Potential Role of Glyphosate, Glyphosate-Based Herbicides, and AMPA in Breast Cancer Development: A Review of Human and Human Cell-Based Studies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Inclusion/Exclusion Criteria
2.2. Search Strategy
2.3. Data Extraction
2.4. Outcome Measures
3. Results
3.1. Human Studies
First Author, Year Published | Study Design, Setting, Population, Period | Exposure Assessment | Glyphosate, AMPA, and/or GBH(s) | Method (LOD/LOQ), Corrections for Urine Concentration | Exposure Range/Median | Outcome Measures | Results | Strengths | Weaknesses |
---|---|---|---|---|---|---|---|---|---|
Eaton et al., 2022 [30] | Prospective cohort study; Northern Karst region of Puerto Rico; 205 pregnant women (18–40 years old) from the PROTECT birth cohort; 2012–2017 | Urinary Gly and AMPA levels at 16–20 (Visit 1) and 24–28 (Visit 3) weeks gestation | Gly and AMPA | GC-MS/MS (LOD: 0:20 µg/L), corrected for specific gravity | Median Gly level was 0.50 ng/mL (IQR: 0.29, 0.79); median AMPA level was 0.26 ng/mL (IQR: 0.17, 0.49). | Levels of oxidative stress biomarkers | An IQR increase in urinary AMPA was associated with higher 8-iso-PGF2α metabolite levels in mixed-effects model (6.71% [95% CI 1.51–12.17%]) and at visit 3 specifically (9.03% [95% CI 0.55–18.21%]). An IQR increase in Gly was associated with higher 8-iso-PGF2α levels only at visit 3 (7.23% [95% CI 0.11–14.86%]). | One of few studies to measure human exposure to both Gly and AMPA. First human study to look at association between AMPA and oxidative stress biomarkers. The use of two time points allowed for greater statistical power and determination of susceptibility periods. | Observational study so causality is indeterminable. The 8-iso-PGF2α/PGF2α ratio method used to show differences between oxidative stress and inflammation may not be an accurate representation. |
Franke et al., 2021 [28] | Nested case–control pilot study; Hawaii; 250 women (45–75 years old) from the Multiethnic Cohort; 2001–2006 | Overnight urinary AMPA concentrations | AMPA | LC/HRAM-MS (LLOQ: 0.001 ng/mL), uncorrected and corrected for urinary creatinine | Urinary AMPA levels ranged from <LLOQ to 3698 ng/L. Adjusted geometric mean in cases was 0.087 ng/mg (95% CI 0.055–0.119); in controls was 0.063 ng/mg (95% CI 0.032–0.095). | Incident breast cancer | Urinary AMPA was associated with increased breast cancer risk. Highest vs. lowest quintile—OR 4.49; 95% CI 1.46–13.77 Second vs. lowest quintile—OR 3.03; 95% CI 1.02–9.03 | First prospective study to look at associations between urinary AMPA levels and breast cancer risk (measured by liquid chromatography mass spectrometry). | Observational study so causality is indeterminable. Used only one urine sample, may not be representative of usual AMPA exposure. |
Lesseur et al., 2021 [9] | Pilot study nested within prospective cohort; UCSF, URMC, UMN, UW; 94 pregnant women and their term infants from The Infant Development and the Environment Study (TIDES) pregnancy cohort; August 2010–August 2012 | Urinary Gly and AMPA levels in 2nd trimester mothers | Gly and AMPA | UPLC-MS/MS (Gly LOD: 0.014 ng/mL; LOQ: 0.041 ng/mL), (AMPA LOD: 0.013 ng/mL; LOQ: 0.04 ng/mL), corrected for specific gravity | Urinary Gly levels ranged from 0.01 to 1.9 ng/mL (median: 0.22 ng/mL); AMPA levels ranged from 0.01 to 6 ng/mL (median: 0.14 ng/mL). | Anogenital distance (AGD) in newborns | Maternal urinary Gly was associated with longer (unadjusted) AGD-AC (p = 0.05). Maternal urinary AMPA was associated with longer AGD-AF (p = 0.01). | First study to look at association between maternal urinary Gly/AMPA levels and AGD in human newborns. Multicenter TIDES study included data from various geographic areas of the US. | Observational study so causality is indeterminable. Only one urine sample in 2nd trimester, which does not correspond with masculinization programming window. |
