New research has put to rest a theory that claimed to explain an important pathway by which the weedkiller chemical glyphosate has toxic effects on the human body, GM Watch reported recently.
Source: gmwatch.org
The theory has been promoted over several years by researchers who claimed that glyphosate substitutes for the amino acid glycine in the proteins that make up our body tissues, causing protein misfolding and toxicity. This hypothetical substitution was said to lead to a large array of human diseases, including diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), hypothyroidism, Alzheimer’s, Parkinson’s, prion diseases, lupus, non-Hodgkin’s lymphoma, infertility, hypertension, osteoporosis, fatty liver disease, and chronic kidney disease.
However, no direct evidence exists for glyphosate substituting for glycine in proteins, including those in the bodies of mammals. So a group of researchers led by Dr Michael Antoniou of King’s College London decided to put the glyphosate-glycine substitution theory to the test. They treated growing breast cancer cells with glyphosate over a 6-day period. Then they extracted protein from the cells and tested it using an analytical tool called proteomics, to see if it had taken up any glyphosate. They also tested an untreated group of cells as a control.
They found that glyphosate did not substitute for glycine in the cells’ proteins. The results confirmed the findings of earlier studies in bacteria. The researchers concluded that this particular theory about how glyphosate affects humans and other mammals is incorrect.
In their published paper, the researchers commented on their findings: “Although our results will not come as a surprise to most of the scientific community, we believe they are nonetheless important in helping to clarify the debate on glyphosate toxicity in which many scientific hypotheses are considered as evidence of harm, ultimately influencing political debates, without being carefully tested in a controlled laboratory setting.”
However, Dr. Antoniou emphasises that the new research doesn’t show glyphosate is safe: “We know that there are other mechanisms for glyphosate’s toxicity, including oxidative stress, a process that can cause DNA damage that could in turn lead to cancer. And a large body of research links exposure to glyphosate and glyphosate-based herbicides with diseases such as cancer and fatty liver disease.”
Dr. Antoniou clarified that just because his group’s research shows that glyphosate is not incorporated into proteins, that is completely different from saying it doesn’t accumulate in the body’s tissues. Scientists still do not know for certain if glyphosate accumulates in the body, as the necessary research has not been done. But if glyphosate does accumulate in the body, it is not through being incorporated into proteins.
Dr. Antoniou concluded, “We hope our study will help focus researchers’ attention on other aspects of glyphosate’s safety that are better supported by experimental evidence, such as its impact on reproduction, development, cancer, and microbiomes, especially of the gut.”
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Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells
Michael N. Antoniou, Armel Nicolas, Robin Mesnage, Martina Biserni, Francesco V. Rao & Cristina Vazquez Martin
BMC Research Notes 12, Article number: 494 (2019)
bmcresnotes.biomedcentral.com/articles/10.1186/s13104-019-4534-3 (open access)
Abstract
Objectives
Glyphosate (N-phosphonomethyl glycine) and its commercial herbicide formulations have been shown to exert toxicity via various mechanisms. It has been asserted that glyphosate substitutes for glycine in polypeptide chains leading to protein misfolding and toxicity. However, as no direct evidence exists for glycine to glyphosate substitution in proteins, including in mammalian organisms, we tested this claim by conducting a proteomics analysis of MDA-MB-231 human breast cancer cells grown in the presence of 100 mg/L glyphosate for 6 days. Protein extracts from three treated and three untreated cell cultures were analysed as one TMT-6plex labelled sample, to highlight a specific pattern (+/+/+/−/−/−) of reporter intensities for peptides bearing true glyphosate treatment induced-post translational modifications as well as allowing an investigation of the total proteome.
Results
Comparative statistical analysis of global proteome changes between glyphosate treated and non-treated samples did not show significant differences. Crucially, filtering of data to focus analysis on peptides potentially bearing glycine for glyphosate replacement revealed that the TMT reporter intensity pattern of all candidates showed conclusively that they are all false discoveries, with none displaying the expected TMT pattern for such a substitution. Thus, the assertion that glyphosate substitutes for glycine in protein polypeptide chains is incorrect.
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Bless you for your research
For the life of me, I can’t see how the results of this experiment on breast cancer cells in vitro allows us to reach any scientifically valid conclusion at all about what happens in a living human body where the glycine is used in, I imagine, hundreds of chemical pathways that are not even present in breast cancer cells. As far as I can see, the results of an experiment like this tells us pretty close to nothing worth knowing. Anyone who thinks that it does couldn’t possibly understand the first thing about science.
