Pesticide Exposure Modifies DNA Methylation of Coding Region of <i>WRAP53α</i>, an Antisense Sequence of <i>p53,</i> in a Mexican Population

Paredes-Céspedes, Diana M; Herrera-Moreno, José Francisco; Bernal-Hernández, Yael Yvette; Medina-Díaz, Irma Martha; Salazar, Ana María; Ostrosky‐Wegman, Patricia; Barrón-Vivanco, Briscia Socorro; Rojas-García, Aurora Elizabeth

doi:10.1021/acs.chemrestox.9b00153

Cited by 12 publications

(5 citation statements)

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“…For instance, the study of DNA methylation levels in Long Interspersed Nucleotide Element 1 was found to be a surrogate for changes in global DNA methylation levels caused by exposure to pesticides in farmers ( Alexander et al , 2017 ). Epigenetic biomarkers can also be more specific as in the case of the methylation levels of WRAP53 , which is antisense to TP53 , was found to be associated to pesticide exposure in a Mexican population ( Paredes-Céspedes et al , 2019 ). Epigenetic signatures can also be compound-specific such as for smoking, and even inform on smoking habits and time since smoking cessation ( Kaur et al , 2019 ).…”

Section: Discussionmentioning

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: Discussionmentioning

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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show abstract

“…For instance, the study of DNA methylation levels in Long Interspersed Nucleotide Element 1 (LINE-1) was found to be a surrogate for changes in global DNA methylation levels caused by exposure to pesticides in farmers (Alexander et al 2017). Epigenetic biomarkers can also be more specific as in the case of the methylation levels of WRAP53 , which is antisense to TP53 , was found to be associated to pesticide exposure in a Mexican population (Paredes-Céspedes et al 2019). Epigenetic signatures can also be compound-specific such as for smoking, and even inform on smoking habits and time since smoking cessation (Kaur et al 2019).…”

Section: Discussionmentioning

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

Mandrioli³

et al. 2021

Preprint

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Background. Health effects from exposure to glyphosate-based herbicides is an intense matter of debate. Toxicity including genotoxicity of glyphosate alone has been repeatedly tested over the last 40 years. Contrastingly, few studies have conducted comparative investigations between glyphosate and its commercial herbicide formulations, such as Roundup. We thus performed the first in-depth comparative toxicogenomic evaluation of glyphosate and a typical European Union Roundup formulation by determining alterations in transcriptome and epigenome profiles. Methods. Glyphosate and the European Union reference commercial formulation Roundup MON 52276 (both at 0.5, 50, 175 mg/kg bw/day glyphosate equivalent concentration) were administered to rats in a subchronic 90-day toxicity study. Standard clinical biochemistry and kidney and liver histopathology was performed. In addition, transcriptomics and DNA methylation profiling of liver and selective gene expression analysis of kidneys was conducted. Furthermore, a panel of six mouse embryonic reporter stem cell lines validated to identify carcinogenic outcomes (DNA damage, oxidative stress, and protein misfolding) were used to provide insight into the mechanisms underlying the toxicity of glyphosate and 3 Roundup formulations. Results. Histopathology and serum biochemistry analysis showed that MON 52276 but not glyphosate treatment was associated with a statistically significant increase in hepatic steatosis and necrosis. Similar lesions were also present in the liver of glyphosate-treated groups but not in the control group. MON 52276 altered the expression of 96 genes in liver, with the most affected biological functions being TP53 activation by DNA damage and oxidative stress as well as the regulation of circadian rhythms. The most affected genes in liver also had their expression similarly altered in kidneys. DNA methylation profiling of liver revealed 5,727 and 4,496 differentially methylated CpG sites between the control group and the group of rats exposed to glyphosate and MON 52276, respectively. Direct DNA damage measurement by apurinic/apyrimidinic lesion formation in liver was increased with glyphosate exposure. Mechanistic evaluations showed that two Roundup herbicides but not glyphosate activated oxidative stress and misfolded protein responses. Conclusions. Taken together, the results of our study show that Roundup herbicides are more toxic than glyphosate, activating mechanisms involved in cellular carcinogenesis and causing gene expression changes reflecting DNA damage. This further highlights the power of high-throughput omics methods to detect metabolic changes, which would be missed by relying solely on conventional biochemical and histopathological measurements. Our study paves the way for future investigations by reporting a panel of gene expression changes and DNA methylation sites, which can serve as biomarkers and potential predictors of negative health outcomes resulting from exposure to glyphosate-based herbicides.

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“…OCs were found to be significantly higher in subjects with CDH1 methylation. Exposure to OPs and pyrethroids results in WRAP53α hypermethylation [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic processes involved in response to pesticide exposure in human populations: a systematic review and meta-analysis

Rohr,

Karen,

Francisco

et al. 2024

Environmental Epigenetics

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In recent decades, the use of pesticides in agriculture has increased dramatically. This has resulted in these substances being widely dispersed in the environment, contaminating both exposed workers, communities living near agricultural areas, and via contaminated foodstuffs. In addition to acute poisoning, chronic exposure to pesticides can lead to molecular changes that are becoming better understood. Therefore, the aim of this study was to assess, through a systematic review of the literature, what epigenetic alterations are associated with pesticide exposure. We performed a systematic review and meta-analysis including case-control, cohort, and cross-sectional observational epidemiological studies to verify the epigenetic changes, such as DNA methylation, histone modification, and differential microRNA expression, in humans that had been exposed to any type of pesticide. Articles published between the years 2005 to 2020 were collected. Two different reviewers performed a blind selection of the studies using the Rayyan QCRI software. Post-completion, the data of selected articles were extracted and analyzed. Most of the 28 articles included evaluated global DNA methylation levels, and the most commonly reported epigenetic modification in response to pesticide exposure was global DNA hypomethylation. The meta-analysis revealed a significant negative correlation between Alu methylation levels and β-HCH, pp’-DDT, and pp’-DDE levels. In addition, some specific genes were reported to be hypermethylated in promoter regions, such as CDKN2AIGF2, WRAP53α, and CDH1, while CDKN2B and H19 were hypomethylated due to pesticide exposure. The expression of microRNAs was also altered in response to pesticides, as miR-223, -518d-3p, -597, -517b, and 133b that are associated with many human diseases. Therefore, this study provides evidence that pesticide exposure could lead to epigenetic modifications, possibly altering global and gene-specific methylation levels, epigenome-wide methylation, and micro-RNA differential expression.

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Pesticide Exposure Modifies DNA Methylation of Coding Region of WRAP53α, an Antisense Sequence of p53, in a Mexican Population

Cited by 12 publications

References 59 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

Comparative toxicogenomics of glyphosate and Roundup herbicides by mammalian stem cell-based genotoxicity assays and molecular profiling in Sprague-Dawley rats

Epigenetic processes involved in response to pesticide exposure in human populations: a systematic review and meta-analysis

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