Lucia et al., 2022 [11] | Cross-sectional study; Southern California; 392 postmenopausal women aged 45 to 66 years; 2017–2019 | First morning urinary Gly and AMPA levels on 2 days within a 10-day period | Gly and AMPA | LC-MS/MS (Gly—LOD: 0.014 ng/mL; LOQ: 0.041 ng/mL), (AMPA—LOD: 0.013 ng/mL; LOQ: 0.040 ng/mL), adjusted for urinary creatinine | Median Gly level was 0.12 ng/mL (IQR: 0.06, 0.22) and median AMPA level was 0.06 ng/mL (IQR: 0.02, 0.12). | DNA methylation level at >850,000 CpG sites | Urinary AMPA was associated with increased epigenetic age acceleration (p = 0.04). Urinary Gly was associated with DNA methylation of regions in the promoters of MSH4, KCNA6, ABAT, and NDUFAF2/ERCC8. Urinary AMPA was associated with DNA methylation in the ESR1 promoter. | Largest study on urinary Gly and AMPA levels in a nonagricultural setting. Most recent practices were used to analyze DNA methylation. Two urine samples were used per participant to provide a better representation of usual Gly/AMPA exposure. | Observational study so causality is indeterminable. Also indeterminable if differences in DNA methylation will affect gene expression due to lack of gene expression data. |
3.2. Human Breast Cell Studies
First Author, Year Published | Chemical Used | Cell Line(s) | Treatment | Outcome Measures | Assays/Techniques Used | Main Findings | Proposed Mechanisms |
---|---|---|---|---|---|---|---|
Antoniou et al., 2019 [53] | Gly | MDA-MB-231 | 100 mg/L Gly for 6 days | Global proteome changes; presence of glyoxylate-modified cysteines or glycine to Gly substitutions | RPLC-MS/MS/MS | No global proteome changes; Gly did not substitute for glycine nor did glyoxylation occur in proteins. | Potential Gly toxicity is not through glycine substitution. |
Coppola et al., 2022 [41] | Gly | MCF-7 and MCF-12A | For cell viability, apoptosis/necrosis, and ATP levels: 230 pM, 2.3 nM, 23 nM, 230 nM, or 2.3 µM of Gly For other outcomes: 2.3, 23, or 230 nM of Gly | Cell viability; cell proliferation; apoptosis and necrosis; ATP levels; intracellular ROS levels; estradiol (E2) secretion; gene expression of nuclear receptors (ERα, ERβ, AR, AhR and PgR) | MTS; CyQuant; RealTime-Glo Annexin V Apoptosis and Necrosis; Mitochondrial ToxGlo; ROS Detection; Estradiol ELISA; real-time PCR | MCF-7: Gly reduced cell viability at 2.3 nM, 230 nM, and 2.3 µM and decreased cell proliferation at 230 pM; 230 nM and 2.3 µM decreased intracellular ATP levels; 2.3 nM increased E2 secretion; 2.3 nM downregulated ERα and Erβ, whereas 23 nM upregulated ERα; 23 and 230 nM upregulated AR; 2.3 and 230 nM downregulated PgR; 23 nM upregulated AhR MCF-12A: Gly reduced cell proliferation at 23 nM, 230 nM, and 2.3 µM; 2.3 nM increased apoptosis at 7 and 8 h; all concentrations reduced ROS; 230 nM increased E2 secretion; all concentrations (2.3, 23, and 230 nM) upregulated ERα and ERβ and downregulated PgR; 23 and 230 nM downregulated AR; 2.3 and 23 nM downregulated AhR | Gly may increase mitochondrial membrane permeability, increasing intracellular calcium concentrations and thus reducing ATP synthesis. Gly might alter balance of ERα and ERβ receptors, affecting mammary gland development. Gly increased E2 secretion, which could activate vascular endothelial growth factor transcription, and may lead to mammary gland angiogenesis. |