While the results of this experiment are interesting and worth taking into account, the conclusions that are drawn by the study’s authors should never have even passed through the peer review process (assuming that there was one.) Sadly, this appears to be true of the conclusions drawn by more than half of the “scientific” research that is being published these days, especially in medical journals.
Glyphosate is miss-making the proteins that make connective tissue: muscle, tendon, the net under your skin that holds your body in (cellulite). None of these were mentioned in this article. See the work of Dr Stephanie Seneff.
I am thrilled that this paper was published, only I can’t for the life of me figure out why they reached the conclusion they reached. If you read the paper carefully, you will see that they found at least sixteen specific human proteins where glyphosate was subsituted at specific places where glycine should have been present. Others can now reproduce their results on all kinds of interesting cell cultures and tissue samples, to recover more proteins with specific glyphosate substitutions. The specific substitutions they found even make sense to me in terms of my predictions of a “glyphosate susceptible motif.” The only reason they claim that their results are invalid is because they found an essentially equal number of protein substitutions in the “control” cells. But guess what? All the cells had been chronically exposed to glyphosate starting when they were resident in a woman’s body and throughout their lives being maintained in an in vitro culture with (probably) glyphosate-contaminated nutrient broth. I believe that glyphosate makes proteins difficult to clear, which is why they accumulate over time. Check out my interpretation of their paper here: people.csail.mit.edu/seneff/does_glyphosate_substitute.html
Dear Greg, the proposed replacement of glycine by glyphosate takes place at the level of mRNA translation to proteins. The translation machinery is the same in every cell of the body. Thus, although what you say is correct in that the human breast cancer cell line we used as a model system will have some biochemical pathways that distinguish it from other cell types, this is of no consequence for the question we have addressed, which does not involve biochemical pathways but the universal mRNA translation machinery. This is why we conclude that what we found in the breast cancer cells is generally applicable to all cell types and even different complex organisms as all share the same mRNA translation machinery for the linking of amino acids into proteins. Hope this helps to clarify matters. Michael
Dear Karen, the mis-incorporation of glyphosate in place of glycine in proteins such as collagens was a hypothesis put forward by Stephanie Seneff (and Anthony Samsel). But this was just a hypothesis without any definitive, conclusive evidence as to whether this actually takes place. The replacement of glycine by glyphosate in proteins may be a reasonable hypothesis to put forward but like all hypotheses this needed to be tested by direct experimentation to prove it one way or another. What we describe in our publication highlighted in this Sustainable Pulse posting is a direct testing of this hypothesis. Our results clearly show that glyphosate cannot substitute for glycine in proteins and thus the original hypothesis put forward by Stephanie and Anthony is incorrect. This is way all science works; one hypothesises based on the evidence at the time. If the experimental testing of the hypothesis shows that it is incorrect then so be it and science move on to address other issues on the topic. Michael
I can’t comprehend why Prof. Antoniou claims that his research did not find any glyphosate substitutions for glycines. Below is what you can derive from the captions above the plots in Figure 3.
15 peptide sequences with perfect matches to known human proteins. G* indicates where glyphosate substituted for glycine. Most of these proteins are known to be expressed by breast cancer cells, and many are implicated in bad outcomes in cancer. Most of them match my criteria for a vulnerable glycine – small amino acid immediately to the left and a positively charged amino acid in the near vicinity. How all of these could possibly be viewed as false alarms is beyond my ability to imagine.
