Bibliography Tag: glyphosate and epigenetic impacts

Lorenz et al., 2019

Lorenz, V., Milesi, M. M., Schimpf, M. G., Luque, E. H., & Varayoud, J.; “Epigenetic disruption of estrogen receptor alpha is induced by a glyphosate-based herbicide in the preimplantation uterus of rats;” Molecular and Cellular Endocrinology, 2019, 480, 133-141; DOI: 10.1016/j.mce.2018.10.022.


Previously, we have shown that perinatal exposure to a glyphosate-based herbicide (GBH) induces implantation failures in rats. Estrogen receptor alpha (ERalpha) is critical for successful implantation. ERalpha transcription is under the control of five promoters (E1, OT, O, ON, and OS), which yield different transcripts. Here, we studied whether perinatal exposure to a GBH alters uterine ERalpha gene expression and prompts epigenetic modifications in its regulatory regions during the preimplantation period. Pregnant rats (F0) were orally treated with 350mg glyphosate/kg bw/day through food from gestational day (GD) 9 until weaning. F1 females were bred, and uterine samples were collected on GD5 (preimplantation period). ERalpha mRNA levels and its transcript variants were evaluated by RT-qPCR. Enzyme-specific restriction sites and predicted transcription factors were searched in silico in the ERalpha promoter regions to assess the methylation status using the methylation-sensitive restriction enzymes-PCR technique. Post-translational modifications of histones were studied by the chromatin immunoprecipitation assay. GBH upregulated the expression of total ERalpha mRNA by increasing the abundance of the ERalpha-O transcript variant. In addition, different epigenetic changes were detected in the O promoter. A decrease in DNA methylation was observed in one of the three sites evaluated in the O promoter. Moreover, histone H4 acetylation and histone H3 lysine 9 trimethylation (H3K9me3) were enriched in the O promoter in GBH-exposed rats, whereas H3K27me3 was decreased. All these alterations could account for the increase in ERalpha gene expression. Our findings show that perinatal exposure to a GBH causes long-term epigenetic disruption of the uterine ERalpha gene, which could be associated with the GBH-induced implantation failures. FULL TEXT


Cai et al., 2020

Cai, Wenyan, Zhang, Feng, Zhong, Lixin, Chen, Dongya, Guo, Haoran, Zhang, Hengdong, Zhu, Baoli, & Liu, Xin; “Correlation between CYP1A1 polymorphisms and susceptibility to glyphosate-induced reduction of serum cholinesterase: A case-control study of a Chinese population;” Pesticide Biochemistry and Physiology, 2020, 162, 23-28; DOI: 10.1016/j.pestbp.2019.07.006.


Glyphosate (GLP) is one of the most common herbicides worldwide. The serum cholinesterase (ChE) may be affected when exposed to glyphosate. Reduction of serum ChE by herbicides is probably related to cytochrome P450 (CYP450) family polymorphisms. We suspect that the abnormal ChE caused by GLP could be correlated with the CYP family members. To determine whether CYP1B1 (rs1056827 and rs1056836) and CYP1A1 (rs1048943) gene polymorphisms and individual susceptibility to GLP-induced ChE abnormalities were interrelated in the Chinese Han population, we performed this genetic association study on a total of 230 workers previously exposed to GLP, including 115 cases with reduced serum ChE and 115 controls with normal serum ChE. Two even groups of cases and controls were enrolled. The CYP1A1 and CYP1B1 polymorphisms in both groups were genotyped using TaqMan. Subjects with the CYP1A1 rs619586 genotypes showed an increased risk of GLP-induced reduction of serum ChE, which was more evident in the following subgroups: female,>35 years old, history of GLP exposure time<10 years and>10 years, nonsmoker and nondrinker. The results show that CYP1A1 rs619586 was significantly associated with the GLP-induced reduction in serum ChE and could be a biomarker of susceptibility for Chinese GLP exposed workers. Because of a large number of people exposed to glyphosate, this study has a significance in protecting their health.  FULL TEXT

Duforestel et al., 2019

Duforestel, Manon, Nadaradjane, Arulraj, Bougras-Cartron, Gwenola, Briand, Joséphine, Olivier, Christophe, Frenel, Jean-Sébastien, Vallette, François M., Lelièvre, Sophie A., & Cartron, Pierre-François; “Glyphosate Primes Mammary Cells for Tumorigenesis by Reprogramming the Epigenome in a TET3-Dependent Manner;” Frontiers in Genetics, 2019, 10; DOI: 10.3389/fgene.2019.00885.


