Genotoxicity evaluation of 2,4-D, dicamba and glyphosate alone or in combination with cell reporter assays for DNA damage, oxidative stress and unfolded protein response

Mesnage, Robin; Brandsma, Inger; Moelijker, Nynke; Zhang, Gaonan; Antoniou, Michael

doi:10.1016/j.fct.2021.112601

Cited by 24 publications

(14 citation statements)

References 56 publications

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“…Note: the ToxTracker assay data presented in this figure were obtained from one series of experiments testing numerous herbicides all run in parallel. Additional results from this series of experiments are presented in a separate publication ( Mesnage et al, 2021c ). Hence, the same glyphosate data forms the comparative control for both sets of results shown in Figure 2 of our previous Food and Chemical Toxicology publication and Figure 2 of this Toxicological Sciences article.…”

Section: Resultsmentioning

confidence: 99%

Comparative Toxicogenomics of Glyphosate and Roundup Herbicides by Mammalian Stem Cell-Based Genotoxicity Assays and Molecular Profiling in Sprague-Dawley Rats

Mesnage

Ibragim

Mandrioli

et al. 2021

Toxicological Sciences

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Whether glyphosate-based herbicides (GBHs) are more potent than glyphosate alone at activating cellular mechanisms, which drive carcinogenesis remains controversial. As GBHs are more cytotoxic that glyphosate, we reasoned they may also be more capable of activating carcinogenic pathways. We tested this hypothesis by comparing the effects of glyphosate with Roundup GBHs both in vitro and in vivo. First, glyphosate was compared with representative GBHs namely MON 52276 (EU), MON 76473 (UK) and MON 76207 (USA) using the mammalian stem cell-based ToxTracker system. Here, MON 52276 and MON 76473, but not glyphosate and MON 76207, activated oxidative stress and unfolded protein responses. Second, molecular profiling of liver was performed in female Sprague-Dawley rats exposed to glyphosate or MON 52276 (both at 0.5, 50, 175 mg/kg bw/day glyphosate) for 90 days. MON 52276 but not glyphosate increased hepatic steatosis and necrosis. MON 52276 and glyphosate altered the expression of genes in liver reflecting TP53 activation by DNA damage and circadian rhythm regulation. Genes most affected in liver were similarly altered in kidneys. Small RNA profiling in liver showed decreased amounts of miR-22 and miR-17 from MON 52276 ingestion. Glyphosate decreased mir-30 while miR-10 levels were increased. DNA methylation profiling of liver revealed 5,727 and 4,496 differentially methylated CpG sites between the control and glyphosate and MON 52276 exposed animals respectively. Apurinic/apyrimidinic DNA damage formation in liver was increased with glyphosate exposure. Altogether, our results show that Roundup formulations cause more biological changes linked with carcinogenesis than glyphosate.

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Section: Resultsmentioning

confidence: 99%

Comparative Toxicogenomics of Glyphosate and Roundup Herbicides by Mammalian Stem Cell-Based Genotoxicity Assays and Molecular Profiling in Sprague-Dawley Rats

Mesnage

Ibragim

Mandrioli

et al. 2021

Toxicological Sciences

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“…Finally, the ToxTracker assay, a mammalian stem cell-based assay, can be used to evaluate a chemical candidate’s genotoxicity through measurement of the ability to inhibit DNA replication, activate the unfolded protein response, induce cellular stress through P53-dependent or oxidative stress . The ToxTracker assay has been used for the assessment of agrochemicals and can be adapted to screen candidates in early stage A.S. candidate selection concurrently with other in vitro screening methods like the “Ames” (OECD 471) and in vitro micronucleus assays (OECD 487). There is also the option for the ToxTracker aneugen clastogen evaluation (ACE) assay which allows for the determination of genotoxicity MoA …”

Section: Genotoxicitymentioning

confidence: 99%

From Pipeline to Plant Protection Products: Using New Approach Methodologies (NAMs) in Agrochemical Safety Assessment

Henriquez,

Badwaik,

Bianchi

et al. 2024

J. Agric. Food Chem.

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The human population will be approximately 9.7 billion by 2050, and food security has been identified as one of the key issues facing the global population. Agrochemicals are an important tool available to farmers that enable high crop yields and continued access to healthy foods, but the average new agrochemical active ingredient takes more than ten years, 350 million dollars, and 20,000 animals to develop and register. The time, monetary, and animal costs incentivize the use of New Approach Methodologies (NAMs) in early-stage screening to prioritize chemical candidates. This review outlines NAMs that are currently available or can be adapted for use in early-stage screening agrochemical programs. It covers new in vitro screens that are on the horizon in key areas of regulatory concern. Overall, early-stage screening with NAMs enables the prioritization of development for agrochemicals without human and environmental health concerns through a more directed, agile, and iterative development program before animal-based regulatory testing is even considered.

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“…Much research hasproven the adverse effects of chemical herbicides on non-human beings, such as mice, zebrafish, and livestock. Herbicides, including glyphosate, 2,4-Dicholorophenoxy acetic acid (2,4-D), and dicamba, may damage the immune system and cause symptoms of IBD, like diarrhea, bowel inflammation, and maldigestion (77). Especially, people with weakened immune systems are more susceptible to chemical herbicide-related intestinal inflammation (82).…”

Section: Chemical Herbicidesmentioning

confidence: 99%

“…But another explanation is that decreasing acylcarnitine levels can also produce toxicity, suggesting the perturbations in the fatty acid beta-oxidation pathway (92). Dicamba, 2,4-D, and glyphosate alone or in combination, account for genotoxicity in patients with gastrointestinal disorders, including DNA damage, oxidative stress, and unfolded protein response, which contributes to the development of IBD (77). Another herbicide, Propyzamide, can boost gut inflammation by upregulating NF-κB-driven C/EBPβ pro-inflammatory gene and inhibiting AHR signaling pathways, and further, inducing the development of IBD (78).…”

Section: Chemical Herbicidesmentioning

confidence: 99%

Adverse health effects of emerging contaminants on inflammatory bowel disease

Chen

Wang

Mao

et al. 2023

Front. Public Health

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Inflammatory bowel disease (IBD) is becoming increasingly prevalent with the improvement of people's living standards in recent years, especially in urban areas. The emerging environmental contaminant is a newly-proposed concept in the progress of industrialization and modernization, referring to synthetic chemicals that were not noticed or researched before, which may lead to many chronic diseases, including IBD. The emerging contaminants mainly include microplastics, endocrine-disrupting chemicals, chemical herbicides, heavy metals, and persisting organic pollutants. In this review, we summarize the adverse health effect of these emerging contaminants on humans and their relationships with IBD. Therefore, we can better understand the impact of these new emerging contaminants on IBD, minimize their exposures, and lower the future incidence of IBD.

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Genotoxicity evaluation of 2,4-D, dicamba and glyphosate alone or in combination with cell reporter assays for DNA damage, oxidative stress and unfolded protein response

Cited by 24 publications

References 56 publications

Comparative Toxicogenomics of Glyphosate and Roundup Herbicides by Mammalian Stem Cell-Based Genotoxicity Assays and Molecular Profiling in Sprague-Dawley Rats

Comparative Toxicogenomics of Glyphosate and Roundup Herbicides by Mammalian Stem Cell-Based Genotoxicity Assays and Molecular Profiling in Sprague-Dawley Rats

From Pipeline to Plant Protection Products: Using New Approach Methodologies (NAMs) in Agrochemical Safety Assessment

Adverse health effects of emerging contaminants on inflammatory bowel disease

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