Bibliography Tag: 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


Rattan and Flaws, 2019

Rattan, S., & Flaws, J. A.; “The epigenetic impacts of endocrine disruptors on female reproduction across generationsdagger;” Biology of Reproduction, 2019, 101(3), 635-644; DOI: 10.1093/biolre/ioz081.


Humans and animals are repeatedly exposed to endocrine disruptors, many of which are ubiquitous in the environment. Endocrine disruptors interfere with hormone action; thus, causing non-monotonic dose responses that are atypical of standard toxicant exposures. The female reproductive system is particularly susceptible to the effects of endocrine disruptors. Likewise, exposures to endocrine disruptors during developmental periods are particularly concerning because programming during development can be adversely impacted by hormone level changes. Subsequently, developing reproductive tissues can be predisposed to diseases in adulthood and these diseases can be passed down to future generations. The mechanisms of action by which endocrine disruptors cause disease transmission to future generations are thought to include epigenetic modifications. This review highlights the effects of endocrine disruptors on the female reproductive system, with an emphasis on the multi- and transgenerational epigenetic effects of these exposures. FULL TEXT

Alexander et al., 2017

Alexander, M., Koutros, S., Bonner, M. R., Barry, K. H., Alavanja, M. C. R., Andreotti, G., Byun, H. M., Chen, L., Beane Freeman, L. E., Hofmann, J. N., Kamel, F., Moore, L. E., Baccarelli, A., & Rusiecki, J.; “Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study;” Environ Epigenet, 2017, 3(2), dvx005; DOI: 10.1093/eep/dvx005.


Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use x days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics. FULL TEXT

Wang et al., 2020

Wang, G. H., Berdy, B. M., Velasquez, O., Jovanovic, N., Alkhalifa, S., Minbiole, K. P. C., & Brucker, R. M.; “Changes in Microbiome Confer Multigenerational Host Resistance after Sub-toxic Pesticide Exposure;” Cell Host & Microbe, 2020; DOI: 10.1016/j.chom.2020.01.009.


The gut is a first point of contact with ingested xenobiotics, where chemicals are metabolized directly by the host or microbiota. Atrazine is a widely used pesticide, but the role of the microbiome metabolism of this xenobiotic and the impact on host responses is unclear. We exposed successive generations of the wasp Nasonia vitripennis to subtoxic levels of atrazine and observed changes in the structure and function of the gut microbiome that conveyed atrazine resistance. This microbiome-mediated resistance was maternally inherited and increased over successive generations, while also heightening the rate of host genome selection. The rare gut bacteria Serratia marcescens and Pseudomonas protegens contributed to atrazine metabolism. Both of these bacteria contain genes that are linked to atrazine degradation and were sufficient to confer resistance in experimental wasp populations. Thus, pesticide exposure causes functional, inherited changes in the microbiome that should be considered when assessing xenobiotic exposure and as potential countermeasures to toxicity. FULL TEXT

Chung and Herceg, 2020

Chung, F. F., & Herceg, Z.; “The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome;” Environmental Health Perspectives, 2020, 128(1), 15001; DOI: 10.1289/EHP6104.


BACKGROUND: It has been estimated that a substantial portion of chronic and noncommunicable diseases can be caused or exacerbated by exposure to environmental chemicals. Multiple lines of evidence indicate that early life exposure to environmental chemicals at relatively low concentrations could have lasting effects on individual and population health. Although the potential adverse effects of environmental chemicals are known to the scientific community, regulatory agencies, and the public, little is known about the mechanistic basis by which these chemicals can induce long-term or transgenerational effects. To address this question, epigenetic mechanisms have emerged as the potential link between genetic and environmental factors of health and disease.

OBJECTIVES: We present an overview of epigenetic regulation and a summary of reported evidence of environmental toxicants as epigenetic disruptors. We also discuss the advantages and challenges of using epigenetic biomarkers as an indicator of toxicant exposure, using measures that can be taken to improve risk assessment, and our perspectives on the future role of epigenetics in toxicology.

DISCUSSION: Until recently, efforts to apply epigenomic data in toxicology and risk assessment were restricted by an incomplete understanding of epigenomic variability across tissue types and populations. This is poised to change with the development of new tools and concerted efforts by researchers across disciplines that have led to a better understanding of epigenetic mechanisms and comprehensive maps of epigenomic variation. With the foundations now in place, we foresee that unprecedented advancements will take place in the field in the coming years.


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

McEwen et al., 2019

McEwen, L. M., O’Donnell, K. J., McGill, M. G., Edgar, R. D., Jones, M. J., MacIsaac, J. L., Lin, D. T. S., Ramadori, K., Morin, A., Gladish, N., Garg, E., Unternaehrer, E., Pokhvisneva, I., Karnani, N., Kee, M. Z. L., Klengel, T., Adler, N. E., Barr, R. G., Letourneau, N., Giesbrecht, G. F., Reynolds, J. N., Czamara, D., Armstrong, J. M., Essex, M. J., de Weerth, C., Beijers, R., Tollenaar, M. S., Bradley, B., Jovanovic, T., Ressler, K. J., Steiner, M., Entringer, S., Wadhwa, P. D., Buss, C., Bush, N. R., Binder, E. B., Boyce, W. T., Meaney, M. J., Horvath, S., & Kobor, M. S.; “The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells;” Proceedings of the National Academy of Sciences, 2019; DOI: 10.1073/pnas.1820843116.


The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease. 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