The acknowledgment that pollutants might influence the epigenome raises serious concerns regarding their long-term impact on the development of chronic diseases. The herbicide glyphosate has been scrutinized for an impact on cancer incidence, but reports demonstrate the difficulty of linking estimates of exposure and response analysis. An approach to better apprehend a potential risk impact for cancer is to follow a synergistic approach, as cancer rarely occurs in response to one risk factor. The known influence of glyphosate on estrogen-regulated pathway makes it a logical target of investigation in breast cancer research. We have used nonneoplastic MCF10A cells in a repeated glyphosate exposure pattern over 21 days. Glyphosate triggered a significant reduction in DNA methylation, as shown by the level of 5-methylcytosine DNA; however, in contrast to strong demethylating agent and cancer promoter UP peptide, glyphosate-treated cells did not lead to tumor development. Whereas UP acts through a DNMT1/PCNA/UHRF1 pathway, glyphosate triggered increased activity of ten-eleven translocation (TET)3. Combining glyphosate with enhanced expression of microRNA (miR) 182-5p associated with breast cancer induced tumor development in 50% of mice. Culture of primary cells from resected tumors revealed a luminal B (ER+/PR-/HER2-) phenotype in response to glyphosate-miR182-5p exposure with sensitivity to tamoxifen and invasive and migratory potentials. Tumor development could be prevented either by specifically inhibiting miR 182-5p or by treating glyphosate-miR 182-5p-cells with dimethyloxallyl glycine, an inhibitor of TET pathway. Looking for potential epigenetic marks of TET-mediated gene regulation under glyphosate exposure, we identified MTRNR2L2 and DUX4 genes, the hypomethylation of which was sustained even after stopping glyphosate exposure for 6 weeks. Our findings reveal that low pressure but sustained DNA hypomethylation occurring via the TET pathway primes cells for oncogenic response in the presence of another potential risk factor. These results warrant further investigation of glyphosate-mediated breast cancer risk. FULL TEXT

Ren et al., 2019

Ren, X., Dai, P., Perveen, A., Tang, Q., Zhao, L., Jia, X., Li, Y., & Li, C.; “Effects of chronic glyphosate exposure to pregnant mice on hepatic lipid metabolism in offspring;” Environmental Pollution, 2019, 254(Pt A), 112906; DOI: 10.1016/j.envpol.2019.07.074.


Glyphosate is the active ingredient in Roundup, one of the most popular herbicides in the world, and its toxicity has caused increasing concerns. The present study aims to investigate the toxic effects of prenatal exposure to pure glyphosate or Roundup on lipid metabolism in offspring. During gestational days (GDs), ICR mice (from Institute of Cancer Research) were given distilled water, 0.5% glyphosate solution (w/v, 0.5 g/100 ml) or 0.5%-glyphosate Roundup solution orally. The livers and serum samples of the offspring were collected on gestational day 19 (GD19), postnatal day 7 (PND7) and PND21. The results showed a significant decrease in the body weight and obvious hepatic steatosis with excessive lipid droplet formation in offspring. Moreover, the concentrations of lipids such as triglycerides (TGs), total cholesterol (T-CHO), and low-density lipoprotein cholesterols (LDL-C) increased to a significant extent in both the serum and livers. Furthermore, there were significant differences in the expression levels of the genes SREBP1C, SREBP2, Fasn, Hmgcr, Hmgcs and PPARa, which are related to lipid biosynthesis or catabolism in the liver. These results demonstrate that chronic prenatal exposure to glyphosate can result in lipid metabolism disruption in the offspring of mice, as glyphosate exerts a negative influence on the expression of lipogenesis genes. FULL TEXT

International Federation of Gynecology and Obstetrics, 2019

International Federation of Gynecology and Obstetrics; “Removal of glyphosate from global usage: A Statement by the FIGO Reproductive and Developmental Environmental Health Committee,” Available at:, Date posted: 07/31/2019, Date accessed: 8/6/2019.


The International Federation of Gynecology and Obstetrics (FIGO), a professional group that advocates for OB/GYN groups around the world.   They work with the World Health Organization and United Nations to consult on women and children’s health and wellness issues, recommends that all glyphosate use be phased out due to “the recognised impact on the health and well-being of women and newborn children worldwide.”

