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Glyphosate induces human breast cancer cells growth via estrogen receptors

Siriporn Thongprakaisang^a, Apinya Thiantanawat^{b, c}, Nuchanart Rangkadilok^{a, c}, Tawit Suriyo^c, Jutamaad Satayavivad^{a, c, d}

^a Environmental Toxicology Program, Chulabhorn Graduate Institute, Kamphaengphet 6 Road, Laksi, Bangkok 10210, Thailand
^b Applied Biological Sciences Program, Chulabhorn Graduate Institute, Kamphaengphet 6 Road, Laksi, Bangkok 10210, Thailand
^c Laboratory of Pharmacology, Chulabhorn Research Institute, Kamphaengphet 6 Road, Laksi, Bangkok 10210, Thailand
^d Center of Excellence on Environmental Health and Toxicology, Office of the Higher Education Commission, Ministry of Education, Bangkok, 10400, Thailand

http://dx.doi.org/10.1016/j.fct.2013.05.057

Highlights

– Glyphosate at 10-12 to 10-6 M promoted growth of T47D cells via estrogen receptors.
– Glyphosate produced the activation of ERE which can be blocked by ICI 182780.
– Glyphosate altered estrogen receptors by increasing expression ratio of ER and ER.
– Glyphosate had an additive effect with genistein on ERE activation and cell growth.

Abstract

Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10-12 to 10-6 M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.

http://www.sciencedirect.com/science/article/pii/S0278691513003633
Food and Chemical Toxicology
Available online 9 June 2013

Glyphosate is the primary active constituent of the commercial pesticide Roundup®. The present results show that acute Roundup® exposure at low doses (36ppm, 0.036g/L) for 30min induces oxidative stress and activates multiple stress-response pathways leading to Sertoli cell death in prepubertal rat testis. The pesticide increased intracellular Ca2+ concentration by opening L-type voltage-dependent Ca2+ channels (L-VDCC) as well as endoplasmic reticulum IP3 and ryanodine receptors, leading to Ca2+ overload within the cells, which set off oxidative stress and necrotic cell death. Similarly, 30min incubation of testis with glyphosate alone (36ppm) also increased 45Ca2+ uptake. These events have been prevented by the antioxidants Trolox® and ascorbic acid. Activated protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K) and the mitogen-activated protein kinases (MAPKs), such as ERK1/2 and p38MAPK have played a role in eliciting Ca2+ influx and cell death. Roundup® decreased the levels of reduced glutathione (GSH) and increased the amounts of thiobarbituric reactive species (TBARS) and protein carbonyls. Also, exposure to the glyphosate-Roundup® has stimulated the activity of glutathione peroxidase, glutathione reductase, glutathione-S-transferase, gamma-glutamyl transferase (γGT), catalase, superoxide dismutase and glucose-6-phosphate dehydrogenase, supporting downregulated GSH levels. Glyphosate has been described as an endocrine disruptor affecting the male reproductive system; however, the molecular basis of its toxicity remains to be clarified. We could propose that Roundup® toxicity, implicating in Ca2+ overload, cell signaling misregulation, stress response of the endoplasmic reticulum and/or depleted antioxidant defenses could contribute to Sertoli cell disruption of spermatogenesis that could impact male fertility. 

Entropy 2013, 15(4), 1416-1463; doi:10.3390/e15041416
Open access: http://www.mdpi.com/1099-4300/15/4/1416

Abstract:

Glyphosate, the active ingredient in Roundup®, is the most popular herbicide used worldwide. The industry asserts it is minimally toxic to humans, but here we argue otherwise. Residues are found in the main foods of the Western diet, comprised primarily of sugar, corn, soy and wheat. Glyphosate’s inhibition of cytochrome P450 (CYP) enzymes is an overlooked component of its toxicity to mammals. CYP enzymes play crucial roles in biology, one of which is to detoxify xenobiotics. Thus, glyphosate enhances the damaging effects of other food borne chemical residues and environmental toxins. Negative impact on the body is insidious and manifests slowly over time as inflammation damages cellular systems throughout the body. Here, we show how interference with CYP enzymes acts synergistically with disruption of the biosynthesis of aromatic amino acids by gut bacteria, as well as impairment in serum sulfate transport. Consequences are most of the diseases and conditions associated with a Western diet, which include gastrointestinal disorders, obesity, diabetes, heart disease, depression, autism, infertility, cancer and Alzheimer’s disease. We explain the documented effects of glyphosate and its ability to induce disease, and we show that glyphosate is the “textbook example” of exogenous semiotic entropy: the disruption of homeostasis by environmental toxins.

Conclusion:

This paper presents an exhaustive review of the toxic effects of the herbicide, glyphosate, the active ingredient in Roundup®, in humans, and demonstrates how glyphosate’s adverse effects on the gut microbiota, in conjunction with its established ability to inhibit the activity of cytochrome P450 enzymes, and its likely impairment of sulfate transport, can remarkably explain a great number of the diseases and conditions that are prevalent in the modern industrialized world. Its effects are insidious, because the long-term effects are often not immediately apparent. The pathologies to which glyphosate could plausibly contribute, through its known biosemiotic effects, include inflammatory bowel disease, obesity, depression, ADHD, autism, Alzheimer’s disease, Parkinson’s disease, ALS, multiple sclerosis, cancer, cachexia, infertility, and developmental malformations. Glyphosate works synergistically with other factors, such as insufficient sun exposure, dietary deficiencies in critical nutrients such as sulfur and zinc, and synergistic exposure to other xenobiotics whose detoxification is impaired by glyphosate. Given the known toxic effects of glyphosate reviewed here and the plausibility that they are negatively impacting health worldwide, it is imperative for more independent research to take place to validate the ideas presented here, and to take immediate action, if they are verified, to drastically curtail the use of glyphosate in agriculture. Glyphosate is likely to be pervasive in our food supply, and, contrary to being essentially nontoxic, it may in fact be the most biologically disruptive chemical in our environment.