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AquAdvantage© Salmon, next to its smaller, natural Atlantic Salmon counterpart

In the absence of feeding studies the commercial release of GM salmon is too hazardous to consider Prof. Joe Cummins

This report has been submitted to US Food and Drug Administration on behalf of the Institute of Science in Society. © I-SIS.org.uk

The United States Department of Health and  Human Services Food and Drug Administration Veterinary Medicine Advisory Committee will meet on 19 September 2010, and on 20 September 2010, it will consider issues regarding the safety and effectiveness of the new animal drug that is the subject of a new animal drug application (NADA) concerning AquAdvantage salmon produced by AquaBounty Technologies, Inc. These genetically engineered Atlantic salmon are intended to grow faster than conventionally bred Atlantic salmon [1]. The new drug being considered is a growth hormone gene that was transferred from Chinook salmon to the genome of the Atlantic salmon.  Both the gene and the protein it produces are presumed to be a new veterinary drug that is to be released to the environment in the genetically modified (GM) Salmon.


The AquaBounty Salmon

The AquAdvantage Salmon to be released is a triploid female Atlantic salmon carrying a single copy of the stably integrated a-form of the growth hormone construct, opAFP-GHc2 at the a-locus in the EO-1a line. For the use covered in this EA, the product subject to regulatory approval is an eyed-egg (fertile egg) produced at a specific site on Prince Edward Island, Canada (PEI), and delivered to a specific site in Panama for grow-out (i.e., culture to market size) and processing for retail sale in the United States. The opAFP-GHc2 construct consists of regulatory sequences from an ocean pout AFP gene and protein-coding sequence from a chinook salmon grown hormone (GH) gene [2].

The founder animal from which the AquAdvantage line derives was a mosaic, transgenic female (EO-1) generated by injecting the construct into the fertilized eggs of wild Atlantic salmon. Two rapidly-growing, transgenic F1-progeny of EO-1 were selected for further development and found to harbor two independently segregating integrated copies of the construct: a functional a-form and a non-functional ß-form. The breeding of six subsequent generations has led to the establishment of an AquAdvantage Salmon line (EO-1a) with a single copy of the integrated transgene. The broodstock used in spawning of AquAdvantage Salmon are homozygous females (i.e., having two copies of the transgene) that have been phenotypically sex-reversed for breeding purposes (for example, oral administration of female hormone 17ß-oestradiol to juvenile males leads to complete sex reversal in Atlantic Salmon). These neomales are crossed with non-transgenic female Atlantic salmon to produce eggs containing a single-copy of the transgene that are pressure-shocked to induce triploidy (a condition of possessing three complements of chromosomes instead of the normal two, or diploid), which renders the fish sterile. Therefore, the salmon.deriving from these eggs are females incapable of reproduction. The fish that develop from these eggs have an enhanced growth rate compared to non-transgenic Atlantic salmon [2].

Producing grow out GM salmon in Panama provides a further environmental control of the  GM salmon. Any adults that could possibly escape from confinement will be unable to survive in the warm ocean waters off Panama [2].  Rearing of the Salmon in Panama will require a cool source of water because salmon and trout reared in warm water develop physical defects and undesirable mushy taste.

The briefing packet [3] deals with a number of issues pertinent to the safety of GM salmon. One area of particular concern is that triploids that are commonly used in fish species introduced to provide benefits such as control of weeds (by carp) or as sports fish such as trout that are capable of displacing native fish species.  In many cases, the triploids were leaky in the sense that some fertile fish were found among the sterile triploids. A few fertile fish may have a pronounced impact on a native stock.  The briefing packet reports that fertilized GM salmon eggs are subjected to pressure shock treatment in order to render the offspring triploid with two copies of the genome coming from the non-GM female and one copy from the homozygous neomale  gynogen (a male that has been turned into fertile female by hormone treatment). Female triploid salmon are effectively reproductively incompetent. The estimated sample average percent of triploidy for 5 crosses ranges from 99.7 -99.9 percent. For the triploidy rate estimates within a cross, the minimum range was 99.7-100 percent and the maximum range was 98.9-100 percent [3].  It amounts to 1-3 fertile GM salmon in 1000, which could have a long term effect in a wild population but would have little impact in a Panama fish farm. Leaky sterile triploids that revert to a few fertile fish  have been a recurrent problem [4] (Floating Transgenic Fish in a Leaky Triploid Craft, SiS 24). Some 1.1 percent exceptional diploids were observed in pressure shock-induced triploid growth hormone transgenic Coho salmon. Although sperm appears to fertilize and activate egg development in diploid exceptions, paternal chromosomes are not consistently contributing to the developing zygote’s genome. It will be important to assess the fertility of these exceptional “diploid” individuals to determine whether rare cytological events occurring at fertilization may influence the utility and effectiveness of pressure-shock-induced triploidy for biocontainment [5].

Other growth hormone transgenic salmon

Other growth hormone transgenic salmon have been developed and studied. The results of those studies are relevant to the GM Atlantic salmon and the prospects for their release. GM Coho salmon has been modified with the gene construct OnMTGH1 containing the sockeye salmon metallothionine regulatory sequences (promoter and terminator) spliced to a sockeye salmon growth hormone gene.  It caused enhanced growth, which was associated with gene expression impacts on metabolic pathways. Insulin-like growth factor-I (IGF-I) was increased over the wild Coho salmon [6,7]. IGF-1 is of interest because it has been Implicated in promotion of human cancer. IGF-1 was also studied in AquaAdvantage GM salmon  it was found to be enhanced  in the GM salmon but  its levels were considered safe for human consumption [3]. 