FIGO points out the conflicting opinions about the safety of glyphosate, as evidenced by the EPA and IARC’s diametric designations as “non-carcinogenic” and “probably carcinogenic,” respectively.  But, they argue, given that the most recent meta-analysis from February 2019 found “a compelling link between non-Hodgkins lymphoma and glyphosate,” and rodent studies have demonstrated the potential for transgenerational epigenetic changes,  FIGO urges governments to apply the precautionary principal and prioritize “establishing safety, now and across generations, prior to exposure to chemical products.” They conclude: “We recommend that glyphosate exposure to populations should end with a full global phase out.” FULL TEXT

Teleken et al., 2019

Teleken, J. L., Gomes, E. C. Z., Marmentini, C., Moi, M. B., Ribeiro, R. A., Balbo, S. L., Amorim, E. M. P., & Bonfleur, M. L.; “Glyphosate-based herbicide exposure during pregnancy and lactation malprograms the male reproductive morphofunction in F1 offspring;” Journal of Developmental Origins of Health and Disease, 2019, 1-8; DOI: 10.1017/s2040174419000382.


One of the most consumed pesticides in the world is glyphosate, the active ingredient in the herbicide ROUNDUP(R). Studies demonstrate that glyphosate can act as an endocrine disruptor and that exposure to this substance at critical periods in the developmental period may program the fetus to induce reproductive damage in adulthood. Our hypothesis is that maternal exposure to glyphosate during pregnancy and lactation in mice will affect the development of male reproductive organs, impairing male fertility during adult life. Female mice consumed 0.5% glyphosate-ROUNDUP(R) in their drinking water [glyphosate-based herbicide (GBH) group] or filtered water [control (CTRL) group] from the fourth day of pregnancy until the end of the lactation period. Male F1 offspring were designated, according to their mother’s treatment, as CTRL-F1 and GBH-F1. Female mice that drank glyphosate displayed reduced body weight (BW) gain during gestation, but no alterations in litter size. Although GBH male F1 offspring did not exhibit modifications in BW, they demonstrated delayed testicular descent. Furthermore, at PND150, GBH-F1 mice presented a lower number of spermatozoa in the cauda epididymis and reduced epithelial height of the seminiferous epithelium. Notably, intratesticular testosterone concentrations were enhanced in GBH-F1 mice; we show that it is an effect associated with increased plasma and pituitary concentrations of luteinizing hormone. Therefore, data indicate that maternal exposure to glyphosate-ROUNDUP(R) during pregnancy and lactation may lead to decreased spermatogenesis and disruptions in hypothalamus-pituitary-testicular axis regulation in F1 offspring.

Kubsad et al., 2019

Kubsad, D., Nilsson, E. E., King, S. E., Sadler-Riggleman, I., Beck, D., & Skinner, M. K.; “Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology;” Scientific Reports, 2019, 9(1), 6372; DOI: 10.1038/s41598-019-42860-0.


Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations. FULL TEXT

Milesi et al., 2018

Milesi, Maria M, Lorenz, Virginia, Pacini, Guillermina, Repetti, Maria R, Demonte, Luisina D, Varayoud, Jorgelina, & Luque, Enrique H, “Perinatal exposure to a glyphosate-based herbicide impairs female reproductive outcomes and induces second-generation adverse effects in Wistar rats,” Archives of Toxicology, 2018, 92(8), 2629-2643. DOI: 10.1007/s00204-018-2236-6.


Glyphosate-based herbicides (GBHs) are the most globally used herbicides raising the risk of environmental exposition. Here, we investigated whether perinatal exposure to low doses of a GBH alters the female reproductive performance, and/or induced second-generation effects related to congenital anomalies or growth alterations. Pregnant rats (F0) received a GBH through food, in a dose of 2 mg (GBH-LD: GBH-low dose group) or 200 mg (GBH-HD: GBH-high dose group) of glyphosate/kg bw/day from gestational day (GD) 9 until weaning. Body weight gain and vaginal canal-opening of F1 females were recorded. Sexually mature F1 females were mated to evaluate their reproductive performance by assessing the pregnancy rate, and on GD19, the number of corpora lutea, the implantation sites (IS) and resorption sites. To analyze second-generation effects on F2 offspring, we analyzed the fetal morphology on GD19, and assessed the fetal length and weight, and the placental weight. GBH exposure neither altered the body weight gain of F1 females, nor vaginal opening onset. Although all GBH-exposed F1 rats became pregnant, a lower number of IS was detected. F2 offspring from both GBH groups showed delayed growth, evidenced by lower fetal weight and length, associated with a higher incidence of small for gestational age fetuses. In addition, higher placental weight and placental index were found in F2 offspring from GBH-HD dams. Surprisingly, structural congenital anomalies (conjoined fetuses and abnormally developed limbs) were detected in the F2 offspring from GBH-HD group. In conclusion, perinatal exposure to low doses of a GBH impaired female reproductive performance and induced fetal growth retardation and structural congenital anomalies in F2 offspring. FULL TEXT