www.uniprot.org/blast/
Basic local alignment search tool (BLAST)
1. AIRQTSELTLG*K = zinc finger protein 624
2. DG*QDRPLTKINSVK Pleckstrin homology domain-containing family A member 5
3. DKPSRGVG*GSK protein NRDE2 homolog
4. EPVASLEQEEQG*K Double homeobox protein A
5. G*ELVMQYK diacylglycerol kinase gamma
6. GKELSG*LG*SALK Very long-chain specific acyl-CoA dehydrogenase, mitochondrial
7. KDGLG*GDK Probable G-protein coupled receptor 158
8. LFSMAHTVALDLAAINIQRG*R Peroxidasin homolog
9. LTLFVNG*QPRPLESSQVK Protein TFG
10. NEKYLG*FGTPSNLGK ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial
11.RTVCAKSIFELWG*HGQSPEELYSSLK RNA (guanine(10)-N2)-methyltransferase homolog
12.TG*FIASFLDFLK Glutamine and serine-rich protein 1
13.TPILTVLICLG*HLPK Isoform 3 of Leukocyte immunoglobulin-like receptor subfamily A member 2
14.VGCSAVTVG*VLGQAQGSAPWTSAFK Putative uncharacterized protein ENSP00000334305 Q3C1V9
15.VTG*QLSVINSK Protein O-mannosyl-transferase 2
Dear Stephanie
The peptide sequences from Figure 3 in our paper, which you list in your posting as well as in your blog on the MIT staff site, are of course going to be derived from human proteins. This is because we conducted our proteomics analysis with a human breast cancer cell line. The * by the G residue in the peptide sequence highlights a glycine residue that could potentially be replaced by glyphosate. The * does not in any way suggest that this substitution has actually taken place. As we say in our paper, these peptides were filtered out from the bulk proteomics analysis as good candidates to look for the glycine-glyphosate substitution. Figure 3 depicts a comparison of the molecular mass of these peptides between the control untreated cells (red histogram bars) and the glyphosate treated cells (blue histogram bars). If there had been any substitution of the glycine residues with glyphosate in the treated cells, then the molecular mass of these peptides would have substantially increased so that the height of the blue bars would have been much higher than the bars of the controls. As one can see clearly, this has simply not happened. The histogram bars in the control and glyphosate treated samples are essentially the same height and there is no statistically significant difference between them. Thus, there has been no glyphosate for glycine substitution and your interpretation of our results is therefore incorrect. Michael
Dear Stephanie
It struck me that I should also add a fundamental observation in the biology of our cell cultures that again argues strongly against glyphosate-glycine substitution in proteins. As we in show in the Supplementary Table (accessible online) and refer to in the main text of our paper, the human breast cancer cells we used grew at the same rate in the presence of glyphosate as the control untreated cells and retained their normal characteristics over the course of the 6 days of the experiment. This confirmed our previous published observation where we observed no growth inhibition by glyphosate of the same cell type at not only the same concentration used here (100mg/L) but even at a huge 10-fold higher concentration (1000mg/L; see Mesnage R et al. (2017) Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 108(Pt A): 30-42). If glyphosate was being incorporated in place of glycine resulting in misfolded and dysfunctional proteins as you suggest, then we would expect cells to not grow as well, senesce and die even during the 6-day period of treatment.
Your suggestion of glyphosate for glycine substitution in proteins is akin to the mechanism of action of certain antibiotics. For example, puromycin works by causing incorporation of the wrong amino acid at a given position of a protein during its synthesis. Mammalian cells treated with puromycin rapidly die as they accumulate abnormal proteins that cannot perform the functions the cell requires to maintain its viability. Similarly, if glyphosate was substituting for glycine then the resulting abnormal and dysfunctional proteins would result in rapid cell death.
The human breast cancer cells we used have a population doubling time of about 38 hours. This means that each cell in the culture would have divided at least 3-4 times during the 6 days of the experiment, which is reflected in the approximately 20-fold increase in cell numbers we observed by the end of the culture period. The point is this. The additional proteins that are needed to pass on to daughter cells would require a vast amount of new protein synthesis through the successive rounds of cell division. If these newly synthesised proteins were defective through glyphosate incorporation in place of glycine, then this would be incompatible with cell health and survival. The fact that the cells treated with glyphosate grew at normal rates tells us that all is well and that normal proteins are being produced to maintain cell health; that is, abnormal protein production by glyphosate incorporation into proteins cannot be taking place. Michael
It was a question raised over 50 years ago — to have an answer 50 years late is at least something. Glyphosate has apparent antibiotic properties — any guesses the MOA for prokaryotes could interact with transcription/translation machinery?
ITt is good to see robust scientific discourse, even though I was happy with Stephanie and Anthony’s hypothesis. However I wish more emphasis was given to the interruption of the three amino acids, tyrosine, tryptophan and phenylalanine, by glyphosate, which is causing the vast majority of ill effects on the environment and public health, particularly women, the unborn and developing child.
Just the disruption of thyroid hormone production from tyrosine, especially allied with fluoride from drinking water, antibiotics etc., is having huge health, social and environmental impact and the costs of dealing with these is ruining economies world wide now and ruining the prospects of future generations.
I suspect the emphasis of the cancer effect of glyphosate is a smoke screen set up by industry and regulatory authorities to hide these far more serious, in my opinion, effects from the public.
Frank Rowson