated a huge literature and clinical applications showing the activity and cellular incorporation of DNA administered by oral, inhalation, injection, vaginal or dermal application (Molling 1997,Donnoley et al 1997 and Gurunathan et al 2000). Ingestion of bacteria does not appear to be an effective means of delivering DNA because the bacterial cell walls effectively contain the nucleic acid (for example, in yogurt the milk products are digested but the bacteria of the culture are passed intact). Lysis genes have been found necessary and effective in triggering release of DNA for mucosal vaccine delivery (Jani and Mekalanos 200). In contrast, the crops eaten by animals release oligonucleotides and DNA peptide complexes during digestion and such molecules circulate to a significant degree.

The bacterial genes used in constructing GM crops have a property that impacts on the immune system over and above the ability to produce antibodies. Eukaryote DNA has relatively low frequencies of the dinucleotide motif CpG and that motif is methylated and plays a role in gene regulation while bacteria and their viruses have a high frequency of the CpG motif that is usually unmethylated. Apparently the CpG motif in DNA molecules and oligonucleotides provides a signal that the immune system recognizes and initiates a primary sequence of reactions leading to activation of the immune system leading to inflammation (Manders and Thomas 2000 and Gurunathan et al 2000).Gung et al (1999) found that bacterial DNA CpG caused septic arthritis. Hemmi et al (2000) found that there is a receptor protein that recognizes bacterial DNA. Oligonucleotides rich in the CpG motif are used to enhance immunization. Inflammation is an essential part of the immune response but it adversely affects existing conditions such as autoimmune disease. Furthermore, it has been found that CpG oligonucleotides rescue B cell lymphoma cells from anti-IgM mediated growth inhibition (Han et al 1999). The oligonucleotide acts as a promoter of lymphoma.

Finally, Gorecki and Simons (1999) pointed out a danger to the fetus in DNA vaccination of the mother. That danger was the creation of tolerance in the fetus leading to individuals more susceptible to infection and/or they may become carriers. The introduction of genes with bacterial CpG motif to the fetus is likely to have untoward consequences.

In conclusion, the bacterial genes used in GM crops have been found to have significant impacts on the individuals ingesting GM crops. The impacts include inflammation, arthritis and lymphoma promotion.

References

  1. Deng,G, Nilsson,A,Verdrengh,M,Collins,Land Tarkowski,A "intra-articularly located bacteria containging CpG motifs induces arthritis" 1999 Nature Medicine 5,702-6
  2. Donnelly,J,Ulmer,U,Shiver,J and Lui,M. "DNA Vaccines"1997 Annu Rev Immunol 15,617-48
  3. Gorecki,D and Simons,J "The dangers of DNA vaccination" 1999 Nature Medicine 5,126
  4. Guunathan,S,Klinman,D and Seder,R. "DNA Vaccines" 2000 Annu Rev. Immunol 18,927-74
  5. HEMMI, H,TAKEUCHI, O, KAWAI, T, KAISHO, T, SATO,S, SANJO, H,MATSUMOTO,M, HOSHINO,K, WAGNER, H, TAKEDA,K and AKIRA,S "A Toll-like receptor recognizes bacterial DNA"2000 Nature 408, 740 - 745
  6. Hsu,S,Chung,S,Robertson,D,Ralph,L,Chelvarajan,R and Bondada,S 1999 "CpG oligodeoxynucleotides rescue BKS-2 immature B cell lymphoma from anti-Ig-M-mediated growth inhibition by up-regulating of egr-1" International Immunology 6,871-9
  7. Jain,V and Mekalanos,J "Use of lambda phage S and R gene products in an inducible lysis system from Vibrio cholerae and Salmonella enterica servovar Typhimurium-Based vaccine delivery systems" 2000 Infection and Immunity 68,986-9
  8. Laird,P and Jaenisch,R "THE ROLE OF DNA METHYLATION IN CANCER GENETICS AND EPIGENETICS" Annu. Rev. Genet. 1996. 30:441–64
  9. Manders,P and Thomas,R "Immunology of DNA vaccines: CpG motifs and antigen presentation" Inflamm Res 49,199-205
  10. Martienssen,R and Colot,V "DNA Methylation and Epigenetic Inheritance
  11. in Plants and Filamentous Fungi" 2001 SCIENCE VOL 293:1070-5
  12. Molling,K "Naked DNA for vaccine or therapy" 1997 JMolMed 75,242-6
  13. Verma,S and Eckstein,F "MODIFIED OLIGONUCLEOTIDES:Synthesis and Strategy for Users" Annu. Rev. Biochem. 1998. 67:99–134
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