Landrigan and Belpoggi, 2018

Landrigan, P. J., and Belpoggi, F.,”The need for independent research on the health effects of glyphosate-based herbicides,” Environmental Health, 17(1), 51, 2018, doi:10.1186/s12940-018-0392-z.


BACKGROUND: Glyphosate, formulated as Roundup, is the world’s most widely used herbicide. Glyphosate is used extensively on genetically modified (GM) food crops designed to tolerate the herbicide, and global use is increasing rapidly. Two recent reviews of glyphosate’s health hazards report conflicting results. An independent review by the International Agency for Research on Cancer (IARC) found that glyphosate is a “probable human carcinogen”. A review by the European Food Safety Agency (EFSA) found no evidence of carcinogenic hazard. These differing findings have produced regulatory uncertainty.

REGULATORY ACTIONS: Reflecting this regulatory uncertainty, the European Commission on November 27 2017, extended authorization for glyphosate for another 5 years, while the European Parliament opposed this decision and issued a call that pesticide approvals be based on peer-reviewed studies by independent scientists rather than on the current system that relies on proprietary industry studies.

RAMAZZINI INSTITUTE RESPONSE: The Ramazzini Institute has initiated a pilot study of glyphosate’s health hazards that will be followed by an integrated experimental research project. This evaluation will be independent of industry support and entirely sponsored by worldwide crowdfunding. The aim of the Ramazzini Institute project is to explore comprehensively the effects of exposures to glyphosate-based herbicides at current real-world levels on several toxicological endpoints, including carcinogenicity, long-term toxicity, neurotoxicity, endocrine disrupting effects, prenatal developmental toxicity, the microbiome and multi-generational effects. FULL TEXT

Soloneski et al., 2016

Sonia Soloneski, Celeste Ruiz de Arcaute, and Marcelo L. Larramendy, “Genotoxic effect of a binary mixture of dicamba and glyphosate-based commercial herbicide formulations on Rhinella arenarum (Hensel, 1867) (Anura, Bufonidae) late-stage larvae,” Environmental Science and Pollution Research, 2016, 23:17, DOI: 10.1007/S11356-016-6992-7.


The acute toxicity of two herbicide formulations, namely, the 57.71 % dicamba (DIC)-based Banvel(®) and the 48 % glyphosate (GLY)-based Credit(®), alone as well as the binary mixture of these herbicides was evaluated on late-stage Rhinella arenarum larvae (stage 36) exposed under laboratory conditions. Mortality was used as an endpoint for determining acute lethal effects, whereas the single-cell gel electrophoresis (SCGE) assay was employed as genotoxic endpoint to study sublethal effects. Lethality studies revealed LC5096 h values of 358.44 and 78.18 mg L(-1) DIC and GLY for Banvel(®) and Credit(®), respectively. SCGE assay revealed, after exposure for 96 h to either 5 and 10 % of the Banvel(®) LC5096 h concentration or 5 and 10 % of the Credit(®) LC5096 h concentration, an equal significant increase of the genetic damage index (GDI) regardless of the concentration of the herbicide assayed. The binary mixtures of 5 % Banvel(®) plus 5 % Credit(®) LC5096 h concentrations and 10 % Banvel(®) plus 10 % Credit(®) LC5096 h concentrations induced equivalent significant increases in the GDI in regard to GDI values from late-stage larvae exposed only to Banvel(®) or Credit(®). This study represents the first experimental evidence of acute lethal and sublethal effects exerted by DIC on the species, as well as the induction of primary DNA breaks by this herbicide in amphibians. Finally, a synergistic effect of the mixture of GLY and DIC on the induction of primary DNA breaks on circulating blood cells of R. arenarum late-stage larvae could be demonstrated.  FULL TEXT