De Almeida et al., 2018 [45] | Gly, Roundup, and Wipeout | MCF7 and MDA-MB-231 | 0–500 µg/mL of Gly, Roundup (Ro), or Wipeout (Wo) for 24 h | Cell viability and genotoxicity | MTT; comet | Gly (500, 1000 µg/mL), Ro (500, 800 µg/mL), and Wo (500 µg/mL) induced DNA damage in MDA-MB-231. No cytotoxic effects were observed for MCF7 and MDA-MB-231. | Gly, Ro, and Wo might cause toxic effects through non-estrogenic mechanisms. |
Gasnier et al., 2009 [47] | Gly and 4 Roundup (R) formulations | MDA-MB453-kb2 | 2% solutions (and consecutive dilutions up to 10−7) of 1 of 4 R formulations (7.2 g/L, 360 g/L, 400 g/L, 450 g/L of Gly) or Gly alone (360 g/L) for 24 h | Anti-androgenic effects (on androgen receptor) | Luciferase reporter gene | All R formulations and Gly lowered DHT-mediated transcriptional activity. | Gly might bind to a steroid receptor. Adjuvants might form vesicles that intensify Gly effects by enhancing stability, cell penetration, and bioavailability. |
Hokanson et al., 2007 [48] | Gly | MCF-7 | Gly at 0.1, 0.01, 0.001 or 0.0001% dilutions of the 15% stock for 18 h with or without 3 × 10−10 M E2 | Gene expression | DNA microarray; quantitative real-time PCR | At 0.00023% Gly, HIF1 was upregulated (more than twofold) and CXCL12 and EGR1 downregulated (more than 50%). Gly plus estrogen had greater effects than estrogen alone. | Gly and estrogen might synergistically affect gene expression, potentially damaging adult and fetal cells. Altered levels of EGR1, HIF1, and CXCL12 may initiate apoptosis, increase tumor angiogenesis, inactivate tumor suppressor genes, and disrupt immune surveillance. |
Lin and Garry, 2000 [44] | Gly and Roundup | MCF-7 | Different concentrations that included up to 10 µg/mL for 72 h (cell viability) or 7 days (cell proliferation) | Cell viability; cell proliferation; apoptosis | FACS | Gly (0.228–2.28 µg/mL) and Roundup (1–10 µg/mL) induced cell proliferation in CD-treated (lacking estrogen) and non-CD-treated cultures. At cytotoxic concentrations, they induced necrosis (reduced cell viability and loss of cell membrane integrity). | Gly and Roundup might use a non-estrogenic mechanism to induce cell proliferation. Dependence on estrogenic mechanism is unknown for cytotoxic effects. |
Mesnage et al., 2017 [42] | Gly, 4 GBH formulations, POEA (adjuvant) | MCF-7, T47D, T47D-KBluc, and MDA-MB-231 | 10−6 to 107 μg/L of Gly, GBH, or adjuvants for 6 days (ER-mediated cell proliferation), 24 h (ERE-mediated transcription), or 48 h (transcriptomics analysis) | ER-mediated cell proliferation (MCF-7, T47D, MDA-MB-231); transcriptomics analysis (MCF-7); ERE-mediated transcription (T47D-KBluc); molecular dynamic simulations | E-screen-MTT; ERE-luciferase reporter gene; microarray; RNA sequencing | Gly ≥ 10,000 μg/L promoted proliferation of MCF-7 cells and T47D less so; no effect in MDA-MB-231. Gly, but not Roundup nor POEA, increased ERE-mediated expression at ≥1000 μg/L; ER antagonist ICI 182,780 blocked this. Gly altered MCF-7 gene expression but not through ERα activation. Gly binding energy calculation predicts a weak and unstable interaction with ERα‘s active site. | Gly might activate ERα via a ligand-independent mechanism, possibly through the PKA pathway, but only at relatively high concentrations so humans exposed to Gly at typical levels would not be expected to exhibit ER activation. |