Triploid Salmon

Triploid salmon that are not genetically modified have some detrimental effects worth discussing. Ocean migration and recapture of tagged triploid mixed sex and all female Atlantic salmon were released from  rivers in Ireland. Overall triploids recovery was 12  to 24 percent of their diploid siblings released [8].  The triploids seem to provide easy prey for predators. Gene expression related to gene dosage was studied in Chinook salmon; the results showed that triploidization may lead to unpredictable performance and fitness outcomes [9]. Vibrosis is one of the most prevalent fish diseases caused by bacteria. Vibriosis caused by Vibrio anguillarum has been particularly devastating in the marine culture of salmonid fish.  Transcription studies comparing diploid and triploid Chinook salmon indicated that, under stress, the triploids showed reduced ability to combat the disease causing bacterium [10].  Triploid all female Atlantic salmon are known to be prone to skeletal deformities, particularly in the lower jaw.  The triploids fish were defective in recovery from swimming exhaustion [11].  The problem of skeletal deformities in triploid female Atlantic salmon has been recognized in the AquAdvantage salmon [3].

Conclusion

The institute of Science in Society earlier commented [12] (Transgenic Animals for Food Not Proven Safe, SiS 410): “FDA’s guidelines on commercial release of transgenic animals ignore known hazards of GMOs and totally inadequate to protect the public from genetic and epigenetic damages that may result from transgenic foods.” The situation has hardly changed.

In the case of GM AquAdvantage salmon, it is puzzling to find that FDA describes AquAdvantage salmon as a veterinary drug but does not appear to have required animal feeding studies followed by complete tissue necropsy of the fed animals. It appears as if FDA is prepared to dance in the dark as the public are fed GM salmon. In the absence of feeding studies the commercial release of GM salmon is too hazardous to consider. Also, the many defects of the GM fish and the additional costs needed to raise the fish may well make it commercially undesirable as well as dangerous.

References:

  1. Kux L.  Veterinary Medicine Advisory Committee; Notice of Meeting Food and Drug Administration [Docket No. FDA–2010–N–0001] Federal Register / Vol. 75, No. 165 / Thursday, August 26, 2010 / Notices 52605
  2. Aqua Bounty Technologies, Inc. Environmental Assessment for AquAdvantage® Salmon Submitted to the Center for Veterinary Medicine US Food and Drug Administration For Public Display August 25, 2010 http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/UCM224760.pdf
  3. BRIEFING PACKET AquAdvantage Salmon Food and Drug Administration Center for Veterinary Medicine Veterinary Medicine Advisory Committee September 20, 2010 http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/UCM224762.pdf
  4. Cummins J. Floating transgenic crops in a leaky triploid craft. Science in Society 24, 32, 2003.
  5. Devlin R.Sakhrania D, Biagia C, Eoma K. Occurrence of incomplete paternal-chromosome retention in GH-transgenic coho salmon being assessed for reproductive containment by pressure-shock-induced triploidy.  Aquaculture 2010, 104,1-4. 66-78
  6. Higgs D Suttona J, Kima H, Oakesa J. Smitha J, Biagia C, Rowshandelia M, Devlin R. Influence of dietary concentrations of protein, lipid and carbohydrate on growth, protein and energy utilization, body composition, and plasma titres of growth hormone and insulin-like growth factor-1 in non-transgenic and growth hormone transgenic coho salmon, Oncorhynchus kisutch (Walbaum). Aquaculture 2009, 286,  1-2, 127-137
  7. Raven PA, Uh M, Sakhrani D, Beckman BR, Cooper K, Pinter J, Leder EH, Silverstein J, Devlin RH. Endocrine effects of growth hormone overexpression in transgenic coho salmon. Gen Comp Endocrinol. 2008 Oct;159(1):26-37
  8. Wilkins NP, Cotter D, O’Maoiléidigh N. O cean migration and recaptures of tagged, triploid, mixed-sex and all-female Atlantic salmon (Salmo salar L.) released from rivers in Ireland. Genetica. 2001;111(1-3):197-212.
  9. Johnson RM, Shrimpton JM, Cho GK, Heath DD. Dosage effects on heritability and maternal effects in diploid and triploid Chinook salmon (Oncorhynchus tshawytscha).Heredity. 2007 May;98(5):303-10
  10. Ching B, Jamieson S, Heath JW, Heath DD, Hubberstey A.Transcriptional differences between triploid and diploid Chinook salmon (Oncorhynchus tshawytscha) during live Vibrio anguillarum challenge.Heredity. 2010 Feb;104(2):224-34.
  11. Lijalada M, Powell M. Effects of lower jaw deformity on swimming performance and recovery from exhaustive exercise in triploid and diploid Atlantic salmon Salmo salar L. Aquaculture 2009, 290,  1-2,145-154
  12. Cummins J and Ho MW. Transgenic animals for food not proven safe. Science in Society 41, 43-45, 2009.

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