Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines

Abstract

Glyphosate is a broad-spectrum herbicide that is used worldwide. It represents a potential harm to surface water, and when commercially mixed with surfactants, its uptake is greatly magnified. The most well-known glyphosate-based product is Roundup. This herbicide is potentially an endocrine disruptor and many studies have shown the cytotoxicity potential of glyphosate-based herbicides. In breast cancer (BC) cell lines it has been demonstrated that glyphosate can induce cellular proliferation via estrogen receptors. Therefore, we aimed to identify gene expression changes in ER+ and ER- BC cell lines treated with Roundup and AMPA, to address changes in canonical pathways that would be related or not with the ER pathway, which we believe could interfere with cell proliferation. Using the Human Transcriptome Arrays 2.0, we identified gene expression changes in MCF-7 and MDA-MB-468 exposed to low concentrations and short exposure time to Roundup Original and AMPA. The results showed that at low concentration (0.05% Roundup) and short exposure (48h), both cell lines suffered deregulation of 11 canonical pathways, the most important being cell cycle and DNA damage repair pathways. Enrichment analysis showed similar results, except that MDA-MB-468 altered mainly metabolic processes. In contrast, 48h 10mM AMPA showed fewer differentially expressed genes, but also mainly related with metabolic processes. Our findings suggest that Roundup affects survival due to cell cycle deregulation and metabolism changes that may alter mitochondrial oxygen consumption, increase ROS levels, induce hypoxia, damage DNA repair, cause mutation accumulation and ultimately cell death. To our knowledge, this is the first study to analyze the effects of Roundup and AMPA on gene expression in triple negative BC cells. Therefore, we conclude that both compounds can cause cellular damage at low doses in a relatively short period of time in these two models, mainly affecting cell cycle and DNA repair.

Environmental Exposure to Pesticides and Breast Cancer in a Region of Intensive Agribusiness Activity in Brazil: A Case-Control Study

“…Also, in the final model, women 50 years of age and older who reported early menarche were 2.08 times more likely to develop breast cancer. This finding is significant, especially due to two aspects: First, it shows that the increasing trend in cancer incidence cannot be attributed only to the ageing of the population, but also due to the diffusion of carcinogenic agents in the environment [22]; second, it reinforces the hypothesis that chronic exposure to low doses of pesticides in different life cycles of human development produces a general increase in carcinogenic processes [22,34]. In the same vein, a meta-analysis study including 118,964 women with invasive breast cancer and 306,091 without the disease found that the risk for the disease increased by 5% for each year of early onset menarche [35].…”

“…This means that a large part of its population is exposed directly or indirectly to pesticides. The most used active ingredients of pesticides used in soybean, corn, and sugarcane crops are Glyphosate, 2,4 Dichlorophenoxyacetic, and Trifuralin, which have been associated with breast cancer [22,23,24]. In addition, in 2018, breast cancer was the most commonly reported, representing 48.98% of all registered cases of cancer among women in Brazil [25].…”

Analysis of Biomechanical Parameters of Muscle Soleus Contraction and Blood Biochemical Parameters in Rat with Chronic Glyphosate Intoxication and Therapeutic Use of C60 Fullerene

“…Glyphosate is an endocrine disruptor in chronic ingestion, exhibiting high cytotoxicity. The previously obtained results [ 36 ] show that it affects survival due to deregulation of the cell cycle and metabolic changes that can alter mitochondrial oxygen consumption, increase free radical levels, damage DNA, cause hypoxia, accumulation of mutations and, ultimately, cell death. It was also shown that after exposure to the herbicide for 8 days at a concentration of 0.95 mg/L, there was an increase in the amount of TBARS in muscle and brain tissues.…”

Assessment of Glyphosate Impact on the Agrofood Ecosystem

“…Walsh et al [ 186 ] detected disturbed progesterone yield, but only with the full formula, which altered puberty progression and reduced serum testosterone in pre-pubertal Wistar rats at 5 mg kg −1 day −1 . Some authors [ 187 , 188 , 189 ] recognized the non-monotonicity of glyphosate itself on a human hormone-reliant cell line of breast cancer. They found the effect to be propitiated by the oestrogen feedback and hindered by inclusion of an oestrogen receptor antagonist.…”