Stur et al., 2019 [40] | AMPA and Roundup | MDA-MB-468 and MCF-7 | 0.01 to 10 mM of AMPA or 0.01% to 0.3% of Roundup for 3, 15, 24, and 48 h | Cell viability; gene expression | MTT; microarray | Roundup was more toxic than AMPA. After 48 h of 0.05% Roundup (1.1 mM Gly) exposure, 11 canonical pathways * were deregulated in both cell lines, including a more pronounced downregulation of cyclins and DNA damage repair pathways in MCF-7. 48 h of 10 mM AMPA exposure resulted in less differentially expressed genes, with most associated with metabolism in MDA-MB-468. | Roundup may deregulate ER-independent pathways related to cell cycle, DNA repair, and metabolism, which could change mitochondrial oxygen consumption, cause hypoxia, increase ROS, prevent DNA repair resulting in mutation buildup, and induce cell death. |
Thongprakaisang et al., 2013 [43] | Gly | T47D, T47D-KBluc, and MDA-MB-231 | 10−12 to 10−6 M of Gly or estradiol (positive control) | Cell viability/number; estrogenicity and anti-estrogenicity of Gly (estrogen response element (ERE) transcription activity); ERα and ERβ expression | MTT; ERE-luciferase reporter gene; Western blot | Without E2 in the medium, Gly resulted in a 15–30% proliferation of T47D cells. Gly had no effect on the growth of hormone-independent MDA-MB-231 cells both in the absence/presence of E2. 1 nM of ER antagonist ICI 182780 weakened E2’s and Gly’s proliferative effects, while 10 nM completely inhibited the latter. In T47D-KBluc cells, Gly induced ERE activation 5–13-fold. When co-incubated, Gly suppressed E2-induced ERE activation. In T47D cells, Gly increased ERα and ERβ levels in a dose-dependent manner after 6 h exposure, but only ERα levels increased at the highest Gly concentration (10−7 M) after 24 h exposure. | Gly’s proliferative and stimulatory effects may occur via ER signaling since an ER antagonist inhibited this proliferation. At the ligand site of ERs, hydrophilic Gly may bind in a polar pocket. When the endogenous agonist E2 is present, Gly acts as an antagonist. Gly acts like a weak xenoestrogen that quickly activated ERβ while ERα activation was slower and longer. |
Zhang et al., 2020 [46] | Gly | MELN | 500, 1000, and 1500 nM Gly | Aromatase activity; estrogenic activity; molecular dynamics | ELISA; luciferase reporter gene | Gly inhibited up to 30% of aromatase activity in a dose-dependent manner but did not interfere in the binding between E2 and ERα nor increase estrogen-responsive transcription. | Gly inhibits aromatase by potentially binding to an allosteric site. |
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Gly | glyphosate |
GBH | glyphosate-based herbicide |
AMPA | aminomethylphosphonic acid |
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Schluter, H.M.; Bariami, H.; Park, H.L. Potential Role of Glyphosate, Glyphosate-Based Herbicides, and AMPA in Breast Cancer Development: A Review of Human and Human Cell-Based Studies. Int. J. Environ. Res. Public Health 2024, 21, 1087. https://doi.org/10.3390/ijerph21081087
Schluter HM, Bariami H, Park HL. Potential Role of Glyphosate, Glyphosate-Based Herbicides, and AMPA in Breast Cancer Development: A Review of Human and Human Cell-Based Studies. International Journal of Environmental Research and Public Health. 2024; 21(8):1087. https://doi.org/10.3390/ijerph21081087
Chicago/Turabian StyleSchluter, Hannah M., Hajar Bariami, and Hannah Lui Park. 2024. "Potential Role of Glyphosate, Glyphosate-Based Herbicides, and AMPA in Breast Cancer Development: A Review of Human and Human Cell-Based Studies" International Journal of Environmental Research and Public Health 21, no. 8: 1087. https://doi.org/10.3390/ijerph21081087